Erectile Dysfunction Cardiovascular Risk: A Sentinel in Primary Care

Erectile dysfunction is an early marker of cardiovascular risk: across 14 cohort studies, men with it had a 44% higher hazard of cardiovascular events and a 62% higher hazard of myocardial infarction, and in men with both conditions it preceded coronary symptoms by a mean of 24 months.

A symptom reported without prompting, predicting cardiovascular death at a magnitude comparable to diabetes, usually closes the visit with a prescription instead of opening a vascular assessment.

Erectile dysfunction cardiovascular risk is among the better-quantified sentinel associations in vascular medicine and one of the least acted upon. The patient at the center of Chapter 9 of The Angry Gut, by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, had postprandial abdominal pain, atrial fibrillation, hypertension on three agents and erectile dysfunction reported to a different physician, and four endoscopies preceded any arterial imaging. The video above, Your Gut Is Suffocating, frames that presentation as one endothelial failure reported by three organs. For a screening practice the questions are who to measure, what functional testing shows, and what a finding changes.

How much does erectile dysfunction raise cardiovascular risk?

Vlachopoulos and colleagues pooled 14 cohort studies with 92,757 participants and found a hazard of 1.44 (95% CI 1.27-1.63) for total cardiovascular events in men with erectile dysfunction, and 1.62 (95% CI 1.34-1.96) for myocardial infarction. A later synthesis of 25 studies and 154,794 people estimated excess risk of 43% for cardiovascular disease, 59% for coronary disease, 34% for stroke and 33% for all-cause death, strongest in men over 55 and where the symptom was under seven years old. In the COBRA cohort of men with chronic coronary syndrome and both conditions, sexual dysfunction preceded coronary symptoms in 93%, by a mean of 24 months.

A nationally representative US sample adds durability: 4,110 men followed a median 16.3 years, with erectile dysfunction predicting cardiovascular death at 1.57, a magnitude the authors placed alongside diabetes, hypertension and stroke. Exposure was a single survey item, which should dilute rather than inflate the estimate. In a European community cohort of 1,788 men aged 40 to 79, erectile dysfunction predicted death at 1.40 (95% CI 1.13-1.74) independent of total and unbound testosterone and of estradiol, while low libido did not. The vascular symptom carried the signal; the hormonal one did not.

Why is erectile dysfunction an early sign of heart disease?

Endothelial nitric oxide synthase, deprived of cofactor and substrate, uncouples and generates superoxide, described as a major driver of endothelial dysfunction and atherogenesis. Oxidized LDL acting through LOX-1 recruits NADPH oxidase toward the same end; in 4,658 people followed 19.5 years, the top tertile of soluble LOX-1 predicted first myocardial infarction at HR 1.76 (1.40-2.21). Penile arteries are small and nitric oxide dependent, so they declare failure early.

The splanchnic bed is the less obvious reporter. Mesenteric flow rises 30-150% after a meal, and significant mesenteric stenosis appears in 6-29% of post-mortem and ultrasound series, possibly 67% of people over 80. The European guideline names the expectation of a cachectic patient as a diagnostic pitfall. Inflammatory bowel disease shows the systemic version: across 41 studies, flow-mediated dilation was reduced (effect size 0.73) and pulse wave velocity increased (0.76), with heterogeneity high enough to read as direction rather than magnitude.

Two exposures sit outside the medication list. Habitual antiseptic mouthwash suppresses the oral bacteria that reduce dietary nitrate to nitrite; in 15 treated hypertensives three days raised systolic pressure 2.3 mm Hg, and in a cohort twice-daily use carried an incidence rate ratio of 1.85 for new hypertension. A null in 17 healthy young women is real and population-specific. Degraded frying oil is the second: in 538 households, more degraded kitchen oil tracked hypertension after adjustment, while the single randomized one-meal trial enrolled 19 healthy men and so excluded the failing endothelium. Exposure concentrates where fryer oil is changed least often, among patients with the fewest food options.

Who to measure

• Men reporting erectile dysfunction without a documented cardiovascular risk assessment, particularly those over 55 or with symptoms of recent onset.
• Erectile dysfunction accompanied by hypertension, dysglycemia, atrial fibrillation or tobacco use.
• Postprandial abdominal pain, food avoidance or weight loss in a patient with vascular risk factors, in parallel with mesenteric imaging.
• Inflammatory bowel disease with cardiometabolic risk factors.
• Treated hypertension that remains difficult to control in a habitual antiseptic rinse user.

What functional testing shows, and what it does not

Measura [Cardiometabolic and Autonomic Health Analysis] provides functional vascular and metabolic measurement, not anatomic imaging. Arterial stiffness and endothelial function assesses large-artery rigidity and endothelium-dependent dilatory capacity, the systemic correlate of the nitric oxide failure described above. Pulse volume recording captures segmental limb volume waveforms, and the ankle-brachial index, with toe-brachial measurement where vessels are noncompressible, characterizes lower-extremity arterial disease that often travels with the same risk profile. Laboratory panels define glycemic, insulin and lipid status.

Measura does not image mesenteric vessels. Suspected chronic mesenteric ischemia requires vascular imaging arranged separately, and a normal limb or stiffness study does not exclude it. Nor is there a blood shortcut: 75 studies of 9,914 patients found no biomarker reaching conclusive accuracy for intestinal ischemia. Findings return to the ordering physician.

What a finding changes

An abnormal endothelial or stiffness result in a man presenting with erectile dysfunction converts a urologic encounter into a documented cardiovascular risk assessment. The PRINCETON IV consensus describes erectile dysfunction as a risk marker and enhancer and advises considering coronary calcium scoring in men at intermediate risk; in MESA, coronary calcium above 100 predicted subsequent erectile dysfunction at an odds ratio of 1.43. A measured finding supports that evaluation, informs risk-factor intensification by the treating physician and establishes a baseline for reassessment. It argues nothing against phosphodiesterase inhibitor therapy, which works; the concern is the visit that ends when the prescription is written.

Dr. Padda is direct that his own training ran the other way: route each complaint to the organ that reports it, erection to urology, meal pain to gastroenterology, pressure to cardiology. The correction is procedural rather than heroic. Make the sentinel symptom a trigger.

Workflow and documentation

A standing order keyed to an erectile dysfunction diagnosis or a phosphodiesterase inhibitor prescription makes the screen independent of who is in clinic. The annual wellness visit review of systems is a practical place to ask the question most men will not volunteer, and results belong in structured fields as described in getting results into the record. The patient-facing version is the patient article on endothelial dysfunction, the full appraisal sits on the Chapter 9 book companion page, and the dietary fat and supplement side is in fish oil, atrial fibrillation and screening.

Frequently asked questions

References

• Vlachopoulos, C. V., Terentes-Printzios, D. G., Ioakeimidis, N. K., Aznaouridis, K. A., & Stefanadis, C. I. (2013). Prediction of cardiovascular events and all-cause mortality with erectile dysfunction: A systematic review and meta-analysis of cohort studies. Circulation: Cardiovascular Quality and Outcomes, 6(1), 99-109. https://doi.org/10.1161/CIRCOUTCOMES.112.966903
• Montorsi, P., Ravagnani, P. M., Galli, S., Rotatori, F., Veglia, F., Briganti, A., Salonia, A., Dehò, F., Rigatti, P., Montorsi, F., & Fiorentini, C. (2006). Association between erectile dysfunction and coronary artery disease. Role of coronary clinical presentation and extent of coronary vessels involvement: The COBRA trial. European Heart Journal, 27(22), 2632-2639. https://doi.org/10.1093/eurheartj/ehl142
• Zhao, B., Hong, Z., Wei, Y., Yu, D., Xu, J., & Zhang, W. (2019). Erectile dysfunction predicts cardiovascular events as an independent risk factor: A systematic review and meta-analysis. The Journal of Sexual Medicine, 16(7), 1005-1017. https://doi.org/10.1016/j.jsxm.2019.04.004
• Antonio, L., Wu, F. C. W., Moors, H., Matheï, C., Huhtaniemi, I. T., Rastrelli, G., Dejaeger, M., O’Neill, T. W., Pye, S. R., Forti, G., Maggi, M., Casanueva, F. F., Slowikowska-Hilczer, J., Punab, M., Tournoy, J., & Vanderschueren, D. (2022). Erectile dysfunction predicts mortality in middle-aged and older men independent of their sex steroid status. Age and Ageing, 51(4), afac094. https://doi.org/10.1093/ageing/afac094
• Bhattacharyya, S., Miller, L. E., Rojanasarot, S., & Patel, D. P. (2025). Association of erectile dysfunction with all-cause and cardiovascular mortality in US men: Findings from NHANES 2001-2004 with 16-year follow-up. International Journal of Impotence Research. Advance online publication. https://doi.org/10.1038/s41443-025-01218-z
• Schiopu, A., Björkbacka, H., Narasimhan, G., Loong, B. J., Engström, G., Melander, O., Orho-Melander, M., & Nilsson, J. (2023). Elevated soluble LOX-1 predicts risk of first-time myocardial infarction. Annals of Medicine, 55(2), 2296552. https://doi.org/10.1080/07853890.2023.2296552
• Terlouw, L. G., Moelker, A., Abrahamsen, J., Acosta, S., Bakker, O. J., Baumgartner, I., Boyer, L., Corcos, O., van Dijk, L. J., Duran, M., Geelkerken, R. H., Illuminati, G., Jackson, R. W., Kärkkäinen, J. M., Kolkman, J. J., Lönn, L., Mazzei, M. A., Nuzzo, A., Pecoraro, F., … Bruno, M. J. (2020). European guidelines on chronic mesenteric ischaemia – joint United European Gastroenterology, European Association for Gastroenterology, Endoscopy and Nutrition, European Society of Gastrointestinal and Abdominal Radiology, Netherlands Association of Hepatogastroenterologists, Hellenic Society of Gastroenterology, Cardiovascular and Interventional Radiological Society of Europe, and Dutch Mesenteric Ischemia Study group clinical guidelines on the diagnosis and treatment of patients with chronic mesenteric ischaemia. United European Gastroenterology Journal, 8(4), 371-395. https://doi.org/10.1177/2050640620916681
• Wu, H., Xu, M., Hao, H., Hill, M. A., Xu, C., & Liu, Z. (2022). Endothelial dysfunction and arterial stiffness in patients with inflammatory bowel disease: A systematic review and meta-analysis. Journal of Clinical Medicine, 11(11), 3179. https://doi.org/10.3390/jcm11113179
• Rosen, R. C., Miner, M., Burnett, A. L., Blaha, M. J., Ganz, P., Goldstein, I., Kim, N., Kohler, T., Lue, T., McVary, K., Mulhall, J., Parish, S. J., Sadeghi-Nejad, H., Sadovsky, R., Sharlip, I., & Kloner, R. A. (2024). Proceedings of PRINCETON IV: PDE5 inhibitors and cardiac health symposium. Sexual Medicine Reviews, 12(4), 681-709. https://doi.org/10.1093/sxmrev/qeae043
• Bondonno, C. P., Liu, A. H., Croft, K. D., Considine, M. J., Puddey, I. B., Woodman, R. J., & Hodgson, J. M. (2015). Antibacterial mouthwash blunts oral nitrate reduction and increases blood pressure in treated hypertensive men and women. American Journal of Hypertension, 28(5), 572-575. https://doi.org/10.1093/ajh/hpu192

Related reading

• Fish Oil and Atrial Fibrillation: Measuring Before the Capsule
• Vitamin D Screening: Who Has an Indication and What Falls Risk Adds
• Arterial Stiffness and Endothelial Function

Fish Oil and Atrial Fibrillation: Measuring Before the Capsule

Fish oil raises atrial fibrillation risk in a dose-related way: across seven pooled cardiovascular trials, the hazard ratio was 1.12 at 1 g daily or below and 1.49 above 1 g. Omega-3 use above 1 g daily belongs in the vascular history and in the selection rule for metabolic and vascular screening.

Patients with gut symptoms and metabolic risk increasingly arrive self-dosed on omega-3 capsules. The trial record argues for measuring the terrain before endorsing the capsule.

The fish oil atrial fibrillation association is dose-related in pooled cardiovascular trials, and it is seldom weighed when a patient with abdominal symptoms or metabolic risk starts a high-dose capsule unprompted. Playing above is Your Gut Wall Is What You Fried Last Week, drawn from Chapter 8 of The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, which argues that the intestinal epithelium is rebuilt from dietary fat every few days and that structural lipids are a food question. For a screening practice the questions are narrower: what the fat exposure actually is, what the supplement adds to risk, and which measurements change management.

Does fish oil cause atrial fibrillation, and at what dose?

Gencer and colleagues pooled seven cardiovascular outcome trials covering 81,210 patients, mean age 65, with average follow-up of 4.9 years. Incident atrial fibrillation carried a hazard ratio of 1.12 (95% CI 1.03-1.22) at doses of 1 g daily or below, 1.49 above 1 g, and 1.11 for each additional gram. An independent meta-analysis of 15 trials returned RR 1.25 (95% CI 1.10 to 1.41), alongside modest reductions in major cardiovascular events (RR 0.95) and myocardial infarction (RR 0.90), with no overall excess of bleeding. The inflammatory bowel disease trials used 2 to 4 g daily, inside the higher band.

The supplement list therefore belongs in the vascular history. Rhythm assessment itself is electrocardiographic and sits outside a Measura protocol; what measurement adds is the metabolic and vascular context in which that rhythm risk is being accepted.

Does fish oil help Crohn’s disease or ulcerative colitis?

Enthusiasm traces to a 1996 trial of enteric-coated fish oil in Crohn’s disease, in which 11 of 39 treated patients relapsed against 27 of 39 controls. EPIC-1 and EPIC-2 then randomized 738 patients at 98 centers to 4 g daily as monotherapy. One-year relapse was 31.6% versus 35.7% in the first trial and 47.8% versus 48.8% in the second. Cochrane pooling of six trials gave RR 0.77; restricted to the two trials at low risk of bias, the estimate became 0.88 (95% CI 0.74 to 1.05). The ulcerative colitis review holds three trials and 138 patients, RR 1.02, an interval too wide to interpret. Omega-3 raised diarrhea (RR 1.36) and upper gastrointestinal symptoms (RR 1.65).

Design limits what those nulls can say. The trials enrolled a single disease and excluded the patient who presents with insulin resistance, hypertension, disordered sleep and a long medication list. For that patient the practice relies on mechanism and states the tier plainly: a food-based recommendation about membrane composition, not a trial-tier claim about a capsule.

Exposure misclassification in the fat literature

Much of the reassurance about dietary polyunsaturated fat, and much of the alarm, rests on circulating biomarkers that index an intact fatty acid, usually sampled once. That design cannot distinguish fresh oil from oil degraded by storage, heat and repeated use, which is how a large share of commercial fried fat reaches patients. The practice does not describe seed oils as toxic. It treats unmeasured oxidative degradation as a classification error in the exposure variable, one that biases toward the null for the degraded fraction.

Dairy fat carries the mirror-image problem. Plasma pentadecanoic acid tracked lower incident type 2 diabetes across 16 prospective cohorts (HR 0.80, 95% CI 0.73-0.87), yet it is the standard biomarker of dairy intake and cannot identify the food source. Assays add a second layer: resolvin D1 measures near 30 pg/ml by mass spectrometry and above 2,000 pg/ml by commercial ELISA, a gap attributed to cross-reactivity. Interpret any lipid-derived marker by its method before its magnitude.

Who to measure

A selection rule keyed to exposure rather than to gastrointestinal symptoms alone:

• Omega-3 supplementation above 1 g daily, particularly when self-initiated for gut or joint complaints.
• Chronic abdominal symptoms with metabolic features such as central adiposity, dysglycemia or elevated triglycerides.
• A dietary history dominated by fried or commercially prepared food.
• Hypertension or established vascular disease, where rhythm and vascular risk compound.
• Normal body weight with metabolic abnormalities, a phenotype BMI conceals.

Measura [Cardiometabolic and Autonomic Health Analysis] offers three measurements that fit this patient. Laboratory panels define glycemic and insulin status and the triglyceride and HDL pattern. Arterial stiffness and endothelial function assesses large-artery rigidity and the capacity of the endothelium to dilate. Bioimpedance body composition separates lean and fat compartments. Measura does not quantify tissue fatty acid composition, does not diagnose inflammatory bowel disease, and returns findings to the ordering physician.

What a finding changes

An abnormal vascular or metabolic result does not settle whether a given patient should take fish oil. It moves the decision from a population estimate to the individual: whether a high-dose capsule is supported by an indication a trial has actually tested, whether the dietary fat pattern warrants structured change, and whether separate rhythm evaluation is indicated. It also establishes a baseline. An epithelium that turns over in days responds to sustained dietary change, and the patient described in Chapter 8 improved over about five months with no way to credit any single change. Remeasurement documents whether the terrain moved.

Dr. Padda is candid that he once held the opposite view. As a strict vegetarian he cooked in the oils the guidelines endorsed and counseled patients accordingly, and the correction came from pathology rather than from a trial. The same discipline applies to the capsule: if the indication has not been tested, measure before endorsing it.

Workflow and documentation

A standing order keyed to omega-3 doses above 1 g on the medication list makes the screen reproducible. The medication review in an annual wellness visit is a natural trigger point, and results belong in structured fields covered by getting results into the record. The patient-facing account is the patient article on seed oils and testing, the full study appraisal is on the Chapter 8 book companion page, and the vascular follow-on, endothelial nitric oxide and the erectile sentinel, is in erectile dysfunction as a cardiovascular risk marker.

Frequently asked questions

References

• Gencer, B., Djousse, L., Al-Ramady, O. T., Cook, N. R., Manson, J. E., & Albert, C. M. (2021). Effect of long-term marine ω-3 fatty acids supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes: A systematic review and meta-analysis. Circulation, 144(25), 1981–1990. https://doi.org/10.1161/CIRCULATIONAHA.121.055654
• Yan, J., Liu, M., Yang, D., Zhang, Y., & An, F. (2024). Efficacy and safety of omega-3 fatty acids in the prevention of cardiovascular disease: A systematic review and meta-analysis. Cardiovascular Drugs and Therapy, 38(4), 799-817. https://doi.org/10.1007/s10557-022-07379-z
• Belluzzi, A., Brignola, C., Campieri, M., Pera, A., Boschi, S., & Miglioli, M. (1996). Effect of an enteric-coated fish-oil preparation on relapses in Crohn’s disease. The New England Journal of Medicine, 334(24), 1557–1560. https://doi.org/10.1056/NEJM199606133342401
• Feagan, B. G., Sandborn, W. J., Mittmann, U., Bar-Meir, S., D’Haens, G., Bradette, M., Cohen, A., Dallaire, C., Ponich, T. P., McDonald, J. W. D., Hébuterne, X., Paré, P., Klvana, P., Niv, Y., Ardizzone, S., Alexeeva, O., Rostom, A., Kiudelis, G., Spleiss, J., … Greenberg, G. R. (2008). Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC randomized controlled trials. JAMA, 299(14), 1690–1697. https://doi.org/10.1001/jama.299.14.1690
• Lev-Tzion, R., Griffiths, A. M., Leder, O., & Turner, D. (2014). Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews, 2014(2), CD006320. https://doi.org/10.1002/14651858.CD006320.pub4
• Turner, D., Steinhart, A. H., & Griffiths, A. M. (2007). Omega 3 fatty acids (fish oil) for maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews, CD006443. https://doi.org/10.1002/14651858.CD006443.pub2
• Imamura, F., Fretts, A., Marklund, M., Ardisson Korat, A. V., Yang, W.-S., Lankinen, M., Qureshi, W., Helmer, C., Chen, T.-A., Wong, K., Bassett, J. K., Murphy, R., Tintle, N., Yu, C. I., Brouwer, I. A., Chien, K.-L., Frazier-Wood, A. C., Del Gobbo, L. C., Djoussé, L., … Mozaffarian, D. (2018). Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies. PLoS Medicine, 15(10), e1002670. https://doi.org/10.1371/journal.pmed.1002670
• Schebb, N. H., Kühn, H., Kahnt, A. S., Rund, K. M., O’Donnell, V. B., Flamand, N., Peters-Golden, M., Jakobsson, P.-J., Weylandt, K. H., Rohwer, N., Murphy, R. C., Geisslinger, G., FitzGerald, G. A., Hanson, J., Dahlgren, C., Alnouri, M. W., Offermanns, S., & Steinhilber, D. (2022). Formation, signaling and occurrence of specialized pro-resolving lipid mediators — what is the evidence so far? Frontiers in Pharmacology, 13, 838782. https://doi.org/10.3389/fphar.2022.838782

Related reading

• Orthostatic Intolerance in Hypermobility: A Primary Care Screen
• Erectile Dysfunction Cardiovascular Risk: A Sentinel in Primary Care
• Laboratory Panels

Orthostatic Intolerance in Hypermobility: A Primary Care Screen

Orthostatic intolerance affects 35.9% of patients with hypermobile Ehlers-Danlos syndrome or hypermobility spectrum disorder in pooled data, so every hypermobile patient warrants a screen. Autonomic nervous system testing and cardiac autonomic reflex tests measure it, with results returned to the ordering physician.

Hypermobile patients arrive with normal GI workups and decades of symptoms. The orthostatic and autonomic burden that travels with the diagnosis is common, measurable and usually undocumented.

Orthostatic intolerance is one of the most common extra-intestinal findings in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder, and one of the least often measured in practice. These patients usually arrive through a gastroenterology or rheumatology door with a normal workup and a long history. The collagen biology is laid out in Collagen Is the Wall, Not the Paint, a chapter video for The Angry Gut (Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes). For the treating physician the useful questions are operational: which comorbidities to screen for, which red flags change the referral, and how autonomic, balance and body-composition measurement fits a primary care workflow.

What conditions travel with hypermobility beyond the gut?

A 2026 meta-analysis pooled gastrointestinal and extra-intestinal data in this population. Chronic gut symptoms carried an odds ratio of 4.29 against controls; nearly two thirds, 65.3%, had one or more chronic gut complaints, and 44.2% fulfilled diagnostic criteria for a disorder of gut-brain interaction. The leading gut findings were upper tract: reflux at 41.3%, heartburn at 34.7%, functional dysphagia at 34.2%.

The extra-intestinal tail is where screening matters. Pooled prevalence ran 49% for chronic fatigue, 35.9% for orthostatic intolerance, 38.2% for migraine and 27.9% for fibromyalgia. Postural tachycardia pooled at 21.9%, but its interval of 5.2% to 59.1% makes the point estimate nearly useless for counseling. A global survey adds self-reported dysautonomia in 71.4%, chronic pain in 98.9%, a mean of 24 comorbid conditions and a mean diagnostic delay of 22.1 years. Survey data are self-selected, but a 22-year delay describes a care model, not a rare disease.

What the motility data argue

If lax collagen simply produced a lax bowel, manometry should show it. In 239 consecutive symptomatic patients undergoing antroduodenal manometry, 50 with hypermobility and 189 without, overall dysmotility and delayed gastric emptying did not differ, and enteric dysmotility turned up in 13% of hypermobile patients versus 34% of the others (p = 0.006). It is a single-unit research letter without a healthy comparison group. It still shifts the question. When the bowel moves normally and the patient remains symptomatic, the autonomic and orthostatic burden deserves a measurement before another GI study is ordered.

My own error belongs here. I used to think of the intestinal lining as a construction site: deliver the protein and the wall goes up. The pediatric enteropathy trials, where feeding barely moved biomarkers or growth, proved that model incomplete. Raw material is necessary, and a lining under sustained attack, the first brain running on metaflammation, does not rebuild on supply alone.

Red flags that change the referral

• Vascular features. Vascular Ehlers-Danlos arises from a type III procollagen defect. In the classic cohort, bowel rupture accounted for about a quarter of complications, a quarter of patients had a first complication by age 20, and median survival was 48 years. Hypermobility with arterial or bowel events is not a primary care screening problem.
• New malabsorption with a medication change. In collagenous sprue, where drug exposure was documented, 30 of 38 cases involved a medication tied to sprue-like injury, most often an angiotensin receptor blocker, and 37 of 50 improved on repeat biopsy. Read the medication list before labeling a small-bowel finding idiopathic.
• A casual supplement plan in a sick patient. Among 1,223 ICU patients with multiorgan failure randomized in a glutamine trial, mortality at 28 days was 32.4% with glutamine and 27.2% without. That signal belongs to intensive care, but it argues against treating amino acid products as harmless in unwell patients.

How is orthostatic intolerance measured, and what does each finding change?

Measura [Cardiometabolic and Autonomic Health Analysis] has no connective-tissue assay and does not diagnose hypermobility disorders or postural tachycardia. It measures the regulatory and compositional consequences, with results returned to the ordering physician.

• Autonomic nervous system testing and cardiac autonomic reflex tests document heart rate and blood pressure responses to standardized maneuvers, including postural change. An abnormal response supports referral and orthostatic counseling; a normal one redirects the workup.
• Heart rate variability gives a repeatable index of autonomic balance for follow-up.
• Vestibular and balance testing converts symptomatic orthostasis into a documented fall-risk finding.
• Bioimpedance body composition quantifies the muscle compartment. In a review of randomized trials of collagen hydrolysate, muscle outcomes were inconsistent and mostly positive only with exercise, so a low lean mass argues for loading and adequate protein rather than a powder.

Pair the measurements with a dietary protein estimate. The bowel-rest data are the human anchor: 14 days of parenteral feeding thinned the mucosa from 645 to 512 microns, and permeability lagged behind structural recovery after refeeding. Isolation, poor dentition and low appetite remove protein quietly, and none of them appears on a panel.

Documentation and workflow

Hypermobile patients accumulate referrals without a coordinating record. A standing order can attach an orthostatic symptom screen, autonomic testing and balance testing to a documented hypermobility diagnosis or a chronic unexplained upper-GI complaint with a normal structural workup. Fall-risk and functional findings belong in the annual wellness visit, and the pairing with falls work is described in cognitive assessment and fall prevention. Where results enter the chart is covered in getting results into the record. The full evidence file sits in the companion deep dive for The Angry Gut, and the patient explanation is EDS and POTS for patients. For the gastric absorption side, see intrinsic factor antibody screening.

Frequently asked questions

References

• Kulin, D., Holtmann, G., Fairlie, T., Staller, K., Nurko, S., Keefer, L., Drossman, D. A., Jones, M. P., Talley, N. J., & Ford, A. C. (2026). Meta-analysis: Chronic gastrointestinal symptoms and comorbidities in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. Alimentary Pharmacology & Therapeutics, 64(5), 574–589. https://doi.org/10.1111/apt.70856
• Daylor, V., Griggs, M., Weintraub, A., Byrd, R., Petrucci, T., Huff, M., Byerly, K., Fenner, R., Gensemer, C., Norris, R. A., & Patel, S. (2025). Defining the chronic complexities of hEDS and HSD: A global survey of diagnostic challenges, life-long comorbidities, and unmet needs. Journal of Clinical Medicine, 14(16), 5636. https://doi.org/10.3390/jcm14165636
• Sweerts, K. W. E., Mujagic, Z., Keszthelyi, D., & Conchillo, J. M. (2025). Analysis of antroduodenal motility in patients with hypermobility spectrum disorders/hypermobile Ehlers-Danlos syndrome. Alimentary Pharmacology & Therapeutics, 61(4), 702-705. https://doi.org/10.1111/apt.18471
• Pepin, M., Schwarze, U., Superti-Furga, A., & Byers, P. H. (2000). Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. The New England Journal of Medicine, 342(10), 673–680. https://doi.org/10.1056/NEJM200003093421001
• Stirrat, T., Wilkey, M., Kim, S., Waterman, A., & Mattar, M. (2026). Collagenous sprue across five decades (1970-2025): A systematic review. Scandinavian Journal of Gastroenterology, 61(5), 577–585. https://doi.org/10.1080/00365521.2026.2641509
• Heyland, D., Muscedere, J., Wischmeyer, P. E., Cook, D., Jones, G., Albert, M., Elke, G., Berger, M. M., & Day, A. G. (2013). A randomized trial of glutamine and antioxidants in critically ill patients. The New England Journal of Medicine, 368(16), 1489–1497. https://doi.org/10.1056/NEJMoa1212722
• Brueckheimer, P. J., Costa Silva, T., Rodrigues, L., Zague, V., & Isaia Filho, C. (2025). The effects of type I collagen hydrolysate supplementation on bones, muscles, and joints: A systematic review. Orthopedic Reviews, 17, 129086. https://doi.org/10.52965/001c.129086
• Buchman, A. L., Moukarzel, A. A., Bhuta, S., Belle, M., Ament, M. E., Eckhert, C. D., Hollander, D., Gornbein, J., Kopple, J. D., & Vijayaroghavan, S. R. (1995). Parenteral nutrition is associated with intestinal morphologic and functional changes in humans. JPEN. Journal of Parenteral and Enteral Nutrition, 19(6), 453–460. https://doi.org/10.1177/0148607195019006453
• Rachmadi, R. A., Ariani, Y., & Alatas, F. S. (2024). Impact of nutritional supplementation on environmental enteric dysfunction (EED) in children living in rural areas: A systematic review. Arquivos de Gastroenterologia, 61, e23159. https://doi.org/10.1590/S0004-2803.24612023-159

Related reading

• Intrinsic Factor Antibody: Screening for Autoimmune Gastritis
• Fish Oil and Atrial Fibrillation: Measuring Before the Capsule
• Autonomic Nervous System Testing

Intrinsic Factor Antibody: Screening for Autoimmune Gastritis

An intrinsic factor antibody is highly specific for autoimmune gastritis but insensitive: 100% specificity and 38% sensitivity in a recent assay comparison, so a negative result settles little. Ordered together with anti-parietal cell antibody, the pair reached 90% sensitivity and 95.7% specificity.

Autoimmune gastritis is found when someone looks for it. The serology fails in predictable directions, and the patients at risk are easy to flag before their nerves and memory pay for the delay.

An intrinsic factor antibody is one of the few results in a B12 workup that can close a diagnosis on its own, and one of the least informative when it comes back negative. Most practices order it late, order it alone, and read a negative as reassurance. The video The Normal B12 That Wasn’t, from The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, walks through a patient who lost four years to exactly that sequence. For a primary care, endocrine, geriatric or pain practice the practical questions are narrower: who to screen for autoimmune gastritis, how to read the serology, and what a finding changes downstream in nerve, balance and cognitive function.

Intrinsic factor antibody vs. parietal cell antibody: how does each test fail?

Anti-intrinsic factor antibody carried a specificity of 100% and a sensitivity of 38% in a recent assay comparison. A United States society review puts its sensitivity under 30% in many studies and notes that it is more often positive later in the disease course. The test that proves the diagnosis turns positive after much of the damage is done. More than half of people with symptomatic B12 deficiency test negative for both antibodies.

Anti-parietal cell antibody has the opposite profile. It is present in 85% to 90% of patients with autoimmune gastritis, but about 10% of the general population carries it, it turns positive in H. pylori gastritis and autoimmune thyroid disease, and it becomes less reliable in patients aged 50 and over, which is where the disease concentrates. Combined, the pair performed at 90% sensitivity with 95.7% specificity.

Two workflow consequences follow. Order both, not one. And do not trend the parietal cell titer: in 282 patients followed for 18 years, neither its presence nor its value predicted histologic progression.

Who to screen: the profile the stereotype hides

The teaching image of an older Northern European woman misses much of the population. In a Miami biopsy series, 60 of 79 cases, 76.0%, were Hispanic, and the median age at first presentation was 51 years in Hispanic patients against 59 in White patients. Symptoms do not select either; in pooled data, gastric precursor lesions were no more common in symptomatic than in asymptomatic people. The median diagnostic delay in the autoimmune gastritis literature is 14 months. A reasonable screening trigger list, built from the same evidence:

• Autoimmune thyroid disease. About 40% of these patients have atrophic body gastritis, and 16% carry pernicious anemia.
• Type 1 diabetes. Risk of autoimmune gastritis runs roughly three to five times the general population.
• Unexplained iron deficiency. In corpus-predominant atrophy it appears in as many as half of patients and often precedes the B12 fall.
• Long-term metformin or acid suppression. In a randomized placebo-controlled trial over 4.3 years, metformin lowered serum B12 by 19%, number needed to harm 13.8. A supply of proton pump inhibitor lasting at least two years was associated with deficiency at an odds ratio of 1.65.
• Gastric bypass. Pooled randomized trials put its B12 deficiency risk at 1.86 times that of sleeve gastrectomy.

Case-finding pays off in the data. In the Italian network cohort, 15.3% of antibody-positive patients were identified by active search rather than symptoms, against 2.6% of antibody-negative patients. The social driver sits underneath the pharmacology: a food supply that manufactures insulin resistance and reflux, treated with drugs that draw the vitamin down. That background metaflammation is the terrain the first brain is failing in.

What does a positive or equivocal intrinsic factor antibody change?

I spent years repeating that gastric acid output simply declines with age. It does not; adjusted for gastritis and H. pylori, age had no independent effect. A patient with low acid and low B12 has a lesion, and the workup should treat it as one.

Confirm functional status first. Holotranscobalamin below 25 pmol/L indicates deficiency, and 25 to 70 is indeterminate. Methylmalonic acid above 280 nmol/L suggests suboptimal status in younger patients with normal renal function, and above 750 nmol/L is accepted as definite, read in light of renal impairment, dehydration and small-bowel bacterial overgrowth. Gastrin drawn on a proton pump inhibitor is raised three to five times and reports on the drug. Pepsinogen testing is not available for routine clinical use in the United States.

Then look at the lining. European guidance asks for at least two biopsies from the antrum or incisura and two from the corpus, in separately labeled vials. Only 9% of patients with pernicious anemia were offered gastroscopy at diagnosis in one recent study. The yield is not academic: in 1,598 Italian patients with autoimmune gastritis, presenting with low B12 or low iron predicted neuroendocrine tumors, hazard ratio 16.44, while progression from atrophic gastritis to adenocarcinoma runs about 0.1% to 0.3% per year. On route of replacement, the 2024 English guideline recommends lifelong intramuscular therapy where autoimmune gastritis is the cause; the largest oral trial enrolled only 10.8% intrinsic factor antibody-positive patients.

Pairing the serology with nerve, balance and cognition

Serology locates the cause. It does not tell you what the deficiency has already cost. Measura [Cardiometabolic and Autonomic Health Analysis] measures that downstream picture and returns it to the ordering physician; it does not diagnose gastritis and it does not treat.

• Sudomotor testing quantifies sudomotor output as a window on distal small-fiber integrity.
• Vestibular and balance testing quantifies postural stability in a patient whose sensory neuropathy is changing gait.
• Cognitive assessment sets a baseline before replacement, so recovery or its absence is documented.
• Laboratory panels capture the insulin resistance behind the metformin prescription.

That pairing belongs inside existing fall-risk and cognitive screening, as outlined in cognitive assessment and fall prevention. The related case for functional B12 markers in metformin-treated patients is in metformin and B12 screening beyond the serum level, and the cognitive overlap in B vitamins in mild cognitive impairment.

Documentation, standing orders and workflow

This screen only works if it runs without a physician remembering it. A standing order can attach both gastric antibodies and a functional B12 marker to the trigger list above, flag unexplained low ferritin for the same bundle, and route positives to gastroenterology with the biopsy protocol spelled out. The annual wellness visit already carries cognitive and fall-risk elements that the nerve and balance measurements document, and the same findings support MIPS quality documentation. For operational detail, see making screening reproducible with standing orders. The full evidence file is in the companion deep dive for The Angry Gut, and the patient-facing explanation is atrophic gastritis and B12 absorption.

Frequently asked questions

References

• Osmola, M., Hémont, C., Romańczyk, M., Druet, A., Chapelle, N., Matysiak-Budnik, T., Lenti, M. V., & Martin, J. C. (2025). A comparative study of different assays for autoantibodies detection in patients with autoimmune gastritis. Journal of Translational Autoimmunity, 10, 100294. https://doi.org/10.1016/j.jtauto.2025.100294
• Rustgi, S. D., Bijlani, P., & Shah, S. C. (2021). Autoimmune gastritis, with or without pernicious anemia: epidemiology, risk factors, and clinical management. Therapeutic Advances in Gastroenterology, 14, 17562848211038771. https://doi.org/10.1177/17562848211038771
• Shah, S. C., Piazuelo, M. B., Kuipers, E. J., & Li, D. (2021). AGA Clinical Practice Update on the Diagnosis and Management of Atrophic Gastritis: Expert Review. Gastroenterology, 161(4), 1325–1332.e7. https://doi.org/10.1053/j.gastro.2021.06.078
• Thain, A., Hart, K., & Ahmadi, K. R. (2025). Addressing the gaps in the vitamin B12 deficiency 2024 NICE guidelines: Highlighting the need for better recognition, diagnosis, and management of pernicious anaemia. European Journal of Clinical Nutrition, 79(7), 607-610. https://doi.org/10.1038/s41430-025-01583-4
• Poveda, J. C., Park, J. Y., Garcia-Buitrago, M. T., Singhi, A., Alruwaii, Z., Kumar, S., McDonald, O. G., & Montgomery, E. A. (2024). Autoimmune Metaplastic Atrophic Gastritis (AMAG): Regional Demographics and Their Effect on Prevalence. International Journal of Surgical Pathology, 33(3), 565–570. https://doi.org/10.1177/10668969241271311
• Harrington, D. J., Stevenson, E., & Sobczyńska-Malefora, A. (2024). The application and interpretation of laboratory biomarkers for the evaluation of vitamin B12 status. Annals of Clinical Biochemistry, 62(1), 22–33. https://doi.org/10.1177/00045632241292432
• Lenti, M. V., Miceli, E., Lahner, E., Natalello, G., Massironi, S., Schiepatti, A., Zingone, F., Sciola, V., Rossi, R. E., Cannizzaro, R., De Giorgi, E. M., Gregorio, V., Fazzino, E., Gentile, A., Petrucci, C., Dilaghi, E., Pivetta, G., Vanoli, A., Luinetti, O., … Di Sabatino, A. (2024). Distinguishing Features of Autoimmune Gastritis Depending on Previous Helicobacter pylori Infection or Positivity to Anti-Parietal Cell Antibodies: Results From the Autoimmune gastRitis Italian netwOrk Study grOup (ARIOSO). The American Journal of Gastroenterology, 119(12), 2408–2417. https://doi.org/10.14309/ajg.0000000000002948
• de Jager, J., Kooy, A., Lehert, P., Wulffelé, M. G., van der Kolk, J., Bets, D., Verburg, J., Donker, A. J. M., & Stehouwer, C. D. A. (2010). Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: Randomised placebo controlled trial. BMJ, 340, c2181. https://doi.org/10.1136/bmj.c2181
• Dinis-Ribeiro, M., Libânio, D., Uchima, H., Spaander, M. C. W., Bornschein, J., Matysiak-Budnik, T., Tziatzios, G., Santos-Antunes, J., Areia, M., Chapelle, N., Esposito, G., Fernandez-Esparrach, G., Kunovsky, L., Garrido, M., Tacheci, I., Link, A., Marcos, P., Marcos-Pinto, R., Moreira, L., … Kuipers, E. J. (2025). Management of epithelial precancerous conditions and early neoplasia of the stomach (MAPS III): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG) and European Society of Pathology (ESP) Guideline update 2025. Endoscopy, 57(5), 504–554. https://doi.org/10.1055/a-2529-5025
• National Institute for Health and Care Excellence (NICE) (2024). Vitamin B12 deficiency in over 16s: diagnosis and management (NICE guideline NG239).

Related reading

• MASLD in Primary Care: Screening When Liver Enzymes Look Normal
• Orthostatic Intolerance in Hypermobility: A Primary Care Screen
• Sudomotor Testing

MASLD in Primary Care: Screening When Liver Enzymes Look Normal

MASLD is under-read in primary care: ultrasound detects liver fat only once more than 30% of liver cells are involved, and the routine panel can read normal. GGT, read as a trend inside the reference interval, belongs in the metabolic workup of every patient who meets the definition.

The definition now requires liver fat plus a cardiometabolic risk factor. That places the condition squarely in the metabolic visit, where the routine panel and the ultrasound both under-read it.

MASLD, metabolic dysfunction-associated steatotic liver disease, is now defined by hepatic steatosis plus at least one of five cardiometabolic risk factors, a nomenclature adopted through a Delphi process with 236 panelists from 56 countries. The definition moves the condition into the metabolic visit. The video above, The Alcohol You Never Drank, covers Chapter 5 of The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, which treats the liver as downstream of the first brain: the gut delivers, the liver filters, and the routine workup reads the filter rather than the stream.

Dr. Padda describes closing visits for years with an instruction to lose weight and counting it as management. The evidence below is why that sentence is not a plan for a patient who has already lost and regained the weight more than once.

Why do normal liver enzymes and a clean ultrasound miss MASLD?

There are three structural blind spots. Ultrasound detects steatosis only once more than 30% of hepatocytes are involved, and British guidance states that a raised GGT with metabolic risk factors may indicate fatty liver despite a normal scan. ALT, the enzyme most clinicians follow, came out null for cardiovascular mortality at 0.87 in a dose-response synthesis of 23 studies and 1,067,922 participants, where GGT predicted it at 1.62. And peripheral blood is sampled after first-pass hepatic clearance: in elective abdominal surgery, portal blood was endotoxin-positive in 97% of patients and systemic blood in 4 of 34.

The same guideline is explicit about the trade-off of adding GGT to a first-line panel: abnormal results rise from roughly 15% to roughly 30%. They retained it anyway, because the trial cited against GGT had excluded patients with fatty liver or alcohol-related disease, the groups behind 90% of liver deaths. Specificity was traded for sensitivity in exactly the population a metabolic practice sees.

What does a GGT inside the normal range mean?

GGT behaves as a redox gauge: the ectoenzyme degrades extracellular glutathione to supply cysteine for antioxidant synthesis, and stressed cells upregulate it. Its prognostic signal starts inside the reference interval. In 9,687,066 Korean adults followed a median 8.3 years, the top tertile carried hazard ratios of 1.33 for all-cause and 1.29 for cardiovascular mortality after adjustment for alcohol, BMI and other liver enzymes, and the high tertile for women began at 21 IU/L. In 3,500 non-diabetic British men aged 60 to 79, the top quartile predicted incident diabetes at 3.68 after BMI adjustment and 2.69 after adding insulin resistance. Restricted to never-drinkers in seven pooled Japanese cohorts, the hazard per standard deviation of GGT was 1.81 for coronary death in women and 1.43 for cardiovascular death in men.

The limits are part of the interpretation. GGT is nonspecific, with obesity its commonest cause. It added little to established cardiovascular prediction in pooled British surveys. Mendelian randomization found no causal effect on diabetes (odds ratio 0.88) or coronary disease (1.08). The clinical use follows from those limits: GGT is a trajectory marker of oxidative load in a patient with steatosis, not a target to lower for its own sake and not a substitute for a risk score.

Gut delivery, insulin and the patient trials exclude

The mechanistic case centers on portal delivery. In bariatric surgery patients, portal ethanol was a median 187-fold higher than fasting systemic blood and rose from no steatosis through steatosis to steatohepatitis; blocking alcohol dehydrogenase raised systemic ethanol 15-fold after a meal in fatty liver. Pediatric and murine work places part of the effect in clearance, with reduced hepatic alcohol dehydrogenase activity linked to insulin resistance. Pooled blood endotoxin was higher in simple steatosis (standardized difference 0.86) and steatohepatitis (0.81) independent of BMI. No clinical study has yet tested the causal chain, and in adolescents endotoxin markers tracked total body fat (r = 0.64) rather than histology.

Two biological drivers, gut-derived endotoxin and ethanol on one side and insulin-resistant hepatic handling on the other, converge on the same organ. The third driver is economic: subsidized sweetener in most packaged food supplies the substrate for fermentation. The less obvious point for screening is that the liver responds to what is delivered, not only to how much is eaten. Inulin raised hepatic fat from 20.9% to 26.8% over six weeks in a small trial, while four months of resistant starch lowered intrahepatic triglyceride 9.08%, or 5.89% after adjustment for weight loss. In the largest synbiotic trial, weight loss alone moved liver fat. Both findings can hold at once, and body weight captures neither.

Who should be tested for MASLD?

• Adults meeting the MASLD definition, or with an incidental echogenic liver on imaging done for another reason.
• Patients whose GGT rises across serial panels while staying inside the reference interval.
• Normal-BMI patients with features of insulin resistance, including South Asian patients who are thin outside and fat inside.
• Patients repeatedly counseled to lose weight with no measurement of what changed.

Written selection criteria make that list reproducible across clinicians.

What the measurements add, and what a finding changes

Measura [Cardiometabolic and Autonomic Health Analysis] does not image the liver; confirming steatosis stays with radiology. What it measures is the terrain that decides risk:

• Laboratory panels that read GGT serially beside glucose, insulin and lipids, turning a single in-range value into a trajectory.
• Bioimpedance body composition, which separates fat and muscle compartments and exposes the normal-BMI phenotype that weight-based counseling misses.
• Arterial stiffness and endothelial function, because the mortality signal attached to GGT is largely cardiovascular.

A finding changes management when it relocates the patient. Steatosis with a rising GGT and abnormal vascular measures belongs in active cardiovascular prevention rather than a weight handout. Adverse body composition at normal BMI reframes counseling around insulin and dietary delivery, with lifestyle work prescribed as treatment and its physiological rationale documented. Measurement repeated on a schedule shows whether the terrain moved, which no single panel can.

Workflow and documentation

Build eligibility into standing orders so testing does not depend on who remembers. Findings recorded at the annual wellness visit, beside the cognitive and fall screening already structured there (see cognitive assessment and fall prevention), support the measures discussed in HEDIS and value-based care. The patient version, written for someone holding an echogenic ultrasound report, is what an echogenic liver means. The barrier upstream of the portal vein is covered in metabolic endotoxemia screening, and every cohort cited here is set out with its limits in the Chapter 5 companion. The same unrecognized liver disease can surface as confusion in older patients, which is why screening for cirrhosis in dementia belongs in the cognitive workup.

Frequently asked questions

References

• Rinella, M. E., Lazarus, J. V., Ratziu, V., Francque, S. M., Sanyal, A. J., Kanwal, F., Romero, D., Abdelmalek, M. F., Anstee, Q. M., Arab, J. P., Arrese, M., Bataller, R., Beuers, U., Boursier, J., Bugianesi, E., Byrne, C. D., Castro Narro, G. E., Chowdhury, A., Cortez-Pinto, H., … Newsome, P. N. (2023). A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology, 78(6), 1966-1986. https://doi.org/10.1097/HEP.0000000000000520
• Newsome, P. N., Cramb, R., Davison, S. M., Dillon, J. F., Foulerton, M., Godfrey, E. M., Hall, R., Harrower, U., Hudson, M., Langford, A., Mackie, A., Mitchell-Thain, R., Sennett, K., Sheron, N. C., Verne, J., Walmsley, M., & Yeoman, A. (2018). Guidelines on the management of abnormal liver blood tests. Gut, 67(1), 6-19. https://doi.org/10.1136/gutjnl-2017-314924
• Rahmani, J., Miri, A., Namjoo, I., Zamaninour, N., Maljaei, M. B., Zhou, J. B., Shokouhi Nasab Kermani, R., Kord Varkaneh, H., Fatahi, S., & Zhang, Y. (2019). Elevated liver enzymes and cardiovascular mortality: a systematic review and dose-response meta-analysis of more than one million participants. European Journal of Gastroenterology & Hepatology, 31(5), 555–562. https://doi.org/10.1097/MEG.0000000000001353
• Jacob, A. I., Goldberg, P. K., Bloom, N., Degenshein, G. A., & Kozinn, P. J. (1977). Endotoxin and bacteria in portal blood. Gastroenterology, 72(6), 1268–1270. https://pubmed.ncbi.nlm.nih.gov/858472/
• Cho, E. J., Jeong, S.-M., Chung, G. E., Yoo, J.-J., Cho, Y., Lee, K.-N., Shin, D. W., Kim, Y. J., Yoon, J.-H., Han, K., & Yu, S. J. (2023). Gamma-glutamyl transferase and risk of all-cause and disease-specific mortality: a nationwide cohort study. Scientific Reports, 13(1), 1751. https://doi.org/10.1038/s41598-022-25970-0
• Wannamethee, S. G., Shaper, A. G., Lennon, L., & Whincup, P. H. (2005). Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care, 28(12), 2913-2918. https://doi.org/10.2337/diacare.28.12.2913
• Li, Y., Iso, H., Cui, R., Murakami, Y., Yatsuya, H., Miura, K., Nagasawa, S.-Y., Ueshima, H., & Okamura, T. (2016). Serum gamma-glutamyltransferase and mortality due to cardiovascular disease in Japanese men and women. Journal of Atherosclerosis and Thrombosis, 23(7), 792-799. https://doi.org/10.5551/jat.32698
• Liu, J., Au Yeung, S. L., Lin, S. L., Leung, G. M., & Schooling, C. M. (2016). Liver enzymes and risk of ischemic heart disease and type 2 diabetes mellitus: A Mendelian randomization study. Scientific Reports, 6, 38813. https://doi.org/10.1038/srep38813
• Meijnikman, A. S., Davids, M., Herrema, H., Aydin, O., Tremaroli, V., Rios-Morales, M., Levels, H., Bruin, S., de Brauw, M., Verheij, J., Kemper, M., Holleboom, A. G., Tushuizen, M. E., Schwartz, T. W., Nielsen, J., Brandjes, D., Dallinga-Thie, G. M., Havik, S. R., Ackermans, M. T., … Nieuwdorp, M. (2022). Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nature Medicine, 28(10), 2100–2106. https://doi.org/10.1038/s41591-022-02016-6
• Ni, Y., Qian, L., Siliceo, S. L., Long, X., Nychas, E., Liu, Y., Ismaiah, M. J., Leung, H., Zhang, L., Gao, Q., Wu, Q., Zhang, Y., Jia, X., Liu, S., Yuan, R., Zhou, L., Wang, X., Li, Q., Zhao, Y., … Jia, W. (2023). Resistant starch decreases intrahepatic triglycerides in patients with NAFLD via gut microbiome alterations. Cell Metabolism, 35(9), 1530-1547.e8. https://doi.org/10.1016/j.cmet.2023.08.002

Related reading

• Metabolic Endotoxemia: What to Measure When Zonulin Cannot
• Intrinsic Factor Antibody: Screening for Autoimmune Gastritis
• Laboratory Panels

Metabolic Endotoxemia: What to Measure When Zonulin Cannot

Metabolic endotoxemia is bacterial endotoxin leaking from the gut into the blood at levels that disturb metabolism. Screening it in primary care means measuring the response rather than the exposure: insulin resistance, adipose-driven inflammation and vascular risk.

Barrier failure is measurable and, in one cohort, preceded disease by years. The serum marker patients bring in does not measure it, and the downstream metabolic injury is where screening earns its place.

Metabolic endotoxemia, the passage of bacterial endotoxin from the gut into the circulation at levels that disturb metabolism, is usually filed as a gastroenterology question. Its measurable consequences land in primary care: insulin resistance, adipose inflammation and vascular risk. The accompanying chapter video covers Chapter 4 of The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes. For a screening program the book’s case reduces to three propositions: barrier failure is real and measurable, the serum marker patients arrive with does not measure it, and the downstream metabolic injury is where measurement changes management.

The barrier in question is the outer surface of what the book calls the first brain, with the skull holding the second brain, and metaflammation begins where that barrier fails. Dr. Padda was trained to dismiss a zonulin printout and abandoned the reflex; neither the dismissal nor the printout survives the evidence.

The zonulin assay has failed validation twice

Zonulin was characterized as pre-haptoglobin-2. Scheffler and colleagues measured serum zonulin with the most widely used commercial ELISA in 376 people genotyped for haptoglobin. Readings did not follow genotype, the kit returned signal in individuals who cannot synthesize the target, and it did not detect the purified protein; the leading candidate for what it binds is properdin. Ajamian and colleagues tested two further commercial kits and identified the bound material by mass spectrometry as haptoglobin and a complement protein.

Power and colleagues then ran the comparison that matters clinically, serum zonulin against the lactulose-to-mannitol test in first-degree relatives of patients with Crohn’s disease: r2 = 0.004, p < 0.71. In a head-to-head evaluation of six candidate markers in 78 people, only plasma LBP tracked the sugar test in every cohort; plasma zonulin and plasma I-FABP did not.

The originators now describe zonulin as a family of proteins that includes properdin, a position built on a cultured cell monolayer. Whatever the kits detect does rise with obesity, diabetes, and glucose and lipid markers. That makes the result a vague metabolic signal rather than a barrier measurement, and it should not anchor a diagnosis or an elimination diet in the chart.

How is intestinal permeability measured?

Permeability is measured functionally, with oral sugar probes and timed urine collection. Validation in 60 healthy adults on controlled diets established reference recoveries and three practical constraints. Unlabeled mannitol was present in baseline urine in every participant, so the labeled isotope is required. Between-person variation was large, with a median coefficient of variation of 76.5%. And the conventional lactulose-to-mannitol ratio is a weak statistic: in inflammatory bowel disease, labeled mannitol (P = .003) and lactulose (P = .006) each separated patients from volunteers while the ratio did not (P = .237).

None of this is offered by Measura [Cardiometabolic and Autonomic Health Analysis]; it is a referral-level investigation ordered when a gastrointestinal question warrants it.

Done properly, barrier measurement has prognostic weight in at least one cohort. In 1,420 healthy first-degree relatives of patients with Crohn’s disease followed a median 7.8 years, abnormal baseline permeability predicted Crohn’s disease at a hazard ratio of 3.03 (95% CI, 1.64-5.63), and at 1.62 when restricted to tests done more than three years before diagnosis. The counterpoint belongs beside it: relatives from multiplex families carried a 3.65-fold risk without more permeable barriers, and a graded review of eight studies in obesity and metabolic syndrome found very low to low certainty and no clear relationship. The practice position is that the barrier is one road into metabolic disease, and the evidence tier for the metabolic link is mechanism.

How does endotoxin cause insulin resistance?

The human endotoxin challenge is the cleanest mechanistic evidence. In twenty healthy volunteers given 3 ng/kg intravenously, peripheral insulin sensitivity fell 35% at 24 hours while the acute insulin response was unchanged (711 to 744, P = 0.7), and HOMA-IR rose from 1.56 to 2.17. It was a pharmacological bolus that produced fever, not chronic low-grade exposure, and the investigators say so.

The dietary version is subtler and closer to clinic. After a 910-calorie high-fat, high-carbohydrate meal, plasma endotoxin rose 47%, mononuclear-cell TLR4 and SOCS-3 expression rose, and NF-kappaB binding increased 72%, yet plasma CRP and TNF-alpha did not change. A routine inflammatory marker can stay normal while the signaling that produces insulin resistance is active.

Across ten years in 7,169 adults, the top quartile of endotoxin activity carried 52% higher risk of incident diabetes than the bottom; per unit the hazard ratio was 1.004, and activity rose linearly with the number of metabolic syndrome components. In women in The Gambia measured by mass spectrometry, endotoxin was 57% higher with obesity plus diabetes and no different between women with and without obesity, while adipose macrophage markers rose in a clean gradient across the three groups.

The screening insight is that exposure and response diverge. Eighteen healthy men overfed by 760 kcal a day for eight weeks raised postprandial endotoxemia 160%, yet only half of the postprandial arm mounted an inflammatory response. Everyone was exposed; the terrain decided who was injured. Screening the exposure tells you little. Screening the response, insulin resistance and adipose-driven inflammation, tells you who needs management.

Vascular and cognitive signals worth pairing

Endotoxin’s best-documented destination is the arterial wall. In a Finnish cohort of 2,452 adults followed ten years, high endotoxin activity predicted coronary events at a hazard ratio of 1.88; in the Bruneck population, endotoxin above the 90th percentile carried an odds ratio of 2.9 for developing carotid atherosclerosis, concentrated in smokers. Arterial stiffness and endothelial function measure the vessel the mechanism points at, whichever explanation wins.

The second brain is exposed too. In 51 women given high-saturated-fat and high-oleic meals in crossover, higher baseline LBP predicted less consistent post-meal attention (P = 0.04); endotoxin itself was not measured and two-thirds were breast cancer survivors. That is a thin but specific reason to record a cognitive assessment baseline in the same patients, alongside the work described in cognitive assessment and fall prevention.

Who should be tested for metabolic endotoxemia, and what does a finding change?

• Patients presenting with a commercial zonulin result or a self-directed elimination diet. The result is not actionable; the metabolic question behind it is.
• Long-term daily NSAID users, heavy drinkers and patients with periodontal disease. Each carries a measured barrier or endotoxin exposure, and the indication belongs in the problem list.
• Normal-weight patients with features of insulin resistance. The Gambian gradient followed diabetes, not body size, which is where bioimpedance body composition earns its place over BMI.

Food environments built around high-fat, high-sugar meals, over-the-counter anti-inflammatories, and short visits that reward refills over workups all load the same barrier. A finding changes management when it moves a patient from reassurance to a metabolic plan: laboratory panels quantifying insulin resistance, body composition defining the fat and muscle compartments, and lifestyle work prescribed as treatment with its physiological reason documented. Findings that raise a true gastrointestinal question go to gastroenterology for validated permeability testing. Written selection criteria keep that consistent across clinicians.

Standing orders and documentation

Criteria like these belong in standing orders so they run the same way for every eligible patient rather than by memory. Insulin resistance, body composition and vascular findings documented at the annual wellness visit support the measures described in MIPS and quality reporting, and structured results reach the chart through getting results into the record. The patient-facing version, written for someone holding a zonulin printout, is how to test for leaky gut. The liver, first to receive what crosses the barrier, is the subject of MASLD in primary care, and every study cited here is set out with its limits in the Chapter 4 companion.

Frequently asked questions

References

• Scheffler, L., Crane, A., Heyne, H., Tonjes, A., Schleinitz, D., Ihling, C. H., Stumvoll, M., Freire, R., Fiorentino, M., Fasano, A., Kovacs, P., & Heiker, J. T. (2018). Widely used commercial ELISA does not detect precursor of haptoglobin2, but recognizes properdin as a potential second member of the zonulin family. Frontiers in Endocrinology, 9, 22. https://doi.org/10.3389/fendo.2018.00022
• Power, N., Turpin, W., Espin-Garcia, O., Smith, M. I., CCC GEM Project Research Consortium, & Croitoru, K. (2021). Serum zonulin measured by commercial kit fails to correlate with physiologic measures of altered gut permeability in first degree relatives of Crohn’s disease patients. Frontiers in Physiology, 12, 645303. https://doi.org/10.3389/fphys.2021.645303
• Seethaler, B., Basrai, M., Neyrinck, A. M., Nazare, J. A., Walter, J., Delzenne, N. M., & Bischoff, S. C. (2021). Biomarkers for assessment of intestinal permeability in clinical practice. American Journal of Physiology. Gastrointestinal and Liver Physiology, 321(1), G11–G17. https://doi.org/10.1152/ajpgi.00113.2021
• Khoshbin, K., Khanna, L., Maselli, D., Atieh, J., Breen-Lyles, M., Arndt, K., Rhoten, D., Dyer, R. B., Singh, R. J., Nayar, S., Bjerkness, S., Harmsen, W. S., Busciglio, I., & Camilleri, M. (2021). Development and validation of test for “leaky gut” small intestinal and colonic permeability using sugars in healthy adults. Gastroenterology, 161(2), 463–475.e13. https://doi.org/10.1053/j.gastro.2021.04.020
• Turpin, W., Lee, S.-H., Raygoza Garay, J. A., Madsen, K. L., Meddings, J. B., Bedrani, L., Power, N., Espin-Garcia, O., Xu, W., Smith, M. I., Griffiths, A. M., Moayyedi, P., Turner, D., Seidman, E. G., Steinhart, A. H., Marshall, J. K., Jacobson, K., Mack, D., Huynh, H., … Croitoru, K. (2020). Increased intestinal permeability is associated with later development of Crohn’s disease. Gastroenterology, 159(6), 2092–2100.e5. https://doi.org/10.1053/j.gastro.2020.08.005
• Bona, M. D., Torres, C. H. de M., Lima, S. C. V. C., Morais, A. H. de A., Lima, A. Â. M., & Maciel, B. L. L. (2022). Intestinal barrier permeability in obese individuals with or without metabolic syndrome: a systematic review. Nutrients, 14(17), 3649. https://doi.org/10.3390/nu14173649
• Mehta, N. N., McGillicuddy, F. C., Anderson, P. D., Hinkle, C. C., Shah, R., Pruscino, L., Tabita-Martinez, J., Sellers, K. F., Rickels, M. R., & Reilly, M. P. (2010). Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes, 59(1), 172–181. https://doi.org/10.2337/db09-0367
• Ghanim, H., Abuaysheh, S., Sia, C. L., Korzeniewski, K., Chaudhuri, A., Fernandez-Real, J. M., & Dandona, P. (2009). Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: Implications for insulin resistance. Diabetes Care, 32(12), 2281–2287. https://doi.org/10.2337/dc09-0979
• Laugerette, F., Alligier, M., Bastard, J.-P., Drai, J., Chanséaume, E., Lambert-Porcheron, S., Laville, M., Morio, B., Vidal, H., & Michalski, M.-C. (2014). Overfeeding increases postprandial endotoxemia in men: Inflammatory outcome may depend on LPS transporters LBP and sCD14. Molecular Nutrition & Food Research, 58(7), 1513–1518. https://doi.org/10.1002/mnfr.201400044
• Madison, A. A., Belury, M. A., Andridge, R., Shrout, M. R., Renna, M. E., Malarkey, W. B., Bailey, M. T., & Kiecolt-Glaser, J. K. (2020). Afternoon distraction: A high-saturated-fat meal and endotoxemia impact postmeal attention in a randomized crossover trial. The American Journal of Clinical Nutrition, 111(6), 1150–1158. https://doi.org/10.1093/ajcn/nqaa085

Related reading

• The LF/HF Ratio Is Not Vagal Tone: Autonomic Testing in Gut Patients
• MASLD in Primary Care: Screening When Liver Enzymes Look Normal
• Laboratory Panels

The LF/HF Ratio Is Not Vagal Tone: Autonomic Testing in Gut Patients

The LF/HF ratio is not a measure of vagal tone: it climbs as autonomic input to the heart is removed. RMSSD and high-frequency power are the heart rate variability indices that carry vagal information, measured serially against the patient’s own baseline under matched conditions.

Heart rate variability is a cardiac proxy with a consistent signal in functional and inflammatory gut disease. Its value depends on reporting the right index, under matched conditions, against the same patient.

The LF/HF ratio is still printed on consumer devices and in some reports as sympathovagal balance. In a physiology review of that ratio, it rose from 1.1 to 8.4 when most autonomic input to the heart was removed. An index that climbs as the nerve is taken away cannot be read as vagal tone, and it should not anchor a clinical decision in a patient with functional gut symptoms.

Chapter 3 of The Angry Gut, by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, shown on camera as Two Doctors, One Nerve, argues that bowel symptoms and anxiety in the same patient are one autonomic and inflammatory problem split across two specialties. Measura [Cardiometabolic and Autonomic Health Analysis] measures the cardiac side of that problem and reports to the ordering physician. The questions for a practice are which indices carry vagal information, how large the gut signal really is, and what a finding should change.

Does the LF/HF ratio measure vagal tone?

The Task Force standards set high frequency at 0.15 to 0.40 Hz and made five minutes the short-term recording standard. Two constraints follow. High-frequency power indexes vagal tone only while respiration stays inside that band, roughly nine to twenty-four breaths per minute, which is why RMSSD, less affected by breathing, is the preferred vagal index for most purposes. Recording lengths are also not interchangeable; 24-hour, five-minute and ultra-short values are distinct measurements.

The ratio’s problems are anatomical. Parasympathetic blockade removes at least half of low-frequency power, the sympathetic share of that band is at best a quarter, sympathetic activation may shift high-frequency power by up to ten percent, and prevailing heart rate biases the ratio with no change in nerve activity. Denervated transplanted hearts still show two to eight percent of normal respiratory variation. Report RMSSD and high-frequency power, and leave LF/HF uninterpreted.

Between-subject comparison is the weak use of these indices. Respiratory sinus arrhythmia often correlates strongly with vagal control inside one person and only modestly across people, so the defensible clinical use is serial measurement against the patient’s own baseline under matched conditions. A Measura heart rate variability recording can be repeated for that purpose, and cardiac autonomic reflex tests add standardized provocations to the resting picture.

Is heart rate variability lower in gut disorders?

Pooled across inflammatory bowel disease, RMSSD sat at a standardized difference of -0.71 against controls; removing one influential study shrank the ulcerative colitis estimate to -0.41. In irritable bowel syndrome, a high-frequency deficit appeared in short recordings (-0.35) and was essentially absent in long ones (-0.06). Only 2 of 28 studies in that review confirmed a blinded reader, and its authors judged heart rate variability not yet suitable for monitoring symptoms in either condition.

Within single cohorts the signal is clearer. Among 253 participants with 24-hour recordings, the vagal index ran 39.99 ms in controls and 16.87 ms in functional dyspepsia, and the normal postprandial organization of gastric slow waves was blunted alongside it. In adjusted models, sleep quality outperformed anxiety and depression scores as a predictor of vagal tone, with a coefficient of -1.726 and an adjusted R-squared of 0.583. In Crohn’s disease, vagal tone correlated inversely with circulating TNF (r = -0.48); in irritable bowel syndrome, with plasma epinephrine (r = -0.39); in no group did it follow affect scores.

Stated at its tier, this is a soft instrument with a consistent direction, sensitive to study design, and a proxy for cardiac rather than abdominal vagal tone. It does not measure vagal traffic from the gut. The practice’s position is that it is worth measuring anyway, because the direction holds across cohorts and pooled reviews, and because trial exclusions remove the patients who carry the most risk.

Which gut patients should have autonomic testing?

Reasonable candidates include adults with functional dyspepsia or irritable bowel syndrome whose anxiety is managed on a separate track, patients with inflammatory bowel disease and persistent symptoms, and the cardiometabolic patient the pooled gut analysis excluded: cardiovascular disease, diabetes, kidney failure, alcoholism, or treatment with a beta-blocker or calcium channel blocker. Those groups can be written into selection criteria, with the medication list recorded as a confounder.

A low, reproducible vagal index changes management in three ways. It supports handling the bowel and the anxiety as one case, with gastroenterology and behavioral plans coordinated instead of run in parallel. It moves sleep assessment up the list, since sleep was the strongest predictor in the dyspepsia cohort. And it prompts a look at the metaflammation terrain feeding the ascending signal, through laboratory panels and the broader autonomic nervous system testing battery. A normal value does not exclude a gut-driven problem, and a low one is not a diagnosis.

Can a change in heart rate variability prove an anti-inflammatory vagal effect?

Dr. Padda learned the vagus-to-spleen inflammatory reflex as settled physiology and taught it that way. The route has not held. In rats, vagotomy left endotoxin-induced plasma TNF unchanged while section of the greater splanchnic nerve raised it about fivefold, and anatomical tracing in mice found no significant vagal motor supply to the spleen. Across 15 stimulation studies, pooled effects on TNF, interleukin-6 and interleukin-1 beta were not significant, and a higher risk of bias predicted a larger reported effect.

Two reporting consequences follow. A change in heart rate variability after an intervention is not evidence of an anti-inflammatory vagal effect. And interventions named for vagal tone may leave it untouched: across 13 randomized trials and 965 participants with cardiovascular disease, heart rate variability biofeedback reduced diastolic pressure by 3.23 mmHg without shifting high-frequency power. Stimulation devices and biofeedback programs are treatments, not measurements, and are not part of the Measura protocol.

How should heart rate variability be recorded for serial testing?

Reproducibility is the entire value of a serial autonomic measure, so the protocol has to fix what the physiology responds to: the same device and analysis method, the same time of day and posture, spontaneous breathing with no breathing exercise beforehand, a documented recording length, and a current medication list flagging agents that alter heart rate. Paced breathing inflates almost every index, and two spectral methods applied to one recording return different values. Standing orders make those conditions the default, staffing and workflow covers who runs the recording, and results enter the record as dated, comparable values. For patients followed over time, between-visit monitoring keeps the trend in view. The anatomy behind the proxy is covered in the opening physician post in this series.

The complete evidence file, including the pooled results that shrink the effect, is in the Deep Dive companion. The preceding installment covers the medication load feeding the first brain’s signal to the second brain, in deprescribing starts with a baseline.

Frequently asked questions

References

• Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. (1996). Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation, 93(5), 1043-65. https://pubmed.ncbi.nlm.nih.gov/8598068/
• Laborde, S., Mosley, E., & Thayer, J. F. (2017). Heart rate variability and cardiac vagal tone in psychophysiological research – recommendations for experiment planning, data analysis, and data reporting. Frontiers in Psychology, 8, 213. https://doi.org/10.3389/fpsyg.2017.00213
• Billman, G. E. (2013). The LF/HF ratio does not accurately measure cardiac sympatho-vagal balance. Frontiers in Physiology, 4, 26. https://doi.org/10.3389/fphys.2013.00026
• Grossman, P., & Taylor, E. W. (2007). Toward understanding respiratory sinus arrhythmia: relations to cardiac vagal tone, evolution and biobehavioral functions. Biological Psychology, 74(2), 263-85. https://doi.org/10.1016/j.biopsycho.2005.11.014
• Kim, K.-N., Yao, Y., & Ju, S.-Y. (2020). Heart rate variability and inflammatory bowel disease in humans: a systematic review and meta-analysis. Medicine, 99(48), e23430. https://doi.org/10.1097/MD.0000000000023430
• Sadowski, A., Dunlap, C., Lacombe, A., & Hanes, D. (2021). Alterations in heart rate variability associated with irritable bowel syndrome or inflammatory bowel disease: a systematic review and meta-analysis. Clinical and Translational Gastroenterology, 12(1), e00275. https://doi.org/10.14309/ctg.0000000000000275
• Du, L., Yang, J., Jiang, L., Zeng, G., Shu, Y., & Bi, B. (2026). Postprandial attenuation of gastric slow waves in anxiety-depression, with and without functional dyspepsia: associations with heart rate variability and sleep quality. Frontiers in Medicine, 13, 1890716. https://doi.org/10.3389/fmed.2026.1890716
• Pellissier, S., Dantzer, C., Mondillon, L., Trocme, C., Gauchez, A.-S., Ducros, V., Mathieu, N., Toussaint, B., Fournier, A., Canini, F., & Bonaz, B. (2014). Relationship between vagal tone, cortisol, TNF-alpha, epinephrine and negative affects in Crohn’s disease and irritable bowel syndrome. PLoS One, 9(9), e105328. https://doi.org/10.1371/journal.pone.0105328
• de Melo, P. S., Gianlorenco, A. C., Marduy, A., Kim, C. K., Choi, H., Song, J.-J., & Fregni, F. (2024). A mechanistic analysis of the neural modulation of the inflammatory system through vagus nerve stimulation: A systematic review and meta-analysis. Neuromodulation: Journal of the International Neuromodulation Society, 28(1), 43-53. https://doi.org/10.1016/j.neurom.2024.03.002
• Kaneko, K., Aikawa, G., Sakuramoto, H., Ota, Y., Oyama, Y., Tomooka, M., Naya, K., Fukunaga, T., Sugishima, K., & Yamada, T. (2026). Effects of heart rate variability biofeedback on cardiac autonomic function in patients with cardiovascular disease: a systematic review and meta-analysis. Applied Psychophysiology and Biofeedback. Advance online publication. https://doi.org/10.1007/s10484-025-09765-3

Related reading

• Deprescribing Starts With a Baseline, Not a Drug List
• Metabolic Endotoxemia: What to Measure When Zonulin Cannot
• Heart Rate Variability

Deprescribing Starts With a Baseline, Not a Drug List

Deprescribing should start from a current baseline measurement, not the drug list alone, because the list holds no record of whether the physiology each drug was started for has moved. Measura supplies those measurements; the ordering physician owns every deprescribing decision.

A medication review checks what a patient takes. It rarely checks whether the reasons each drug was started are still true, and that second question needs a measurement.

Deprescribing is usually organized around the drug list: interactions, duplications, criteria for older adults. The list is the wrong unit of analysis for two reasons. It omits the formulation chemistry that makes up most of each tablet’s mass, and it holds no record of whether the physiology each drug was started for has moved. A multi-drug patient reviewed without a current measurement is being deprescribed on memory.

Chapter 2 of The Angry Gut, by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, shown on camera as Two-Thirds of Your Pill Is Not the Drug, builds its argument around a single sixty-eight-year-old on nine prescriptions. Measura [Cardiometabolic and Autonomic Health Analysis] does not audit medications or advise on them. It supplies measurements to the ordering physician, who owns every decision. The sections below cover where those measurements fit a deprescribing workflow and where they do not.

Who should be considered for deprescribing?

The population is large. In one analysis of US prescribing, 39.0% of adults over 65 took at least five prescription medications daily, and a patient on 10 prescriptions ingests an average of 2.8 g of inactive ingredients per day. The index case will be familiar to primary care, pain and geriatric clinicians: a statin, an antihypertensive, metformin, a proton pump inhibitor renewed for eleven years, a daily NSAID, low-dose aspirin, an antidepressant, a laxative and a multivitamin, with bloating, alternating bowel habit and fatigue attributed to age.

Three features should flag the chart. A daily agent whose indication has not been revisited in years. A gastrointestinal symptom managed with another prescription. A symptom attributed to age with no measurement behind the attribution. In the index bag, the laxative was treating what the other eight bottles produced. Those features can be written into selection criteria instead of being left to recall.

What is in a pill besides the drug?

By mass, the most prescribed US oral medications are about 75% inactive ingredient, and 92.8% of oral solids contain at least one potential allergen. Only 28% of active ingredients have a formulation that avoids all of them. The substitution space is still wide: the 18 most prescribed oral drugs average 82.5 alternative formulations per active ingredient, and levothyroxine exists in 140 formulations made by 43 manufacturers. For many patients the actionable move is reformulation rather than discontinuation.

The exposure that matters for the gut is luminal, not systemic. Excipients that never reach meaningful plasma concentrations can sit at hundreds of micromolar to millimolar inside the gastrointestinal tract. Titanium dioxide is the worked example. In rats fed food-grade particles at dietary levels for 100 days, colonic TNF-α rose 26% and IL-8 rose 45%, with no change in paracellular permeability: immune disturbance supported, barrier failure in a healthy animal not shown. Europe removed it from food and kept it in medicines on supply grounds. In the book’s terms, the first brain, the gut, absorbs that exposure at full concentration; the second brain in the skull barely registers it.

Measura does not measure excipient exposure. It is read from the product record by the prescriber and pharmacist.

Can daily NSAIDs injure the small bowel without anyone noticing?

NSAID enteropathy is the injury least likely to reach a problem list. In 40 healthy volunteers given two weeks of a standard NSAID dose, capsule enteroscopy found new pathology in 68% and mucosal breaks in 40%, and fecal calprotectin rose above normal in 75%. In an unselected health-check cohort, aspirin users had small-bowel mucosal breaks at 36.9% against 6.3%, an odds ratio of 6.17. Co-prescribed acid suppression did not protect the small bowel; injury was 2.7 times more frequent with celecoxib plus rabeprazole than with celecoxib plus placebo. The one agent with a healing signal, misoprostol, achieved complete healing in 28.6% against 9.5%.

The counterevidence deserves its tier. A 2026 randomized trial found indomethacin did not raise mannitol-based permeability in healthy volunteers, yet symptom scores rose from 15.5 to 17.3 with an interval excluding zero. The cohort was healthy, dosing lasted six days, and the placebo arms were small. The practice’s position is that the camera findings govern the older multi-drug patient such trials exclude. Capsule endoscopy and calprotectin are gastrointestinal studies performed elsewhere and are not part of the Measura library.

Can medications change the gut microbiome?

Polypharmacy leaves reproducible microbial fingerprints. Across 1,883 human fecal metagenomes, 19 of 41 drugs associated with microbial features; after correcting for concurrent use, the signal contracted to 47 associations involving six drugs, and no drug altered richness. In 4,198 people sampled twice, polypharmacy-related community structures shifted with drug initiation and recovered with cessation. A depletion once proposed as a microbial marker of major depression was explained, in 1,802 people, by SSRI/SNRI status. Any microbiome result in a medicated patient has to be read against the bag. Measura does not run stool or microbiome testing.

What does a baseline measurement add to deprescribing?

The audit question with the most clinical weight is whether each indication still holds, and that is a measurement question. Measura contributes to the terrain side of it, not to drug toxicity:

• Laboratory panels re-establish the metabolic state the metformin and statin were started for and give a dated baseline before any taper or substitution.
• Arterial stiffness and endothelial function testing adds a direct vascular measurement alongside office blood pressure for patients on antihypertensive and lipid therapy.
• Bioimpedance body composition matters because the enteropathy data are not only about drugs. In the same health-check cohort, obesity carried an odds ratio of 2.30 (1.38 to 3.92) for small-bowel breaks and smoking 1.85. Adiposity is a modifiable driver of metaflammation that a medication review never records.
• Indirect calorimetry replaces an estimated resting energy expenditure with a measured one when fatigue has been attributed to age.

Findings change management in concrete ways. A metabolic panel that has normalized reopens the indication discussion for a drug started years earlier. A body-composition result moves weight and tobacco into the same plan as the medication changes. A documented baseline makes it possible to tell, after a reformulation, whether anything moved. Reading guidance sits in interpreting the report.

Building it into the visit

The multi-drug older adult is commonly seen at an annual wellness visit, which many practices already use for a medication review. Attaching a standing measurement protocol to that review keeps it reproducible instead of dependent on whichever clinician has time. Standing orders can define the trigger, such as a daily-medication count, a pharmacologically managed gastrointestinal symptom, or unexplained fatigue, and annual wellness visit integration covers where results land in the encounter. Practices running cognitive assessment and fall prevention pathways can add metabolic and body-composition measurement to the same visit, and the record of what was measured and acted on supports MIPS quality reporting.

Every study summarized here, with its limits and the results that argue the other way, is in the Deep Dive companion. The next chapter moves from the bag to the nerve that reports on it, covered for clinicians in why the LF/HF ratio is not vagal tone.

Frequently asked questions

References

• Reker, D., Blum, S. M., Steiger, C., Anger, K. E., Sommer, J. M., Fanikos, J., & Traverso, G. (2019). “Inactive” ingredients in oral medications. Science Translational Medicine, 11(483), eaau6753. https://doi.org/10.1126/scitranslmed.aau6753
• Pottel, J., Armstrong, D., Zou, L., Fekete, A., Huang, X.-P., Torosyan, H., Bednarczyk, D., Whitebread, S., Bhhatarai, B., Liang, G., Jin, H., Ghaemi, S. N., Slocum, S., Lukacs, K. V., Irwin, J. J., Berg, E. L., Giacomini, K. M., Roth, B. L., Shoichet, B. K., & Urban, L. (2020). The activities of drug inactive ingredients on biological targets. Science, 369(6502), 403–413. https://doi.org/10.1126/science.aaz9906
• Bettini, S., Boutet-Robinet, E., Cartier, C., Coméra, C., Gaultier, E., Dupuy, J., Naud, N., Taché, S., Grysan, P., Reguer, S., Thieriet, N., Réfrégiers, M., Thiaudière, D., Cravedi, J. P., Carrière, M., Audinot, J. N., Pierre, F. H., Guzylack-Piriou, L., & Houdeau, E. (2017). Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon. Scientific Reports, 7, 40373. https://doi.org/10.1038/srep40373
• Maiden, L., Thjodleifsson, B., Theodors, A., Gonzalez, J., & Bjarnason, I. (2005). A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy. Gastroenterology, 128(5), 1172–1178. https://doi.org/10.1053/j.gastro.2005.03.020
• Sun, X., Wang, F., Liu, J., Wu, L., Wang, Z., Chen, X., Wang, M., & Zeng, Q. (2022). Risk factors for small-intestinal mucosal breaks beyond aspirin. Journal of Gastroenterology and Hepatology, 37(8), 1596–1602. https://doi.org/10.1111/jgh.15892
• Watanabe, T., Fujiwara, Y., & Chan, F. K. L. (2019). Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review. Journal of Gastroenterology, 55(5), 481–495. https://doi.org/10.1007/s00535-019-01657-8
• Camilleri, M., Busciglio, I., Carlson, P., Dilmaghani, S., Lupianez-Merly, C., Yang, D. Y., Ryks, M., Ferber, M., Houamel, D., Perot, S., & Montestruc, F. (2026). Indomethacin fails to increase intestinal permeability in healthy volunteers. Clinical and Translational Gastroenterology, 17(1), e00944. https://doi.org/10.14309/ctg.0000000000000944
• Vich Vila, A., Collij, V., Sanna, S., Sinha, T., Imhann, F., Bourgonje, A. R., Mujagic, Z., Jonkers, D. M. A. E., Masclee, A. A. M., Fu, J., Kurilshikov, A., Wijmenga, C., Zhernakova, A., & Weersma, R. K. (2020). Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nature Communications, 11(1), 362. https://doi.org/10.1038/s41467-019-14177-z
• Nagata, N., Nishijima, S., Miyoshi-Akiyama, T., Kojima, Y., Kimura, M., Aoki, R., Ohsugi, M., Ueki, K., Miki, K., Iwata, E., Hayakawa, K., Ohmagari, N., Oka, S., Mizokami, M., Itoi, T., Kawai, T., Uemura, N., & Hattori, M. (2022). Population-level metagenomics uncovers distinct effects of multiple medications on the human gut microbiome. Gastroenterology, 163(4), 1038–1052. https://doi.org/10.1053/j.gastro.2022.06.070
• Natasha, E. E., Mulder, D., Fehse, L., Winter, N. R., Fisch, L., Welzel, M., Bang, C., Meinert, S., Flinkenflügel, K., Borgers, T., Goltermann, J., Leehr, E. J., Culmsee, C., Stein, F., Thomas-Odenthal, F., Usemann, P., Teutenberg, L., Nenadic, I., Straube, B., … Bloemendaal, M. (2026). The effect of SSRI/SNRI antidepressant treatment on the gut microbiota of patients with major depressive disorder. Communications Medicine, 6(1). https://doi.org/10.1038/s43856-026-01782-5

Related reading

• Inflammation and Depression: Identifying the Inflamed Subgroup
• The LF/HF Ratio Is Not Vagal Tone: Autonomic Testing in Gut Patients
• Laboratory Panels

Inflammation and Depression: Identifying the Inflamed Subgroup

Inflammation is linked to depression in a subgroup, not in everyone: a meta-analysis of 30 studies found CRP above 3 mg/L in 27 percent of patients with depression. The treatment signal sits where baseline CRP is high, so identifying that subgroup starts with measurement.

Anti-inflammatory trials in depression fail on average and succeed in the patients whose markers run high. That makes baseline measurement a clinical decision rather than an academic one.

The link between inflammation and depression is real, and it is not universal. Treated as a population average it looks weak; treated as a subgroup question it becomes a screening problem primary care is well placed to solve. The case is set out in Your Anxiety Is a Fire in Your Gut, the video accompanying the first clinical chapter of The Angry Gut, which frames the gut as the first brain and the organ in the skull as the second.

Measura [Cardiometabolic and Autonomic Health Analysis] supplies measurements to that workup. Diagnosis and management remain with the treating physician.

Can inflammation cause depression?

Endotoxin challenge in healthy volunteers produces depressed mood under randomized, placebo-controlled conditions, and in younger women the rise in interleukin-6 tracked the rise in depressed mood. The clinical analogue is interferon therapy for hepatitis C: across 26 prospective studies, the cumulative incidence of induced major depression was 0.25 at 24 weeks and 0.28 at 48. A prior depressive episode (OR 3.96) and higher baseline interleukin-6 predicted it.

Susceptibility varies more than the cytokine response does. In one hundred and fifteen healthy adults challenged with endotoxin, baseline perceived stress, social sensitivity and existing anxiety or depressive symptoms predicted mood decline, yet none of them related to the magnitude of cytokine increases, and differential AP-1 and NF-kB activation was already visible at thirty minutes. The inflammatory stimulus is common. The vulnerability is individual, and it is partly social.

How common is inflamed depression, and who responds to treatment?

A meta-analysis of 30 studies found CRP above 3 mg/L in 27 percent of patients with depression, with an odds ratio of 1.46 against controls, and above 1 mg/L in 58 percent. The inflamed fraction was not explained by sample source, antidepressant treatment, age, BMI or ethnicity.

Infliximab in treatment-resistant depression showed no overall effect but a significant interaction with baseline CRP. Above 5 mg/L, 8 of 13 patients responded against 3 of 9 on placebo, numbers too small to stand alone. Pooled across anti-inflammatory agents added to antidepressants, the effect reached SMD −0.64, from trials that all carried high risk of bias. The signal sits where the markers are high, which makes baseline measurement the decision point.

The strongest counterargument

Mendelian randomization in 68,769 Norwegian adults found no clear causal effect of genetically predicted CRP on depressive symptoms, and a UK Biobank analysis of the interleukin-6 receptor produced an odds ratio of 1.023. These designs estimate lifelong genetic set-points against questionnaire outcomes in general populations. They do not model inflammation acquired through adiposity, diet, barrier failure or repeated antibiotic courses, and none was conducted in metabolically ill, high-CRP patients. They argue against inflammation as the engine of depression population-wide, which is not the claim, and they are silent on the inflamed subgroup.

Where the fire is lit: the first brain

Gut-derived serotonin, roughly 90 to 95 percent of the body’s total, does not cross the blood-brain barrier. Dr. Padda describes having taught patients the opposite for years before the pharmacology corrected him. The routes that matter are vagal afferent signaling and cytokine induction of indoleamine 2,3-dioxygenase, which shunts tryptophan into the kynurenine pathway and leaves less for central synthesis.

Barrier proxies point the same way. Serum IgM and IgA against gram-negative lipopolysaccharide separated patients with major depression from controls with an area under the ROC curve of 90.1 percent. In married couples, hostile interaction tracked lipopolysaccharide-binding protein, and 79 percent of the highest quartile had mean daytime CRP above 3, against 21 percent of the lowest. Stool microbiome signatures are not a usable screen: across 59 case-control studies the shifted taxa were shared between disorders. Measura does not perform stool, breath or microbiome testing.

Inflammation and depression: who to measure and what a finding changes

• Depression or anxiety with metabolic features such as central adiposity or elevated fasting insulin.
• Treatment-resistant or partially responsive depression, particularly with coexisting bowel symptoms.
• Repeated antibiotic exposure or heavy polypharmacy; in vitro, 24 percent of drugs with human targets inhibited at least one gut bacterial strain.
• Positive depression screening at an annual wellness visit with no inflammatory or metabolic markers on file.

A practical measurement set: laboratory panels with CRP and fasting insulin selected by the ordering physician, repeating any elevated CRP because infection, injury and strenuous exercise raise it; bioimpedance body composition to quantify the adipose compartment; and heart rate variability as a resting autonomic index. A confirmed elevated CRP with metabolic findings moves management toward the terrain the book calls metaflammation, running alongside existing psychiatric care. It is not a basis for altering an antidepressant, which remains with the prescriber.

Pairing with cognition, and what intervention evidence supports

In older adults, mood, inflammatory status and cognition are usually raised at the same visits. A structured cognitive assessment recorded alongside the inflammatory markers establishes a baseline for later comparison, in line with the cognitive assessment and fall prevention protocol.

On the intervention side, dietary change carries the strongest data. SMILES randomized adults with major depression to dietary or social support and found a 7.1-point MADRS difference, an effect size of −1.16, remission of 32.3 against 8.0 percent and a number needed to treat of 4.1. Pooled dietary trials look smaller (g = 0.162), but 15 of 16 of them enrolled people without clinical depression. Probiotic effects shrink by nearly a third once high-bias trials are excluded.

Workflow and documentation

Specialty separation is the structural driver: mood, bowel and metabolism are managed in separate clinics, and nobody owns the connection. A standing order tying positive depression screening to CRP, fasting insulin and body composition turns the subgroup question into routine practice. Discrete results in the chart support HEDIS and value-based care documentation and annual wellness visit care plans, and let a repeat CRP be trended rather than rediscovered.

Full effect sizes, confidence intervals, and the transplant and vagus stimulation trials are compiled in the Chapter 1 Deep Dive for The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes. The preceding physician discussion covers autonomic function testing when symptoms begin in the gut. Depression that has lifted still leaves a cognitive risk worth tracking, addressed in remitted depression and cognitive decline.

Frequently asked questions

References

• Udina, M., Castellví, P., Moreno-España, J., Navinés, R., Valdés, M., Forns, X., Langohr, K., Solà, R., Vieta, E., & Martín-Santos, R. (2012). Interferon-induced depression in chronic hepatitis C: A systematic review and meta-analysis. The Journal of Clinical Psychiatry, 73(8), 1128–1138. https://doi.org/10.4088/JCP.12r07694
• Irwin, M. R., Cole, S., Olmstead, R., Breen, E. C., Cho, J. J., Moieni, M., & Eisenberger, N. I. (2019). Moderators for depressed mood and systemic and transcriptional inflammatory responses: A randomized controlled trial of endotoxin. Neuropsychopharmacology, 44(3), 635–641. https://doi.org/10.1038/s41386-018-0259-6
• Osimo, E. F., Baxter, L. J., Lewis, G., Jones, P. B., & Khandaker, G. M. (2019). Prevalence of low-grade inflammation in depression: A systematic review and meta-analysis of CRP levels. Psychological Medicine, 49(12), 1958–1970. https://doi.org/10.1017/S0033291719001454
• Raison, C. L., Rutherford, R. E., Woolwine, B. J., Shuo, C., Schettler, P., Drake, D. F., Haroon, E., & Miller, A. H. (2013). A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers. JAMA Psychiatry, 70(1), 31–41. https://doi.org/10.1001/2013.jamapsychiatry.4
• Köhler-Forsberg, O., N Lydholm, C., Hjorthøj, C., Nordentoft, M., Mors, O., & Benros, M. E. (2019). Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: Meta-analysis of clinical trials. Acta Psychiatrica Scandinavica, 139(5), 404–419. https://doi.org/10.1111/acps.13016
• Bekkevold, O.-J., Damås, J. K., Brumpton, B. M., & Åsvold, B. O. (2023). The causal role of C-reactive protein and interleukin-6 on anxiety and depression symptoms and life satisfaction: Mendelian randomisation analyses in the HUNT study. Psychological Medicine, 53(16), 7561–7568. https://doi.org/10.1017/S0033291723001290
• Kelly, K. M., Smith, J. A., & Mezuk, B. (2021). Depression and interleukin-6 signaling: A Mendelian randomization study. Brain, Behavior, and Immunity, 95, 106–114. https://doi.org/10.1016/j.bbi.2021.02.019
• Maes, M., Kubera, M., & Leunis, J.-C. (2008). The gut-brain barrier in major depression: Intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinology Letters, 29(1), 117–124. https://pubmed.ncbi.nlm.nih.gov/18283240/
• Jacka, F. N., O’Neil, A., Opie, R., Itsiopoulos, C., Cotton, S., Mohebbi, M., Castle, D., Dash, S., Mihalopoulos, C., Chatterton, M. L., Brazionis, L., Dean, O. M., Hodge, A. M., & Berk, M. (2017). A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial). BMC Medicine, 15(1), 23. https://doi.org/10.1186/s12916-017-0791-y
• Maier, L., Pruteanu, M., Kuhn, M., Zeller, G., Telzerow, A., Anderson, E. E., Brochado, A. R., Fernandez, K. C., Dose, H., Mori, H., Patil, K. R., Bork, P., & Typas, A. (2018). Extensive impact of non-antibiotic drugs on human gut bacteria. Nature, 555(7698), 623–628. https://doi.org/10.1038/nature25979

Related reading

• Autonomic Function Testing When Symptoms Begin in the Gut
• Deprescribing Starts With a Baseline, Not a Drug List
• Laboratory Panels

Autonomic Function Testing When Symptoms Begin in the Gut

Autonomic function testing for gut symptoms means heart rate variability, cardiac autonomic reflex tests and sudomotor testing. An abnormal pattern moves the differential toward a systemic autonomic process; a normal pattern does not exclude enteric disease.

Every autonomic test in routine use is taken at the heart or the skin. The complaint often starts in an organ with its own nervous system and a vagal cable built largely for reporting.

Autonomic function testing earns its place in primary care when the ordering physician knows which part of the autonomic system a result actually describes. Patients with bloating, erratic bowels, lightheadedness and fatigue often carry a functional label and no measurement of regulation at all. The anatomy reviewed in You Have the Stomach of a Hyena, the opening video for The Angry Gut, explains why the test belongs in that workup and where its reach ends.

Measura [Cardiometabolic and Autonomic Health Analysis] performs the measurements; interpretation and the plan stay with the treating physician. Dr. Padda notes he taught the body from the top down for years before the fiber anatomy changed how he sequences this workup.

The first brain runs locally

In the book’s vocabulary the enteric nervous system is the first brain and the skull holds the second. The label is evolutionary: gut-wall nervous systems occur in animals such as hydra that have no central nervous system. Standardized whole-mount counts put the human enteric population at 168 million neurons, comparable to spinal cord, spread across at least 26 definable neuron types. Bowel segments with every extrinsic nerve severed still propel their contents.

The clinically relevant detail is where central control matters. It is essential in the esophagus and weighs more in the stomach and distal colon than in the small intestine. In isolated human colon the slow phasic rhythm is myogenic and survives conduction blockade, while blocking enteric transmission lengthened the interval between contractions from 124 to 278.1 seconds. A normal cardiac autonomic study says nothing about that local circuitry, and an abnormal one does not localize to it.

What the vagus carries, measured rather than quoted

The 75 to 90 percent afferent figure repeated in reviews leans partly on a rat study whose authors reported a higher efferent share than accepted estimates. No direct afferent-to-efferent count exists for a human vagus. Human morphometry is more useful: in the abdominal vagus, 94 percent of fibers are unmyelinated, against a myelinated share of 54 percent at the cervical level in the same individuals. That is the profile of fine sensory cable.

Two findings bear directly on test interpretation. Right cervical vagus nerves averaged about one and a half times the effective surface of the left and carried twice as many tyrosine-hydroxylase-positive, catecholaminergic fibers. Fascicle architecture is also species-dependent: the mouse cervical vagus is a single fascicle, whereas the human carries 7 in the neck and 16 in the abdomen. Heart-derived vagal indices therefore sample a mixed cable, and rodent vagal physiology crosses into human interpretation only with care.

Can any test record the gut’s signal to the brain?

Luminal signals reach the brainstem quickly. In mice, neuropod cells synapse onto vagal afferents and transmit within 60 to 800 ms, although only 18.9 percent of CCK-producing enteroendocrine cells contacted a nerve fiber, and whole-nerve firing took on the order of a minute to peak. No bedside instrument records that traffic.

What a practice can record is systemic autonomic regulation, the downstream metabolic terrain, and the medications that alter the upstream gate. Human gastric pH, 1.0 to 2.5 in all 66 ambulatory subjects of one capsule study, is a capsule or probe measurement performed elsewhere. Stool, breath and microbiome studies are likewise outside Measura’s scope and are not offered.

Who needs autonomic function testing, and what does a finding change?

Reasonable candidates, consistent with Measura selection criteria:

• Chronic gastrointestinal symptoms that travel with orthostatic lightheadedness, abnormal sweating or unexplained fatigue.
• Established metabolic disease in which autonomic involvement would change the follow-up plan.
• Long-term acid suppression or heavy polypharmacy, where the medication list is already reshaping what the gut receives.
• Older adults with gut complaints plus a fall history or a cognitive concern.

The core tools are heart rate variability for resting autonomic balance, cardiac autonomic reflex tests for standardized responses to breathing and posture, and sudomotor testing for sweat-gland function in the small nerve fibers of the hands and feet. An abnormal pattern moves the differential from an isolated functional bowel diagnosis toward a systemic autonomic process and justifies trending over time. A normal pattern does not exclude enteric disease; gastroparesis and achalasia disable within the gut itself.

Autonomic results carry the most weight next to laboratory panels and bioimpedance body composition, because the terrain the first brain reports on is metabolic. The chronic end state traced through the book is metaflammation, which is assessed in blood and tissue compartments rather than in a heartbeat.

Pairing with cognition and fall prevention

The second brain is downstream of the first, so a gut-and-autonomic workup in an older patient is incomplete without a cognitive baseline. A structured cognitive assessment recorded at the same encounter gives a reference point for later change, and orthostatic findings belong in the fall-risk plan rather than a separate note. Sequencing is covered in the cognitive assessment and fall prevention protocol.

Workflow, medications and documentation

Specialty separation is the social driver. Gastroenterology owns the bowel, cardiology owns the heart rate, and a patient with symptoms in both rarely has a single owner. A standing order that triggers autonomic testing when defined gut and orthostatic criteria coexist takes that gap out of individual memory. Results filed as discrete values support annual wellness visit care planning and MIPS quality reporting as documentation of a measured, followed finding rather than a symptom list.

Medication reconciliation belongs in the same visit. In three population cohorts totaling 1,815 people, the 211 using a proton pump inhibitor had lower gut microbial diversity, an observational result open to confounding by indication; in a small randomized trial, acid suppression improved colonization by a swallowed organism. These drugs have real indications. The review question is whether the indication still holds, not reflexive discontinuation.

Primary figures and their limits, including the unresolved afferent ratio, are compiled in the Chapter 0 Deep Dive for The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes. The inflammatory consequences for mood are taken up in identifying inflammatory depression in practice.

Frequently asked questions

References

• Furness, J. B., & Stebbing, M. J. (2017). The first brain: Species comparisons and evolutionary implications for the enteric and central nervous systems. Neurogastroenterology and Motility, 30(2), e13234. https://doi.org/10.1111/nmo.13234
• Michel, K., Kuch, B., Dengler, S., Demir, I. E., Zeller, F., & Schemann, M. (2022). How big is the little brain in the gut? Neuronal numbers in the enteric nervous system of mice, Guinea pig, and human. Neurogastroenterology and Motility, 34(12), e14440. https://doi.org/10.1111/nmo.14440
• Furness, J. B., Marklund, U., Czapla, B. J., Bornstein, J. C., & Han, M. N. (2026). Functional characterization and classification of enteric neurons, and regional differences in neural control of digestive functions. Autonomic Neuroscience: Basic & Clinical, 265, 103412. https://doi.org/10.1016/j.autneu.2026.103412
• Carbone, S. E., Dinning, P. G., Costa, M., Spencer, N. J., Brookes, S. J. H., & Wattchow, D. A. (2013). Ascending excitatory neural pathways modulate slow phasic myogenic contractions in the isolated human colon. Neurogastroenterology and Motility, 25(8), 670–676. https://doi.org/10.1111/nmo.12129
• Prechtl, J. C., & Powley, T. L. (1990). The fiber composition of the abdominal vagus of the rat. Anatomy and Embryology, 181(2), 101–115. https://doi.org/10.1007/BF00198950
• Stakenborg, N., Gomez-Pinilla, P. J., Verlinden, T. J. M., Wolthuis, A. M., D’Hoore, A., Farré, R., Herijgers, P., Matteoli, G., & Boeckxstaens, G. E. (2020). Comparison between the cervical and abdominal vagus nerves in mice, pigs, and humans. Neurogastroenterology and Motility, 32(9), e13889. https://doi.org/10.1111/nmo.13889
• Verlinden, T. J. M., Rijkers, K., Hoogland, G., & Herrler, A. (2016). Morphology of the human cervical vagus nerve: implications for vagus nerve stimulation treatment. Acta Neurologica Scandinavica, 133(3), 173-182. https://doi.org/10.1111/ane.12462
• Kaelberer, M. M., Buchanan, K. L., Klein, M. E., Barth, B. B., Montoya, M. M., Shen, X., & Bohórquez, D. V. (2018). A gut-brain neural circuit for nutrient sensory transduction. Science, 361(6408), eaat5236. https://doi.org/10.1126/science.aat5236
• Imhann, F., Bonder, M. J., Vich Vila, A., Fu, J., Mujagic, Z., Vork, L., Tigchelaar, E. F., Jankipersadsing, S. A., Cenit, M. C., Harmsen, H. J. M., Dijkstra, G., Franke, L., Xavier, R. J., Jonkers, D., Wijmenga, C., Weersma, R. K., & Zhernakova, A. (2016). Proton pump inhibitors affect the gut microbiome. Gut, 65(5), 740-748. https://doi.org/10.1136/gutjnl-2015-310376
• Singh, G., Haileselassie, Y., Briscoe, L., Bai, L., Patel, A., Sanjines, E., Hendler, S., Singh, P. K., Garud, N. R., Limketkai, B. N., & Habtezion, A. (2022). The effect of gastric acid suppression on probiotic colonization in a double blinded randomized clinical trial. Clinical Nutrition ESPEN, 47, 70-77. https://doi.org/10.1016/j.clnesp.2021.11.005

Related reading

• Inflammation and Depression: Identifying the Inflamed Subgroup
• Heart Rate Variability