Intestinal Permeability Test: Endpoints for a Stalled Gut Protocol

The intestinal permeability test to use is the dual-sugar lactulose-to-mannitol ratio, ordered through gastroenterology or a reference laboratory, not serum zonulin. Measure it before a repair protocol starts and set the repeat date in advance; the controlled glutamine trial remeasured at the end of its eight-week course.

A patient who plateaus on a gut repair plan needs an endpoint, not another supplement. The dual-sugar test supplies one, and the metabolic terrain around the barrier deserves the same discipline.

An intestinal permeability test earns its place when a patient has addressed the obvious drivers and still has not recovered. Chapter 29 of The Angry Gut, by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, is presented in the video above, A Plateau Is Not a Personality, through a patient about sixty percent improved for five months whose lactulose-to-mannitol ratio stayed elevated after medications, sleep, diet and bile flow had been corrected. The argument is methodological: a measured baseline, doses matched to the trials that tested them, and a remeasurement date fixed before treatment begins.

Serum zonulin is not a permeability measure

Three independent validation studies set the widely used commercial zonulin kit against measured permeability: R = 0.11 in 38 subjects, R = 0.17 in 71 and R = 0.033 in 24, none significant, 133 people in all. The kits were built against the first published zonulin sequence, later shown to be unrelated to the protein, and in serum from 376 members of the Sorbs cohort none of the proteins the antibody captured corresponded to pre-haptoglobin-2. Alessio Fasano, who first described zonulin, co-authored that correction. The reviewers’ recommendation was dual-sugar assays and tissue-level measures, and because pre-haptoglobin-2 is not naturally expressed in mice, rodent serum zonulin findings inherit the problem.

How the dual-sugar intestinal permeability test works, and why it is repeated

Mannitol, the smaller probe, crosses transcellularly and reflects absorptive surface; lactulose crosses paracellularly when junctions loosen. Neither is metabolized, both are excreted in urine over roughly six hours, and the ratio cancels gastric emptying, ingested volume and renal clearance. It is cumbersome and produces no colored report, but it measures the barrier. It is not a Measura test; it is ordered through gastroenterology or a reference laboratory.

Repetition is the point. In the case above the ratio returned to range at twelve weeks; those are practice-reported figures from our own population, not trial outcomes, and individual results vary. Symptom reports are a weak substitute. In a three-arm, open-label polaprezinc eradication trial run across 11 Chinese cities, all arms reported significant symptom improvement at 7, 14 and 28 days, including the arm that received antibiotics alone.

Enrollment determines effect size

Glutamine shows why selection matters. In adults with post-infectious diarrhea-predominant IBS and documented hyperpermeability, 5 g three times daily for eight weeks produced a fifty-point symptom response in 79.6% against 5.8% on placebo, and the lactulose-to-mannitol ratio fell from 0.11 to 0.05, returning to range only in the treated group. A meta-analysis of 39 human glutamine studies, largely in surgical and critically ill patients, found a pooled ratio change of 0.01. The single trial’s effect is much larger because it admitted only patients with a measured leak, excluding everyone with nothing to fix. It comes from one group without replication, and its authors asked for validating trials.

Dr. Padda spent years telling patients that a lining which renews in days needs only rest and time. That holds for acute injury. For a barrier measured open over years, the screening implication is direct: measuring before treating selects the patients most likely to respond and supplies the endpoint that makes a response interpretable.

Dose provenance and endpoint mismatch

Several agents common in gut protocols carry doses from trials that never measured the barrier. Zinc carnosine prevented an indomethacin-induced permeability rise in 10 healthy volunteers at 37.5 mg twice daily, while the 75 mg twice-daily retail dose derives from Helicobacter pylori eradication trials; doubling to 150 mg twice daily added no eradication benefit as adverse events rose from 2.8% to 5.1%. Oral GABA doses come from stress and sleep research, and none of the 14 included studies measured a gastrointestinal endpoint. Larazotide acetate, the only junction-targeted drug taken to phase 3, did not separate from placebo on the dual-sugar ratio in pooled analysis, and phase 3 was terminated without a published efficacy figure. Symptom relief and measured permeability can dissociate, and agent selection remains with the treating clinician.

Nutrient status and the metabolic terrain

Supply deficits are checkable. The global estimate that 17.3% of people are at risk of inadequate zinc intake is a food-supply model; risk rose with the phytate-to-zinc ratio and fell with animal-source zinc, and its authors called for direct biochemical assessment instead of inference. A randomized trial gave 27 Crohn’s patients in remission vitamin D at 2,000 IU a day; permeability held steady on treatment while the placebo arm worsened, and those reaching 75 nmol/L had lower CRP (p = 0.019), a post-hoc responder analysis that favors dosing to a measured level. Glycine synthesis plus diet falls about 10 g a day short of demand in a 70 kg adult, a flux calculation rather than a demonstrated deficiency. The economic driver is the food supply itself: low-priced grain and legume staples carry their own zinc blocker.

The patient who plateaus is also the patient trials exclude, with metabolic disease, a long medication list and disrupted sleep. That is where Measura [Cardiometabolic and Autonomic Health Analysis] applies. It does not measure intestinal permeability. It measures the terrain: laboratory panels for insulin resistance and inflammation, the metaflammation that travels with barrier failure; bioimpedance body composition for lean mass in patients whose diets have narrowed; and indirect calorimetry for measured resting energy expenditure, so nutrition plans for a rebuilding barrier rest on measured demand rather than an estimate. In the book’s language the gut is the first brain and the skull holds the second brain, and these measures describe the metabolic environment both share.

Selection criteria and documentation

Written selection criteria can flag patients with persistent gastrointestinal symptoms plus metabolic risk factors for cardiometabolic measurement, and standing orders keep that consistent. A baseline and a predefined repeat interval, documented through getting results into the record, turn a plateau into a trackable course. The patient version is how long it takes to heal leaky gut; the bile acid workup precedes it in postcholecystectomy diarrhea; and the full study data with limits are in the Chapter 29 companion.

Frequently asked questions

References

• Massier, L., Chakaroun, R., Kovacs, P., & Heiker, J. T. (2021). Blurring the picture in leaky gut research: How shortcomings of zonulin as a biomarker mislead the field of intestinal permeability. Gut, 70(9), 1801-1802. https://doi.org/10.1136/gutjnl-2020-323026
• Scheffler, L., Crane, A., Heyne, H., Tönjes, 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
• Zhou, Q., Verne, M. L., Fields, J. Z., Lefante, J. J., Basra, S., Salameh, H., & Verne, G. N. (2019). Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome. Gut, 68(6), 996-1002. https://doi.org/10.1136/gutjnl-2017-315136
• Arribas-López, E., Zand, N., Ojo, O., Snowden, M. J., & Kochhar, T. (2021). The effect of amino acids on wound healing: A systematic review and meta-analysis on arginine and glutamine. Nutrients, 13(8), 2498. https://doi.org/10.3390/nu13082498
• Mahmood, A., FitzGerald, A. J., Marchbank, T., Ntatsaki, E., Murray, D., Ghosh, S., & Playford, R. J. (2006). Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut, 56(2), 168-175. https://doi.org/10.1136/gut.2006.099929
• Tan, B., Luo, H.-Q., Xu, H., Lv, N.-H., Shi, R.-H., Luo, H.-S., Li, J.-S., Ren, J.-L., Zou, Y.-Y., Li, Y.-Q., Ji, F., Fang, J.-Y., & Qian, J.-M. (2017). Polaprezinc combined with clarithromycin-based triple therapy for Helicobacter pylori-associated gastritis: A prospective, multicenter, randomized clinical trial. PLoS One, 12(4), e0175625. https://doi.org/10.1371/journal.pone.0175625
• Hepsomali, P., Groeger, J. A., Nishihira, J., & Scholey, A. (2020). Effects of oral gamma-aminobutyric acid (GABA) administration on stress and sleep in humans: A systematic review. Frontiers in Neuroscience, 14, 923. https://doi.org/10.3389/fnins.2020.00923
• Hoilat, G. J., Altowairqi, A. K., Ayas, M. F., Alhaddab, N. T., Alnujaidi, R. A., Alharbi, H. A., Alyahyawi, N., Kamal, A., Alhabeeb, H., Albazee, E., Almustanyir, S., & Abu-Zaid, A. (2022). Larazotide acetate for treatment of celiac disease: A systematic review and meta-analysis of randomized controlled trials. Clinics and Research in Hepatology and Gastroenterology, 46(1), 101782. https://doi.org/10.1016/j.clinre.2021.101782
• Wessells, K. R., & Brown, K. H. (2012). Estimating the global prevalence of zinc deficiency: Results based on zinc availability in national food supplies and the prevalence of stunting. PLoS One, 7(11), e50568. https://doi.org/10.1371/journal.pone.0050568
• Raftery, T., Martineau, A. R., Greiller, C. L., Ghosh, S., McNamara, D., Bennett, K., Meddings, J., & O’Sullivan, M. (2015). Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn’s disease: Results from a randomised double-blind placebo-controlled study. United European Gastroenterology Journal, 3(3), 294-302. https://doi.org/10.1177/2050640615572176

Related reading

• Postcholecystectomy Diarrhea: A Measurement-First Workup
• Patient Activation Measure: Why Maintenance Needs Objective Re-Testing
• Laboratory Panels

Postcholecystectomy Diarrhea: A Measurement-First Workup

The workup for postcholecystectomy diarrhea starts by identifying bile acid diarrhea through the bile acid assessment available via gastroenterology, before any empiric antibiotic for overgrowth, which needs a positive breath test as its trigger. A gallstone or cholecystectomy history also belongs in the selection criteria for cardiometabolic measurement.

Patients with loose stools after cholecystectomy are often treated for overgrowth without a positive test. The evidence favors identifying bile acid loss first, and gallbladder disease itself is a cardiometabolic flag.

Postcholecystectomy diarrhea is usually handled as a nuisance to live with or as small intestinal bacterial overgrowth treated on suspicion. Both responses skip a measurement. Chapter 28 of The Angry Gut, by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, is summarized in the video above, The Liver Flush Is Soap, and is built around a patient given four antibiotic courses for overgrowth whose breath tests were negative each time. For a primary care or pain practice the practical content is a sequence: identify bile acid diarrhea, withhold empiric antibiotics that lack a trigger, and treat the gallbladder history as an indication for metabolic screening.

How common is bile acid diarrhea in chronic diarrhea?

At a single teaching hospital, 1,071 consecutive outpatients with chronic diarrhea were scanned, and 42.7% had bile acid diarrhea; prior cholecystectomy was one of three predictors of an abnormal result. Selection did not create the yield. Of all referrals, 61.0% carried no known risk factor, and 35.7% of that subgroup still tested positive. Positives were type II in 51.6%, type III in 36.1% and type I in 12.3%, and 33.9% were severe. Yield showed no downward trend over five years (p = 0.39) while referrals for terminal ileal Crohn’s disease or resection fell, which argues against looser ordering diluting the figure.

One constraint applies in the United States: the scan used in that cohort is not available here, so the prevalence transfers and the diagnostic route does not. Referral to gastroenterology for the bile acid assessment available locally is the practical step. None of these investigations is a Measura test.

Is SIBO common after cholecystectomy?

The intuitive model holds that losing the reservoir lets bacteria ascend. Dr. Padda taught that model, and the cohorts forced a revision. In 146 abdominal surgery patients against 30 healthy controls, overgrowth ran 37.6% versus 13.3%, yet cholecystectomy had the lowest rate at 17.1%, against 36.0% after hysterectomy and 96.2% after gastrectomy; previous gastrectomy and elevated gastrin independently predicted the hydrogen pattern. Among 265 patients with gallbladder disease and 39 controls, positivity peaked in patients with stones in situ, 40.5%, and gallstones were the only independent factor.

Two implications follow. Stasis with the organ present carries more risk than its absence, and gastrin points to failed acid control rather than lost bile after surgery. Empiric antibiotics for overgrowth need a positive test as their trigger, and repeating a course after negative breath tests treats an assumption. The pressure behind the habit is structural: a prescription can be written inside a short encounter, whereas a breath test requires patient preparation and another visit.

Why is gallbladder disease a cardiometabolic finding?

The same gallstone cohort found gallbladder disease independently associated with fatty liver and metabolic syndrome as well as overgrowth. A gallbladder that fails to empty travels with metabolic disease rather than standing alone as a mechanical fault. That makes a gallstone or cholecystectomy history a reasonable entry in selection criteria for cardiometabolic measurement, whatever the bowel complaint.

Physiology supports the association. Luminal bile salts limit endotoxin absorption: in obstructive jaundice, oral deoxycholate given to 12 patients before surgery was followed by no systemic endotoxemia and no postoperative renal impairment. In the book’s frame the gut is the first brain and the skull holds the second brain, and endotoxin crossing a depleted luminal defense is one input to metaflammation. Maldigested fat and the fat-soluble vitamins lost with it add a nutritional dimension that routine follow-up seldom documents.

Surrogates move while patients may not

The bile literature is a lesson in endpoint discipline. A randomized trial of oral ursodeoxycholic acid in 40 jaundiced patients raised bile salt concentrations and lowered portal endotoxemia, yet systemic endotoxemia, renal function, morbidity and mortality were unchanged. Pooled trials of the same drug in primary biliary cholangitis lowered alkaline phosphatase by 257 U/L without reducing mortality, 45 of 699 against 46 of 692. In a two-year trial of 100 patients already on that drug with inadequate response, complete biochemical response in the placebo add-on arm was 0%, so non-response was visible in the blood work and identifiable in advance.

Patients also arrive taking tauroursodeoxycholic acid. Its best metabolic data, in 20 obese adults at 1,750 mg daily for four weeks, showed roughly a 30% gain in hepatic and muscle insulin sensitivity with no gut or liver endpoint recorded. The workflow lesson is identical for prescriptions and supplements: record which value is expected to change and when it will be rechecked. Decisions to start, continue or stop any agent stay with the treating physician.

What Measura adds, and what it does not

Measura [Cardiometabolic and Autonomic Health Analysis] does not measure bile acids, gallbladder function, breath hydrogen or methane, or intestinal permeability; those belong to gastroenterology. It measures the terrain the gallstone data point toward:

• Laboratory panels to quantify insulin resistance and lipid status in a patient whose gallbladder history flags metabolic risk.
• Bioimpedance body composition to define fat and lean compartments where weight or BMI understates risk.

Findings return to the ordering physician, and reading them in clinical context is outlined in interpreting the report.

Standing orders for postcholecystectomy diarrhea

Criteria only hold when they run without anyone remembering them. A gallstone or cholecystectomy history, chronic diarrhea with prior empiric antibiotics, or known fatty liver can each trigger metabolic measurement through standing orders. Insulin resistance and body composition documented at the wellness visit give a baseline and a repeat interval, as described in annual wellness visit integration. The patient-facing version is bile acid malabsorption after gallbladder surgery; bile as a signaling molecule is covered in the bile mechanism post; barrier repair follows in intestinal permeability testing; and every study cited is set out with its limits in the Chapter 28 companion.

Frequently asked questions

References

• Lim, S. J., Gracie, D. J., Kane, J. S., Mumtaz, S., Scarsbrook, A. F., Chowdhury, F. U., Ford, A. C., & Black, C. J. (2019). Prevalence of, and predictors of, bile acid diarrhea in outpatients with chronic diarrhea: a follow-up study. Neurogastroenterology and Motility, 31(9), e13666. https://doi.org/10.1111/nmo.13666
• Kim, Y. J., Paik, C. N., Jo, I. H., Kim, D. B., & Lee, J. M. (2021). Serum gastrin predicts hydrogen-producing small intestinal bacterial overgrowth in patients with abdominal surgery: a prospective study. Clinical and Translational Gastroenterology, 12(1), e00291. https://doi.org/10.14309/ctg.0000000000000291
• Kim, D. B., Paik, C. N., Song, D. S., Kim, Y. J., & Lee, J. M. (2018). The characteristics of small intestinal bacterial overgrowth in patients with gallstone diseases. Journal of Gastroenterology and Hepatology, 33(8), 1477-1484. https://doi.org/10.1111/jgh.14113
• Cahill, C. J., Pain, J. A., & Bailey, M. E. (1987). Bile salts, endotoxin and renal function in obstructive jaundice. Surgery, Gynecology & Obstetrics, 165(6), 519-522. https://pubmed.ncbi.nlm.nih.gov/3120329/
• Thompson, J. N., Cohen, J., Blenkharn, J. I., McConnell, J. S., Barr, J., & Blumgart, L. H. (1986). A randomized clinical trial of oral ursodeoxycholic acid in obstructive jaundice. British Journal of Surgery, 73(8), 634-636. https://doi.org/10.1002/bjs.1800730819
• Rudic, J. S., Poropat, G., Krstic, M. N., Bjelakovic, G., & Gluud, C. (2012). Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database of Systematic Reviews, 12(12), CD000551. https://doi.org/10.1002/14651858.CD000551.pub3
• Corpechot, C., Chazouillères, O., Rousseau, A., Le Gruyer, A., Habersetzer, F., Mathurin, P., Goria, O., Potier, P., Minello, A., Silvain, C., Abergel, A., Debette-Gratien, M., Larrey, D., Roux, O., Bronowicki, J. P., Boursier, J., de Ledinghen, V., Heurgue-Berlot, A., Nguyen-Khac, E., … Poupon, R. (2018). A placebo-controlled trial of bezafibrate in primary biliary cholangitis. New England Journal of Medicine, 378(23), 2171-2181. https://doi.org/10.1056/NEJMoa1714519
• Kars, M., Yang, L., Gregor, M. F., Mohammed, B. S., Pietka, T. A., Finck, B. N., Patterson, B. W., Horton, J. D., Mittendorfer, B., Hotamisligil, G. S., & Klein, S. (2010). Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes, 59(8), 1899-1905. https://doi.org/10.2337/db10-0308
• Shahsavari, K., Ardekani, S. S., Ardekani, M. R. S., Esfahani, M. M., Kazemizadeh, H., Jamialahmadi, T., Iranshahi, M., Khanavi, M., & Hasanpour, M. (2025). Are alterations needed in Silybum marianum (Silymarin) administration practices? A novel outlook and meta-analysis on randomized trials targeting liver injury. BMC Complementary Medicine and Therapies, 25(1), 134. https://doi.org/10.1186/s12906-025-04886-y

Related reading

• SIBO Recurrence Rate: Screening the Host After the Kill
• Intestinal Permeability Test: Endpoints for a Stalled Gut Protocol
• Laboratory Panels

SIBO Recurrence Rate: Screening the Host After the Kill

After breath tests normalized with rifaximin, SIBO recurred in 12.6% of patients at three months, 27.5% at six months and 43.7% at nine months. Those checkpoints make defensible recheck points, and chronic proton pump inhibitor use, which raised recurrence odds more than threefold, is the one predictor a practice can modify.

Eradication succeeds often enough that recurrence gets treated as bad luck. The recurrence data describe a predictable curve, modifiable predictors and a gap between clearance and response that a follow-up plan should be built around.

The SIBO recurrence rate is the number that should shape follow-up after eradication, and it is rarely discussed when the first course is prescribed. The video The Weeds Were Never the Problem, from The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, argues that antibiotic clearance without a plan for what repopulates the bowel produces a shortening cycle. The ruling it lands on is to judge the result on function. For a screening practice that raises concrete questions: when to recheck, which predictors to act on, what microbial testing cannot say, and which host measures document the patient rather than the organisms.

The SIBO recurrence rate curve and its checkpoints

In the recurrence cohort, patients whose breath test normalized after a week of rifaximin tested positive again in 12.6% at three months, 27.5% at six months and 43.7% at nine months, with symptoms rising in parallel with test positivity. Follow-up ended at nine months, so the second year is unmeasured. The retreatment trial in diarrhea-predominant IBS saw 44.1% respond to the open-label phase, and 692 of 1,074 responders, 64.4%, relapsed within eighteen weeks. Retreatment of responders beat placebo modestly, 38.1% against 31.5%, in a population preselected for having responded once.

Those intervals give follow-up its structure. Three, six and nine months are where recurrence was actually measured, which makes them defensible recheck points and natural anchors for standing orders rather than waiting for symptoms to force a visit.

Predictors that are not organisms

Chronic proton pump inhibitor use raised the odds of recurrence more than threefold, prior appendectomy nearly sixfold, and each added year of age carried an odds ratio of 1.09 (95% CI 1.02-1.16). Of the three, only the acid suppression is modifiable, which puts deprescribing review squarely in the recurrence plan. The medication decision belongs to the prescribing clinician after weighing the original indication; the point is that it is reviewed deliberately rather than renewed by default.

There is a structural reason the review rarely happens. A branded antibiotic course arrives with registration trials, packaging and detailing, while fermented food and medication reconciliation have no sponsor and no representative. The kill acquires a guideline line; repopulation acquires a shrug at discharge. Practices that want a different recurrence curve have to build the unglamorous half into workflow, because no one will market it to them.

Clearance is not response

Pooled across 32 studies and 1,331 patients, rifaximin eradication runs 70.8% by intention to treat and 72.9% per protocol, with adverse events at 4.6%. Heterogeneity sits at I2 87-91% across the pooled estimates, and the authors grade the underlying study quality as generally poor. Co-therapy was among three covariates independently associated with higher eradication, a signpost rather than a protocol. The decisive figure is different: among patients whose overgrowth was demonstrably cleared, only 67.7% improved symptomatically. A third leave with a normal test and persistent illness.

That gap is why a normal breath test should not close the episode. Symptom trajectory and host function need their own documentation, recorded at the same checkpoints as the repeat breath test.

What microbial testing cannot tell you

Stool microbiome sequencing, breath testing and fecal calprotectin are different tests performed elsewhere. Measura [Cardiometabolic and Autonomic Health Analysis] does not offer them. Their limits matter for interpretation regardless of who runs them. In a capsule transplant trial in irritable bowel syndrome, fecal diversity rose while quality of life at three months favored placebo. In healthy adults, more than doubling fiber from 21.5 to 45.1 g per day left alpha diversity unchanged cohort-wide, while 6.3 servings a day of fermented food raised diversity and lowered 19 of 93 inflammatory serum proteins, although the primary outcome was not met. Membership is not function.

The post-antibiotic literature explains why. After four days of meropenem, gentamicin and vancomycin in healthy young men, composition approached baseline within about six weeks, yet nine species present in every subject beforehand remained undetectable in most at 180 days, and resistance-gene carriers were selected during the refill. The best post-antibiotic probiotic study found capsule strains delayed native mucosal recovery compared with unaided reconstitution, while autologous stool restored it within days; it measured composition and transcriptome, not clinical end points.

Host function as the follow-up record

If the ruling is function, the record should measure the host. The first brain sits upstream of the second, and persistent metaflammation does not respect the boundary between them. Laboratory panels cover the metabolic and inflammatory picture that a gut-focused workup tends to omit. Bioimpedance body composition and indirect calorimetry document muscle and fat compartments and measured resting energy expenditure in patients whose intake has been restricted across months of symptoms. Heart rate variability records autonomic tone. None of these detects overgrowth, and none substitutes for a repeat breath test; they document how the patient is functioning at the same checkpoints.

Operationally, that means a standing order triggered at the final antibiotic dose, host measures at baseline and at the recurrence checkpoints, and medication review folded into the annual wellness visit. The same measures support documentation for MIPS and quality reporting. Primary studies and their limits are in the book companion, and testing before treating covers the measurement that should precede the first course.

Frequently asked questions

References

• Lauritano, E. C., Gabrielli, M., Scarpellini, E., Lupascu, A., Novi, M., Sottili, S., Vitale, G., Cesario, V., Serricchio, M., Cammarota, G., Gasbarrini, G., & Gasbarrini, A. (2008). Small intestinal bacterial overgrowth recurrence after antibiotic therapy. The American Journal of Gastroenterology, 103(8), 2031-5. https://doi.org/10.1111/j.1572-0241.2008.02030.x
• Lembo, A., Pimentel, M., Rao, S. S., Schoenfeld, P., Cash, B., Weinstock, L. B., Paterson, C., Bortey, E., & Forbes, W. P. (2016). Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome. Gastroenterology, 151(6), 1113-1121. https://doi.org/10.1053/j.gastro.2016.08.003
• Gatta, L., & Scarpignato, C. (2017). Systematic review with meta-analysis: Rifaximin is effective and safe for the treatment of small intestine bacterial overgrowth. Alimentary Pharmacology & Therapeutics, 45(5), 604-616. https://doi.org/10.1111/apt.13928
• Halkjær, S. I., Christensen, A. H., Lo, B. Z. S., Browne, P. D., Günther, S., Hansen, L. H., & Petersen, A. M. (2018). Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebo-controlled study. Gut, 67(12), 2107-2115. https://doi.org/10.1136/gutjnl-2018-316434
• Wastyk, H. C., Fragiadakis, G. K., Perelman, D., Dahan, D., Merrill, B. D., Yu, F. B., Topf, M., Gonzalez, C. G., Van Treuren, W., Han, S., Robinson, J. L., Elias, J. E., Sonnenburg, E. D., Gardner, C. D., & Sonnenburg, J. L. (2021). Gut-microbiota-targeted diets modulate human immune status. Cell, 184(16), 4137-4153.e14. https://doi.org/10.1016/j.cell.2021.06.019
• Palleja, A., Mikkelsen, K. H., Forslund, S. K., Kashani, A., Allin, K. H., Nielsen, T., Hansen, T. H., Liang, S., Feng, Q., Zhang, C., Pyl, P. T., Coelho, L. P., Yang, H., Wang, J., Typas, A., Nielsen, M. F., Nielsen, H. B., Bork, P., Wang, J., … Pedersen, O. (2018). Recovery of gut microbiota of healthy adults following antibiotic exposure. Nature Microbiology, 3(11), 1255-1265. https://doi.org/10.1038/s41564-018-0257-9
• Suez, J., Zmora, N., Zilberman-Schapira, G., Mor, U., Dori-Bachash, M., Bashiardes, S., Zur, M., Regev-Lehavi, D., Ben-Zeev Brik, R., Federici, S., Horn, M., Cohen, Y., Moor, A. E., Zeevi, D., Korem, T., Kotler, E., Harmelin, A., Itzkovitz, S., Maharshak, N., … Elinav, E. (2018). Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell, 174(6), 1406-1423.e16. https://doi.org/10.1016/j.cell.2018.08.047
• Tariq, R., Pardi, D. S., & Khanna, S. (2023). Resolution rates in clinical trials for microbiota restoration for recurrent Clostridioides difficile infection: an updated systematic review and meta-analysis. Therapeutic Advances in Gastroenterology, 16, 17562848231174293. https://doi.org/10.1177/17562848231174293

Related reading

• CIRS Diagnosis: What the Mold Evidence Supports in Screening
• Postcholecystectomy Diarrhea: A Measurement-First Workup
• Laboratory Panels

CIRS Diagnosis: What the Mold Evidence Supports in Screening

No assay in the CIRS diagnosis framework has a published healthy reference interval standardized across laboratories, so the panel cannot yet be read. What the mold evidence supports is immunologic and infectious disease, with the respiratory effects of damp buildings graded sufficient.

Patients now arrive with a water-damaged building, a stalled recovery and a commercial result in hand. The clinical work is separating the established tiers from the marketed ones, then documenting function objectively.

Requests for a CIRS diagnosis, chronic inflammatory response syndrome attributed to water-damaged buildings, now reach primary care, pain, gastroenterology and allergy clinics, usually after an adherent patient has improved partway and plateaued. The video Mold Illness: Fix the Basement, Skip the Panel, from The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, grades the mold literature by evidence tier. For a screening practice the questions are operational: which parts of the framework hold, which assays cannot be interpreted, what belongs in the chart, and where objective function measurement earns a place.

What is established, and at which tier

The mold-related disease with defined mechanisms is immunologic and infectious: asthma, allergic rhinitis, allergic bronchopulmonary aspergillosis, sinusitis and hypersensitivity pneumonitis. The allergy position paper that set out those mechanisms classed the newer proposed syndromes as largely unproved. The 2004 Institute of Medicine synthesis found sufficient evidence associating damp indoor environments with some upper respiratory symptoms, and American medical toxicology still endorses it. A 2024 multi-society European guideline grades respiratory disease as sufficient, atopic eczema as limited or suspected, and gastrointestinal effects as inadequate or insufficient.

Exposure route is the skeptics’ strongest argument, and it is arithmetic rather than rhetoric. The 2025 American College of Medical Toxicology statement identifies diet as the most important source of human mycotoxin exposure and cites modeling that places the maximum inhaled dose in moldy buildings orders of magnitude below demonstrated thresholds for harm. The same statement reports no documented evidence that indoor fungal or mycotoxin inhalation causes a chronic toxic encephalopathy. Occupational medicine reached the equivalent conclusion in 2003.

The CIRS diagnosis panel, and why it cannot yet be read

Measura [Cardiometabolic and Autonomic Health Analysis] performs none of the framework’s assays: no mycotoxin or mycotoxin antibody testing, no urine toxin panels, no HLA-DR/DQ typing, no alpha-MSH, TGF-beta 1, C4a or MMP-9 profile, and no visual contrast sensitivity testing. Those are different tests run elsewhere. The case definition itself is falsifiable, which is to its credit: reduced regulatory neuropeptides, especially MSH, with elevation of at least one of the three inflammatory markers. Outside the originating group it stands neither falsified nor confirmed.

Alpha-MSH is a genuine anti-inflammatory peptide, but it does not behave like a deficiency marker. It rose in normal subjects given endotoxin, fell in sepsis, was elevated in more advanced HIV disease and in more inflamed synovial fluid, and runs lower in healthy elderly people than in young controls. No reference interval from a healthy population, assay standardization, inter-laboratory comparison or pre-analytic stability data has been published. Among the 28 who consented to the primary cholestyramine trial, 25 had an abnormal MSH and 1 an abnormal IgE, and MSH was not re-measured after treatment.

Urine mycotoxin panels fail on the same missing distribution. There is no FDA-approved urine mycotoxin assay. The federal case report is instructive when each value is read against its own line: ochratoxin returned at 2.8 ppb against that analyte’s cutoff of 2.0 ppb, and trichothecenes at 0.4 ppb against a separate cutoff of 0.2 ppb. Both exceeded their thresholds; destructive testing of the building found no water damage or significant fungal growth. The agency does not recommend biologic testing of people who work or live in water-damaged buildings, and the toxicology statement adds that antibody testing is not an accepted exposure measure.

The trial base, stated at its tier

A 2024 review sympathetic to the framework found the Shoemaker Protocol described in 11 of the 13 articles it identified, with minimal peer-reviewed publication from other groups; the randomized base is two cholestyramine trials of 8 and 13 subjects. In the primary trial, 7 randomized to drug improved, 6 on placebo did not until they crossed over, and all relapsed on building reexposure without the drug. That rechallenge was unblinded, and no mycotoxin was measured in any participant, so the result speaks to a bile acid sequestrant rather than to demonstrated toxin clearance.

The single independent replication compared 28 exposed individuals with 30 controls. The handheld contrast chart did not separate the groups; digital contrast sensitivity testing reached 100% sensitivity at 60-80% specificity. Exposure status was assigned from clinical signs with no exposure biomarker, which leaves circularity hard to exclude. Mechanism studies deserve their weight here without apology: trials exclude exactly the patient with polypharmacy, disrupted sleep and a flooded basement, so absence of a trial is a design fact, not a refutation.

Where the evidence is strongest: removing the exposure

The best controlled human data concern remediation. A Cochrane review pooling 12 studies and 8,028 participants found repairs reduced adult wheeze (odds ratio 0.64) and rhinitis (odds ratio 0.57), graded moderate quality, with no difference in children’s asthma days against information alone and no gut outcome in any included study. Occupational medicine and the European guideline, both skeptical of the diagnosis, hold that indoor mold growth should not be tolerated. The defensible plan is remediation, a period living away from the building, and dated symptom tracking.

The drivers under a stalled patient usually stack three deep. Barrier injury at the gut wall, the first brain in the book’s frame, is supported by mycotoxin data from cell, tissue and animal models. Immune activation is established for the allergic and infectious syndromes. The third is structural: in a 1989 survey of 597 households, mold growth appeared in 45.9% of dwellings, and repair falls to whoever owns the building rather than whoever breathes in it.

Documentation and where Measura fits

Stress is not a finding; it records the point at which the workup ended. A defensible chart carries the exposure history with dates, the location-dependent symptom pattern, the non-mold causes excluded, and objective function measures that can be repeated after the building is repaired. That structure belongs in the annual wellness visit and in standing orders with explicit selection criteria rather than in an unvalidated assay.

Measura’s role is host function, not exposure. Laboratory panels address alternative explanations for incomplete recovery, including the metabolic terrain and metaflammation. Cardiac autonomic reflex tests and heart rate variability quantify autonomic regulation when fatigue or orthostatic complaints dominate. Cognitive assessment documents cognition when concentration complaints are prominent and pairs with fall prevention workflows. None of these attributes a symptom to a building. Measured before remediation and repeated after, they turn the patient’s away-better observation into a documented n-of-1 comparison. The graded primary studies are in the book companion.

Frequently asked questions

References

• Bush, R. K., Portnoy, J. M., Saxon, A., Terr, A. I., & Wood, R. A. (2006). The medical effects of mold exposure. The Journal of Allergy and Clinical Immunology, 117(2), 326-333. https://doi.org/10.1016/j.jaci.2005.12.001
• Leikin, J., Holland, M. G., Kurt, T. L., McKay, C. A., & Stolbach, A. I. (American College of Medical Toxicology). (2025). ACMT position statement: Medical toxicology considerations in the diagnosis and treatment of patients with concerns about mold-related inhalation exposures. https://www.acmt.net/wp-content/uploads/2025/08/PS_250813_ACMT-Position-Statement-Mold-Related-Inhalation-Exposures.pdf
• Kawamoto, M., & Page, E. (2015). Notes from the field: Use of unvalidated urine mycotoxin tests for the clinical diagnosis of illness — United States, 2014. MMWR. Morbidity and Mortality Weekly Report, 64(6), 157-158. https://pubmed.ncbi.nlm.nih.gov/25695323/
• Catania, A., Airaghi, L., Garofalo, L., Cutuli, M., & Lipton, J. M. (1998). The neuropeptide alpha-MSH in HIV infection and other disorders in humans. Annals of the New York Academy of Sciences, 840, 848-856. https://doi.org/10.1111/j.1749-6632.1998.tb09622.x
• Dooley, M., Vukelic, A., & Jim, L. (2024). Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment. Annals of Medicine and Surgery (2012), 86(12), 7248-7254. https://doi.org/10.1097/MS9.0000000000002718
• Shoemaker, R. C., & House, D. E. (2006). Sick building syndrome (SBS) and exposure to water-damaged buildings: time series study, clinical trial and mechanisms. Neurotoxicology and Teratology, 28(5), 573-588. https://doi.org/10.1016/j.ntt.2006.07.003
• Jimenez-Barbosa, I. A., Di Lizio, S., Ahn, S. B., Heng, B., Kim, J., Watson, A. J., & Khuu, S. K. (2026). Assessment of visual contrast sensitivity in biotoxin-exposed individuals using four testing methods. Annals of Medicine, 58(1), 2646821. https://doi.org/10.1080/07853890.2026.2646821
• Sauni, R., Verbeek, J. H., Uitti, J., Jauhiainen, M., Kreiss, K., & Sigsgaard, T. (2015). Remediating buildings damaged by dampness and mould for preventing or reducing respiratory tract symptoms, infections and asthma. Cochrane Database of Systematic Reviews, 2015(2), CD007897. https://doi.org/10.1002/14651858.CD007897.pub3
• Platt, S. D., Martin, C. J., Hunt, S. M., & Lewis, C. W. (1989). Damp housing, mould growth, and symptomatic health state. BMJ (Clinical Research Ed.), 298(6689), 1673-1678. https://doi.org/10.1136/bmj.298.6689.1673

Related reading

• Intestinal Methanogen Overgrowth: A Measurement-First Workup
• SIBO Recurrence Rate: Screening the Host After the Kill
• Laboratory Panels

Intestinal Methanogen Overgrowth: A Measurement-First Workup

Intestinal methanogen overgrowth is diagnosed by breath methane, not a stool census: under the North American Consensus, methane of at least 10 ppm at any point is positive. A single fasting value of 10 ppm or more reproduced the full two-hour result at 86.4% sensitivity and 100% specificity.

Exhaled methane is one of the few gut measures that reads microbial activity rather than membership. Its criteria, its error bars and its metabolic company all shape how a primary care workup should run.

Intestinal methanogen overgrowth is one of the few gut diagnoses anchored to a measure of microbial activity rather than a species inventory. Human cells produce no hydrogen or methane, so every molecule on a breath sample reflects fermentation in the patient that day. The practical position is blunt: the census is not the activity, and exhaled hydrogen and methane say more than culture or a commercial stool report. Breath testing is not part of the Measura library; it is ordered through gastroenterology or a reference laboratory. The video Your Gut Bacteria Breathe Out Through Your Mouth presents the argument, and the protocol, performance and workflow detail follow here.

Why can’t a stool test diagnose methanogen overgrowth?

When a European expert group sent one fecal specimen to six commercial microbiome services, diversity verdicts split three ways and the same genus was reported at 14.16% and 8.41%, labeled high at one laboratory and low at another. No service disclosed its reference cohort. The deeper problem survives better laboratories: paired DNA and RNA sequencing in adult men found only 81 of 182 prevalent pathways transcribed, and methanogenesis was encoded and transcribed solely by Methanobrevibacter, rare in DNA yet among the most heavily transcribed pathways. A census averages that signal away. Consensus authors also state that current small bowel culture techniques are not satisfactory for this assessment.

I argued for the RNA readout myself, and it has a limit worth stating. Metatranscriptomic profiles vary within a person nearly as much as between people, so a single sample is durable for composition but not for activity. Breath methane is the activity measure that holds still.

What are the breath test criteria for intestinal methanogen overgrowth?

A breath result without substrate, dose, cutoff and timing is not a finding. The North American Consensus specifies lactulose 10 g or glucose 75 g for overgrowth; a hydrogen rise of at least 20 ppm from baseline by 90 minutes is positive, and methane of at least 10 ppm at any point is positive. Hydrogen, methane and carbon dioxide should be measured together, because methanogens consume four hydrogen molecules per methane molecule and can flatten the hydrogen curve. Before the consensus, thirteen case-control studies had used thirteen different methodologies.

Two older conventions are gone. After reviewing more than 15,000 lactulose tests, the consensus ruled that a double peak has no validity, and it advised against using breath testing to estimate orocecal transit. Preparation calls for four weeks off antibiotics and an 8–12 hour fast; it is not necessary to stop proton pump inhibitors, and no position was reached on probiotics.

The single fasting methane

For methane specifically, the long protocol adds little. A single fasting value of at least 10 ppm reproduced the full two-hour result at 86.4% sensitivity and 100% specificity, correlated with stool Methanobrevibacter smithii load at R = 0.65, stayed stable for 14 weeks untreated and fell within two days of antibiotics. At 5 ppm and above, the fasting value predicted excessive methane production at 96.1% sensitivity and 99.7% specificity. Clinical association is consistent: breath methane and constipation carry an odds ratio of 3.51, and methane-predominant overgrowth has five times the likelihood of constipation of hydrogen-predominant disease. Severity separation is statistically real and clinically small, 5.65 against 4.32 on the constipation scale.

How accurate is breath testing for overgrowth?

Hydrogen-based criteria are where the error bars widen. In 139 symptomatic patients who had both duodenal aspirate culture and glucose breath testing, concordance was 65.5%, and breath sensitivity against culture was 42% with specificity 84%. Pooled case-control data show 35.5% positivity in irritable bowel syndrome and 29.7% in controls. Scintigraphy classified 48% of positive glucose tests as colonic fermentation. A center that adopted the consensus protocol saw positivity move from 29.7% to 39.5%, with the added positives arriving through methane criteria. The society update states that the definition lacks precision and that treatment after a positive test remains largely empiric.

The best evidence that clearing methane changes symptoms is thin: 31 subjects in the intention-to-treat analysis, no true placebo arm, entry at methane above 3 ppm, and a post-hoc split of 15 patients. That is the evidence tier. A mediocre measurement of the right process still outperforms empiric treatment aimed at a name on a stool report.

Sequencing the workup

• Rule out overgrowth before lactose or fructose breath testing. In lactulose-positive irritable bowel syndrome, fructose positivity dropped from 62 to 3% once a week of antibiotics had been given.
• Exclude inflammation early. In adults with irritable bowel symptoms, C-reactive protein of 0.5 or less or calprotectin of 40 µg/g or less leaves an inflammatory bowel disease probability of 1% or lower. Calprotectin does not detect overgrowth.
• Consider fecal elastase-1 where maldigestion is plausible: 0.94 sensitivity and 0.69 specificity at 200 µg/g, with watery stool diluting the result.
• Report which gases were measured. No consensus body has set a hydrogen sulfide threshold, so a sulfide cutoff is the laboratory’s own.

The metabolic overlap Measura can measure

Methane positivity keeps turning up in metabolically abnormal patients. In eleven prediabetic adults with obesity, mean BMI 35.17, and positive for methane, a 10-day neomycin and rifaximin course eliminated breath methane in eight, and in those eight LDL, total cholesterol and 120-minute insulin on glucose tolerance testing improved. Energy harvest did not change, stool methanogen counts did not fall significantly, and there was no control arm. It is a hypothesis, and it supports measuring the metabolic side rather than assuming it. The society update adds a laboratory signature: elevated folate with, less commonly, vitamin B12 deficiency.

Measura [Cardiometabolic and Autonomic Health Analysis] contributes on that side, with results returned to the ordering physician:

• Laboratory panels for insulin with glucose, lipids and nutritional markers in a methane-positive patient with prediabetes or obesity.
• Bioimpedance body composition to separate lean and fat compartments where BMI is the only adiposity figure in the chart.

There is also an incentive problem to name. Commercial stool kits are built around repeat purchase and colored dashboards, while a breath measure that settles the question generates nothing further to sell. That structure explains why patients arrive with folders of reports and no gas measurement. For practice design, see selection criteria and standing orders for screening; the metabolic case in pain populations is in why metabolic health belongs in a pain practice. The patient version is the methane breath test explained, and the full study limits are in the Angry Gut companion deep dive for Chapter 25.

Frequently asked questions

References

• Rezaie, A., Buresi, M., Lembo, A., Lin, H., McCallum, R., Rao, S., Schmulson, M., Valdovinos, M., Zakko, S., & Pimentel, M. (2017). Hydrogen and methane-based breath testing in gastrointestinal disorders: The North American Consensus. The American Journal of Gastroenterology, 112(5), 775-784. https://doi.org/10.1038/ajg.2017.46
• Takakura, W., Pimentel, M., Rao, S., Villanueva-Millan, M. J., Chang, C., Morales, W., Sanchez, M., Torosyan, J., Rashid, M., Hosseini, A., Wang, J., Leite, G., Kowalewski, E., Mathur, R., & Rezaie, A. (2022). A single fasting exhaled methane level correlates with fecal methanogen load, clinical symptoms and accurately detects intestinal methanogen overgrowth. The American Journal of Gastroenterology, 117(3), 470-477. https://doi.org/10.14309/ajg.0000000000001607
• Kunkel, D., Basseri, R. J., Makhani, M. D., Chong, K., Chang, C., & Pimentel, M. (2011). Methane on breath testing is associated with constipation: A systematic review and meta-analysis. Digestive Diseases and Sciences, 56(6), 1612-8. https://doi.org/10.1007/s10620-011-1590-5
• Erdogan, A., Rao, S. S. C., Gulley, D., Jacobs, C., Lee, Y. Y., & Badger, C. (2015). Small intestinal bacterial overgrowth: Duodenal aspiration vs glucose breath test. Neurogastroenterology and Motility, 27(4), 481-9. https://doi.org/10.1111/nmo.12516
• Baker, J. R., Chey, W. D., Watts, L., Armstrong, M., Collins, K., Lee, A. A., Dupati, A., Menees, S., Saad, R. J., Harer, K., & Hasler, W. L. (2021). How the North American Consensus protocol affects the performance of glucose breath testing for bacterial overgrowth versus a traditional method. The American Journal of Gastroenterology, 116(4), 780-787. https://doi.org/10.14309/ajg.0000000000001110
• Quigley, E. M. M., Murray, J. A., & Pimentel, M. (2020). AGA Clinical Practice Update on small intestinal bacterial overgrowth: Expert review. Gastroenterology, 159(4), 1526-1532. https://doi.org/10.1053/j.gastro.2020.06.090
• Mathur, R., Chua, K. S., Mamelak, M., Morales, W., Barlow, G. M., Thomas, R., Stefanovski, D., Weitsman, S., Marsh, Z., Bergman, R. N., & Pimentel, M. (2016). Metabolic effects of eradicating breath methane using antibiotics in prediabetic subjects with obesity. Obesity (Silver Spring), 24(3), 576-82. https://doi.org/10.1002/oby.21385
• Abu-Ali, G. S., Mehta, R. S., Lloyd-Price, J., Mallick, H., Branck, T., Ivey, K. L., Drew, D. A., DuLong, C., Rimm, E., Izard, J., Chan, A. T., & Huttenhower, C. (2018). Metatranscriptome of human faecal microbial communities in a cohort of adult men. Nature Microbiology, 3(3), 356-366. https://doi.org/10.1038/s41564-017-0084-4
• Menees, S. B., Powell, C., Kurlander, J., Goel, A., & Chey, W. D. (2015). A meta-analysis of the utility of C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and fecal lactoferrin to exclude inflammatory bowel disease in adults with IBS. The American Journal of Gastroenterology, 110(3), 444-54. https://doi.org/10.1038/ajg.2015.6
• Pimentel, M., Chang, C., Chua, K. S., Mirocha, J., DiBaise, J., Rao, S., & Amichai, M. (2014). Antibiotic treatment of constipation-predominant irritable bowel syndrome. Digestive Diseases and Sciences, 59(6), 1278-85. https://doi.org/10.1007/s10620-014-3157-8

Related reading

• Food Addiction Screening: What the Questionnaire Cannot Measure
• CIRS Diagnosis: What the Mold Evidence Supports in Screening
• Laboratory Panels

Food Addiction Screening: What the Questionnaire Cannot Measure

A positive craving questionnaire documents what a patient reports. It says nothing about insulin, energy expenditure or autonomic tone, and those are the variables a clinician can actually follow.

Food addiction screening is scored with a self-report instrument, not a biomarker. Pooled across 272 studies, prevalence on the standard scale is 20%, and it reaches 55% in samples where binge eating is already diagnosed. Whether the construct is valid remains open; many defining features of drug addiction do not appear with food, even if the two share neural machinery. A positive screen therefore documents an experience accurately and a disease provisionally. For the clinician, the useful question is what sits underneath it that can be measured and followed. The video Your Sugar Craving Has a Schedule lays out the gut-to-brainstem route; the screening and workup implications follow.

What does a food addiction screen measure, and who was it tested on?

The pooled prevalence carries its own fine print. Clinical samples scored higher than community samples, as expected for a tool used inside eating-disorder programs. Age coverage is thin: two included studies enrolled only children, and none enrolled only older adults. A geriatric patient with a positive score is being compared against almost no one.

In the cohort where the microbiome was sequenced alongside the scale, 19 of 105 women screened positive. Seventeen of those 19 had obesity, against 34 of the 86 who screened negative, and mean BMI ran 35.6 with the label against 29.1 without it. The instrument tracked adiposity more than anything else measured. Alpha diversity did not differ between the groups, which is worth knowing before a patient arrives with a direct-to-consumer stool report as supporting evidence.

Why the framing changes management

The distinction is clinical rather than semantic. If the pattern is addiction in the strict sense, management is abstinence and indefinite relapse prevention. If it is a preference written by exposure, management is changing the exposure and allowing time. The evidence favors the second model more than most clinicians expect.

Normal-weight adults given a daily high-fat, high-sugar snack for eight weeks showed lower preference for low-fat food and greater neural response to food, with no relationship to body weight or metabolic parameters. Separately, inpatients offered ultra-processed and unprocessed diets matched on presented calories, energy density, macronutrients, sugar, sodium and fiber ate 508 kcal a day more on the ultra-processed arm, with the excess coming from carbohydrate and fat and protein intake flat. Weight change tracked intake at r = 0.8.

I spent years delivering eat-less counseling to people whose appetite had been reshaped by the food supply, and I documented the failures as adherence problems. The snack trial is what reframed that for me: preference moved in people whose weight did not. The economic driver belongs in the same note. Refined carbohydrate is the cheapest calorie available because agricultural policy subsidized it, and it is formulated to succeed against the reward circuitry those trials measured.

What does a food addiction questionnaire miss?

A craving history is a reason to measure metabolic and autonomic state, not a substitute for it. Measura [Cardiometabolic and Autonomic Health Analysis] does not score food addiction, sequence stool or treat; it produces measurements that return to the ordering physician.

• Insulin sensitivity. In 45 adults who were not habitual sweetener users, sucralose consumed with carbohydrate, but not sucralose alone, reduced insulin sensitivity over two weeks, and taste preference did not change. An adolescent arm was stopped after HOMA-IR rose above 12.9 in two of three participants. A history of sweetened beverages alongside starch justifies laboratory panels that pair insulin with glucose rather than glucose alone.
• Measured energy expenditure. When intake is the clinical argument, indirect calorimetry replaces a predictive equation with the patient’s measured resting metabolic rate, which gives calorie counseling a denominator the patient cannot dispute.
• Autonomic baseline. Heart rate variability reflects autonomic balance. It is not a readout of vagal gut signaling, and the vagus itself is a weak lever: in 239 patients randomized to reversible vagal blockade or sham, excess weight loss was 24.4% against 15.9% and both co-primary endpoints were missed. HRV documents the terrain those signals travel through.

Who should be tested after a positive food addiction screen?

The reasonable candidates are patients with a positive score and obesity, patients with a binge eating diagnosis, patients whose craving pattern is time-locked and carbohydrate-specific, and patients whose history includes daily sweetened drinks with starchy food. Most will already carry insulin resistance, a mood disorder, disrupted sleep or polypharmacy, which is precisely why no clean trial describes them. Mechanism is the operative evidence tier for this population, and it is sufficient to justify measurement. For context on the denominator, fewer than 7% of US adults are metabolically healthy on the tighter criteria applied to NHANES after 2021, down from fewer than 12.2% on NHANES 2009–2016. In our clinic the figure is under 3%, practice-reported figures from our own population, not trial outcomes, and individual results vary. Formal criteria are outlined in selection criteria.

Reading craving outcomes when a GLP-1 agonist is on board

Semaglutide supplies the strongest human evidence that a gut-derived signal changes food preference. In 72 adults with obesity over 20 weeks, ad libitum intake fell 35%, and after correction for body weight there was no evidence of delayed gastric emptying. At two years, sweet-food craving improvement did not persist while savory craving and craving control did. Craving scores improved in step with weight loss, the eating questionnaire went to a subgroup of 88 on drug and 86 on placebo, and multiplicity was not controlled. Craving response and weight change cannot be separated in that dataset. A pre-treatment metabolic and autonomic baseline gives an independent reference that does not move simply because weight does.

Building it into existing workflow

Craving history fits the dietary and functional review already present in the annual wellness visit. A standing protocol that triggers insulin, measured resting energy expenditure and heart rate variability after a positive screen makes the response reproducible across clinicians; the logic is laid out in making screening reproducible. Results filed as structured data support longitudinal tracking and quality reporting. The patient-facing explanation is in what causes sugar cravings, and the full study-by-study limits are in the Angry Gut companion deep dive for Chapter 24.

Frequently asked questions

References

• Praxedes, D. R. S., Silva-Júnior, A. E., Macena, M. L., Oliveira, A. D., Cardoso, K. S., Nunes, L. O., Monteiro, M. B., Melo, I. S. V., Gearhardt, A. N., & Bueno, N. B. (2022). Prevalence of food addiction determined by the Yale Food Addiction Scale and associated factors: a systematic review with meta-analysis. European Eating Disorders Review, 30(2), 85-95. https://doi.org/10.1002/erv.2878
• Fletcher, P. C., & Kenny, P. J. (2018). Food addiction: a valid concept?. Neuropsychopharmacology, 43(13), 2506-2513. https://doi.org/10.1038/s41386-018-0203-9
• Dong, T. S., Mayer, E. A., Osadchiy, V., Chang, C., Katzka, W., Lagishetty, V., Gonzalez, K., Kalani, A., Stains, J., Jacobs, J. P., Longo, V. D., & Gupta, A. (2020). A distinct brain-gut-microbiome profile exists for females with obesity and food addiction. Obesity, 28(8), 1477-1486. https://doi.org/10.1002/oby.22870
• Edwin Thanarajah, S., DiFeliceantonio, A. G., Albus, K., Kuzmanovic, B., Rigoux, L., Iglesias, S., Hanßen, R., Schlamann, M., Cornely, O. A., Brüning, J. C., Tittgemeyer, M., & Small, D. M. (2023). Habitual daily intake of a sweet and fatty snack modulates reward processing in humans. Cell Metabolism, 35(4), 571-584.e6. https://doi.org/10.1016/j.cmet.2023.02.015
• Hall, K. D., Ayuketah, A., Brychta, R., Cai, H., Cassimatis, T., Chen, K. Y., Chung, S. T., Costa, E., Courville, A., Darcey, V., Fletcher, L. A., Forde, C. G., Gharib, A. M., Guo, J., Howard, R., Joseph, P. V., McGehee, S., Ouwerkerk, R., Raisinger, K., … Zhou, M. (2019). Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metabolism, 30(1), 67-77.e3. https://doi.org/10.1016/j.cmet.2019.05.008
• Dalenberg, J. R., Patel, B. P., Denis, R., Veldhuizen, M. G., Nakamura, Y., Vinke, P. C., Luquet, S., & Small, D. M. (2020). Short-term consumption of sucralose with, but not without, carbohydrate impairs neural and metabolic sensitivity to sugar in humans. Cell Metabolism, 31(3), 493-502.e7. https://doi.org/10.1016/j.cmet.2020.01.014
• Ikramuddin, S., Blackstone, R. P., Brancatisano, A., Toouli, J., Shah, S. N., Wolfe, B. M., Fujioka, K., Maher, J. W., Swain, J., Que, F. G., Morton, J. M., Leslie, D. B., Brancatisano, R., Kow, L., O’Rourke, R. W., Deveney, C., Takata, M., Miller, C. J., Knudson, M. B., … Billington, C. J. (2014). Effect of reversible intermittent intra-abdominal vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial. JAMA, 312(9), 915-922. https://doi.org/10.1001/jama.2014.10540
• Friedrichsen, M., Breitschaft, A., Tadayon, S., Wizert, A., & Skovgaard, D. (2021). The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity. Diabetes, Obesity & Metabolism, 23(3), 754-762. https://doi.org/10.1111/dom.14280
• Wharton, S., Batterham, R. L., Bhatta, M., Buscemi, S., Christensen, L. N., Frias, J. P., Jódar, E., Kandler, K., Rigas, G., Wadden, T. A., & Garvey, W. T. (2023). Two-year effect of semaglutide 2.4 mg on control of eating in adults with overweight/obesity: STEP 5. Obesity, 31(3), 703-715. https://doi.org/10.1002/oby.23673

Related reading

• Cholecystectomy Complications: The Cohort Nobody Re-Screens
• Intestinal Methanogen Overgrowth: A Measurement-First Workup
• Laboratory Panels

Cholecystectomy Complications: The Cohort Nobody Re-Screens

Bile acid diarrhea after gallbladder surgery is testable and treatable, yet 2.1% of patients are ever investigated for it. The cohort is easy to define and almost never measured.

Cholecystectomy complications are counted at thirty days and then stop being counted. The one that surfaces months later is bile acid diarrhea, which has a measured mechanism, an available test and an effective treatment, and it is investigated in a small fraction of patients. The physiology is set out on video in Bile Is a Hormone, Not Soap, chapter 23 of The Angry Gut (Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes). The operational question for a practice is narrower: which post-surgical patients deserve a second look, what the ejection fraction can and cannot decide, and what is worth measuring in the cohort that arrives after the gallbladder is gone.

The cholecystectomy complication that leaves the denominator

A multicenter audit found that of 9,439 patients who underwent the operation, 202, or 2.1%, were ever investigated for postoperative diarrhea. Among those investigated, 62.8% met criteria for bile acid diarrhea, and the median interval from surgery to the scan was 672 days. Read the direction, not the rate: only patients a clinician already suspected were referred, there was no comparison group who kept their gallbladders, and the positive proportion therefore describes the quality of the suspicion.

Prospective counting gives the cleaner estimate. Questionnaires before elective laparoscopic cholecystectomy and again at twelve months, against people coming through a health check, found new functional diarrhea in 6.6% against 0.2%, new dyspepsia in 14.8% against 6.9%, and new chronic abdominal pain in 11.9% against 4.4%. Most pre-existing symptoms improved; chronic diarrhea was the exception. The detail worth keeping is that somatization predicted the new dyspepsia and the new pain but not the new diarrhea, which is the finding that should slow down a functional label.

Why does diarrhea follow gallbladder removal?

The tidy story, that removing the tissue richest in FGF19 causes the diarrhea, was tested head-on and failed: gallbladder hormone content showed no correlation with bowel habit or stool consistency. What survives is delivery timing. After surgery bile acid synthesis rises at least two-fold and the diurnal peak of the hormone flattens, yet serum bile acids, cholesterol and triglycerides did not move in that work, which is exactly why a routine panel gives no hint of it. Bile arriving continuously into a bowel built for a postprandial bolus delivers more to the colon, where bile acids drive secretion.

I ordered ejection fractions for years and treated the cutoff as physiology rather than protocol, which was my mistake to make and worth stating before correcting anyone else’s.

Does the ejection fraction predict relief after gallbladder surgery?

Across 60 healthy volunteers at four centers, the lower limit of normal for the stimulated ejection fraction came out at 38%, and reproducibility depended entirely on the infusion: a coefficient of variation of 19% with the 60-minute infusion, and 52% with the short infusion in common use. In 93 consecutive patients with documented dyskinesia, the stimulated fraction was statistically indistinguishable between those who improved after surgery and those who did not. What predicted relief was the symptom pattern, with classic biliary pain 22 times more likely to be relieved. The operation is the right answer for a real biliary indication; the failure mode is the atypical patient selected on a number that cannot separate the two.

The terrain that arrives with the patient

In a population cohort of 4,307 people, metabolic syndrome ran 67.2% among those who had lost a gallbladder against 51.9% among those who had not, and moderate-to-severe fatty liver 42.7% against 34.2%, with imaging a median of ten years after surgery. Adjustment for metabolic factors removed both associations. That result is usually read as exoneration of the operation; the more useful reading for a practice is that this cohort was metabolically sick before the surgeon met them. Gallstones grow in bile made under hyperinsulinemia and stored in a reservoir rarely asked to empty, so the stone is a marker of the terrain and the surgery leaves the terrain in place. A cohort can adjust that away. A clinic cannot, because it walks in with the patient, and metaflammation in the first brain does not resolve because an organ was removed.

What is not a Measura test, and what is

Measura [Cardiometabolic and Autonomic Health Analysis] does not perform bile acid retention testing, gallbladder ultrasound, cholescintigraphy or breath testing, and it does not diagnose. Retention scanning is not licensed in the United States, which in practice leaves a supervised therapeutic trial with a defined endpoint and stop date as the usual route, decided by the treating clinician or gastroenterologist. What the protocol contributes is the metabolic and functional measurement this cohort almost never receives:

• Laboratory panels characterize glycemic and lipid status and liver markers, which is the terrain that produced the stone and predicts the next decade.
• Bioimpedance body composition separates lean from fat mass in patients who have been avoiding fat and losing muscle, which redirects counseling toward protein and loading.
• Indirect calorimetry replaces a predicted resting expenditure with a measured one before any dietary target is set.
• Where postprandial symptoms coexist with dizziness or presyncope, autonomic nervous system testing documents the regulatory response instead of leaving it described.

Standing orders and documentation

This cohort is easy to define, which makes it easy to protocolize. A standing order can attach a bowel-habit review and cardiometabolic measurement to any patient with a prior cholecystectomy and new or persistent loose stools, so the second look does not depend on who is in the room. The metabolic findings sit naturally in the annual wellness visit and support the measures set out in HEDIS and value-based care, while discrete results in the chart, rather than a scanned summary, are what make repeat measurement usable; see getting results into the record. Selection thresholds for the wider protocol are in the selection criteria.

The full evidence file, including the null results that constrain the mechanism, is in the book companion for The Angry Gut. The patient explanation is what bile actually does.

Frequently asked questions

References

• Farrugia, A., Attard, J. A., Hanmer, S., Bullock, S., McKay, S., Al-Azzawi, M., Ali, R., Bond-Smith, G., Colleypriest, B., Dyer, S., Masterman, B., Okocha, M., Osborne, A., Patel, R., Sallam, M., Selveraj, E., Shalaby, S., Sun, W., Todd, F., … Arasaradnam, R. P. (2021). Rates of bile acid diarrhoea after cholecystectomy: A multicentre audit. World Journal of Surgery, 45(8), 2447-2453. https://doi.org/10.1007/s00268-021-06147-8
• Chang, J. Y., Jung, H.-K., Moon, C. M., Kim, S.-E., Shim, K.-N., Jung, S.-A., & Min, S. K. (2023). Development of functional gastrointestinal disorder symptoms following laparoscopic cholecystectomy: A prospective cohort study. Frontiers in Medicine, 10, 1248465. https://doi.org/10.3389/fmed.2023.1248465
• Farrugia, A., Williams, N., Khan, S., & Arasaradnam, R. P. (2024). Bile acid diarrhoea and metabolic changes after cholecystectomy: A prospective case-control study. BMC Gastroenterology, 24(1), 282. https://doi.org/10.1186/s12876-024-03368-8
• Barrera, F., Azócar, L., Molina, H., Schalper, K. A., Ocares, M., Liberona, J., Villarroel, L., Pimentel, F., Pérez-Ayuso, R. M., Nervi, F., Groen, A. K., & Miquel, J. F. (2015). Effect of cholecystectomy on bile acid synthesis and circulating levels of fibroblast growth factor 19. Annals of Hepatology, 14(5), 710-721. https://pubmed.ncbi.nlm.nih.gov/26256900/
• Ziessman, H. A., Tulchinsky, M., Lavely, W. C., Gaughan, J. P., Allen, T. W., Maru, A., Parkman, H. P., & Maurer, A. H. (2010). Sincalide-stimulated cholescintigraphy: A multicenter investigation to determine optimal infusion methodology and gallbladder ejection fraction normal values. Journal of Nuclear Medicine, 51(2), 277-281. https://doi.org/10.2967/jnumed.109.069393
• Carr, J. A., Walls, J., Bryan, L. J., & Snider, D. L. (2009). The treatment of gallbladder dyskinesia based upon symptoms: Results of a 2-year, prospective, nonrandomized, concurrent cohort study. Surgical Laparoscopy, Endoscopy & Percutaneous Techniques, 19(3), 222-226. https://doi.org/10.1097/SLE.0b013e3181a74690
• Latenstein, C. S. S., Alferink, L. J. M., Darwish Murad, S., Drenth, J. P. H., van Laarhoven, C. J. H. M., & de Reuver, P. R. (2020). The association between cholecystectomy, metabolic syndrome, and nonalcoholic fatty liver disease: A population-based study. Clinical and Translational Gastroenterology, 11(4), e00170. https://doi.org/10.14309/ctg.0000000000000170
• Wedlake, L., A’Hern, R., Russell, D., Thomas, K., Walters, J. R. F., & Andreyev, H. J. N. (2009). Systematic review: The prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Alimentary Pharmacology & Therapeutics, 30(7), 707-717. https://doi.org/10.1111/j.1365-2036.2009.04081.x

Related reading

• Pesticide Exposure Testing: What to Measure When You Cannot
• Food Addiction Screening: What the Questionnaire Cannot Measure
• Laboratory Panels

Pesticide Exposure Testing: What to Measure When You Cannot

Pesticide exposure testing has no validated endpoint for gut effects, and a spot urine level reports the last meal rather than the decade. Measure the terrain instead: laboratory panels, bioimpedance body composition, indirect calorimetry and sudomotor testing each carry a management decision.

Patients ask for a residue test that does not exist. The mechanism is measured, the human endpoint is not, and the screening opportunity sits in the metabolic and autonomic terrain the patient brought with them.

A patient who has read about herbicide residue arrives asking for pesticide exposure testing, and there is no panel that answers her question. No validated method exists for the endpoint she cares about, the effect of a dietary residue on her gut community, and a spot urine level reports her last meal rather than her decade. The mechanistic case is laid out on video in The Antibiotic on Your Salad, chapter 22 of The Angry Gut (Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes). What follows is the screening question: what to tell her, whom to test, and which measurements change management.

What the mechanism claim is, and what it is not

Glyphosate inhibits a single enzyme in the shikimate pathway. Human cells lack the pathway entirely, which is the basis of the human safety assessment and is correct as far as it goes. Bacteria do not lack it. A structural classification of the enzyme, run over thousands of organisms, assigned 54% of core gut species to the vulnerable form, a proportion its authors flagged as conservative. The counter-analysis matters equally: an expression-based census of reference genomes covering most assigned microbial abundance in human fecal metagenomes found the pathway largely incomplete and largely silent, with some organisms possibly degrading the compound rather than being inhibited by it.

The animal work is where the argument has teeth. Rats dosed for ninety days at the European acceptable daily intake accumulated shikimic acid and its dehydro form in the cecum, a substrate pile-up behind the target enzyme in a living mammal at a regulated dose, with no reflection of those cecal metabolites in serum. A mouse study at roughly the American intake reported altered microbiota with inflammatory markers. The European peer review addressed the microbiome question directly and concluded that without standardized regulatory guidance or harmonized criteria, no definitive conclusion can be drawn from the available studies. That is the honest state of it: a measured mechanism, an unmeasured endpoint in people.

Why is there no pesticide exposure test to order?

Three reasons worth having at hand in the room. First, no study relates measured exposure to gut community composition in a human being, so a result would have no interpretive frame. Second, urinary levels are dominated by recent intake: levels were significantly lower in people who had fasted more than eight hours, in the same national sample of 2,310 specimens where 81.2% of Americans aged six and older tested positive. Third, exposure is to a formulation rather than the molecule, and commercial formulations were more cytotoxic than their active ingredients against human cells, while co-formulant identity is treated as confidential and is often described incorrectly in published work. A test of the pure compound, even if it existed, would be answering a question the patient is not living in.

Who to test, and on what trigger

The productive move is to stop chasing the exposure and start measuring the terrain the patient actually presents with. Reasonable triggers for cardiometabolic and autonomic measurement in this population:

• Unexplained bowel symptoms lasting months with a normal structural workup, particularly alongside central adiposity, hypertension or a family history of type 2 diabetes.
• A recent rebuilding window: repeated antibiotic courses, abdominal surgery or an inpatient stay in the preceding year.
• Distal sensory symptoms accompanying the bowel complaint, where small-fiber function has never been documented.
• Patients already committed to dietary change, who need a baseline rather than a lecture, as set out in the selection criteria.

The rebuilding window is the part I would defend hardest, and it is a mechanistic argument rather than a trial result. An expression census describes a settled community at steady state. It does not describe recolonization, when a depleted community must synthesize aromatic amino acids instead of scavenging them. Patients arriving in your office after antibiotics or surgery are living in exactly that interval.

What each finding changes

Measura [Cardiometabolic and Autonomic Health Analysis] holds no residue assay, no urine herbicide level and no stool sequencing, and it does not diagnose. What it returns to the ordering clinician is the measurable terrain, and each result carries a decision with it.

• Laboratory panels establish fuel handling, inflammatory and organ status, converting a vague exposure worry into a treatable metabolic problem. Which laboratory runs the blood work is documented separately.
• Bioimpedance body composition identifies low lean mass in normal-BMI patients, which redirects the plan toward protein adequacy and resistance loading rather than restriction.
• Indirect calorimetry replaces a predicted resting expenditure with a measured one, which changes the dietary prescription and the follow-up target.
• Sudomotor testing documents small-fiber sweat-gland function, supporting or excluding a neuropathic contribution before further gastroenterology referral.
• Where balance, gait or memory concerns coexist, pair the panel with cognitive assessment and fall prevention.

Documentation and workflow

An exposure conversation that ends in measurement is easier to run from a protocol than from improvisation. A standing order can attach laboratory, body composition and small-fiber testing to a defined trigger, so the request does not depend on which clinician is in the room. Metabolic and functional findings belong in the annual wellness visit record, where they support the quality measures described under MIPS and quality reporting. Discrete results in the chart, rather than a scanned report, are what make repeat measurement interpretable; see getting results into the record.

How to answer the question in clinic

Say the three things that are true and stop. The compound’s entire mechanism is inhibition of an enzyme her bacteria carry and her cells do not. At an accepted dose that enzyme was measurably blocked in the gut of a mammal, and the fingerprint never reached blood, which is where the toxicology package looked. The human study pairing exposure with gut composition has not been run, and its entry criteria would exclude the patient asking. Then offer what is measurable. Declining to test for something is not the same as declining to investigate, and patients can tell the difference.

The full evidence file with the counter-case stated at full strength sits in the book companion for The Angry Gut. The patient-facing explanation is what can actually be measured in you.

Frequently asked questions

References

• Leino, L., Tall, T., Helander, M., Saloniemi, I., Saikkonen, K., Ruuskanen, S., & Puigbò, P. (2021). Classification of the glyphosate target enzyme (5-enolpyruvylshikimate-3-phosphate synthase) for assessing sensitivity of organisms to the herbicide. Journal of Hazardous Materials, 408, 124556. https://doi.org/10.1016/j.jhazmat.2020.124556
• Mesnage, R., & Antoniou, M. N. (2020). Computational modelling provides insight into the effects of glyphosate on the shikimate pathway in the human gut microbiome. Current Research in Toxicology, 1, 25-33. https://doi.org/10.1016/j.crtox.2020.04.001
• Mesnage, R., Teixeira, M., Mandrioli, D., Falcioni, L., Ducarmon, Q. R., Zwittink, R. D., Mazzacuva, F., Caldwell, A., Halket, J., Amiel, C., Panoff, J.-M., Belpoggi, F., & Antoniou, M. N. (2021). Use of shotgun metagenomics and metabolomics to evaluate the impact of glyphosate or Roundup MON 52276 on the gut microbiota and serum metabolome of Sprague-Dawley rats. Environmental Health Perspectives, 129(1), 17005. https://doi.org/10.1289/EHP6990
• Ospina, M., Schütze, A., Morales-Agudelo, P., Vidal, M., Wong, L.-Y., & Calafat, A. M. (2022). Exposure to glyphosate in the United States: Data from the 2013-2014 National Health and Nutrition Examination Survey. Environment International, 170, 107620. https://doi.org/10.1016/j.envint.2022.107620
• Ferguson, S., Mesnage, R., & Antoniou, M. N. (2022). Cytotoxicity mechanisms of eight major herbicide active ingredients in comparison to their commercial formulations. Toxics, 10(11), 711. https://doi.org/10.3390/toxics10110711
• Mesnage, R., Benbrook, C., & Antoniou, M. N. (2019). Insight into the confusion over surfactant co-formulants in glyphosate-based herbicides. Food and Chemical Toxicology, 128, 137-145. https://doi.org/10.1016/j.fct.2019.03.053
• Lehman, P. C., Cady, N., Ghimire, S., Shahi, S. K., Shrode, R. L., Lehmler, H.-J., & Mangalam, A. K. (2023). Low-dose glyphosate exposure alters gut microbiota composition and modulates gut homeostasis. Environmental Toxicology and Pharmacology, 100, 104149. https://doi.org/10.1016/j.etap.2023.104149

Related reading

• Opioid-Induced Constipation: Screening in Long-Term Therapy
• Cholecystectomy Complications: The Cohort Nobody Re-Screens
• Laboratory Panels

Opioid-Induced Constipation: Screening in Long-Term Therapy

Opioid-induced constipation is common, under-reported and usually charted as a nuisance. Structured questioning finds it, and the attention and metabolic burden that travels with long-term therapy needs measurement of its own.

Opioid-induced constipation is among the most predictable consequences of long-term opioid therapy and among the least systematically screened. It is usually charted in a side-effect field, managed with a softener, and not revisited. The chapter video The Pain Pill That Paralyzes Your Gut, from The Angry Gut (Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes), argues that the bowel effect belongs on the problem list. For the treating physician the practical questions are how to find it, how to stratify risk by agent and dose, what the note should reflect, and which associated deficits can be measured in the same patient.

Why does opioid-induced constipation go unreported?

Waiting for patients to volunteer the complaint misses a large share of cases. In 1,200 European cancer pain patients on opioids, 59.5% met Rome IV criteria, and only 61.5% of those self-identified as constipated. Prescribing did not close the gap: 72% had a regular laxative or peripherally acting antagonist prescribed, only 66% took it daily, and newer agents were used relatively rarely. That cohort had no non-opioid comparison group, so part of the burden reflects advanced disease.

A patient survey of 322 people on an opioid plus a laxative found 81% constipated, 45% under three stools a week and 58% straining; a third had missed, decreased or stopped their opioid to defecate. The survey recruited symptomatic patients online, so treat the figures as an upper bound. The operational point survives: a structured bowel question at each renewal visit finds what an open-ended review does not, and it surfaces self-directed dose changes the prescriber otherwise never hears about.

Risk stratification by agent and dose

In a Northwest England cohort of 80,475 non-cancer pain patients, with codeine as reference, severe constipation hazard ratios were morphine 1.59, oxycodone 1.46, fentanyl 1.37 and tramadol 0.80, with combination products highest at 1.85 (95% CI 1.66-2.06). Against under 50 MME daily, the 50 to under 120 band carried 1.95 and the band at 120 and above 1.45 (95% CI 1.32-1.60), an inversion most plausibly explained by prophylaxis and closer monitoring at high dose. The endpoint was an enema or suppository given in hospital, so outpatient burden is undercounted.

The effect reaches the esophagus: 24% of 225 chronic users referred for manometry had opioid-induced esophageal dysfunction, 31% on oxycodone, 28% on hydrocodone and 12% on tramadol. Tolerance develops to analgesia but not to the bowel effect, which persists and requires long-term management. A stable patient on an unchanged dose is therefore not a resolved case.

How is opioid-induced constipation treated?

The peripheral effect is separable from central analgesia. In the COMPOSE trials, naldemedine responders reached 47.6% versus 34.6% and 52.5% versus 33.6% on placebo, against a demanding definition held for 9 of 12 weeks. Overall adverse events matched placebo; gastrointestinal events roughly doubled, 40 versus 18 and 42 versus 20. Neither abstract reports an analgesia endpoint. Across 27 randomized trials and 9,149 patients, naloxone and naldemedine ranked most efficacious, with relative risks of non-response of 0.65 and 0.66.

Class caveats matter. Alvimopan was restricted to inpatient use after an association with myocardial infarction, and naloxegol at 25 mg did not restore codeine-slowed transit in opioid-naive volunteers. Lubiprostone improved bowel movement response, 27.1% versus 18.9%, without quality-of-life benefit and with abdominal pain in 7.1% versus 0%. The 2023 Japanese guidelines place naldemedine as a primary option because conventional laxatives address the stool rather than the receptor. Agent selection is the prescriber’s decision; the screening job is to make sure the problem reaches the list.

What are narcotic bowel syndrome and opioid-induced hyperalgesia?

I was taught that opioids silence the migrating motor complex. Human recordings show intravenous morphine inducing out-of-cycle duodenal phase III-like activity in nine of ten subjects, abolished by atropine: contraction without propagation. Narcotic bowel syndrome, abdominal pain that worsens despite continued or escalating dosing, develops in roughly 6% of long-term users and is considered centrally mediated. Across 27 trials and 1,630 surgical patients, higher intraoperative dosing produced worse postoperative pain, small and below usual clinically important thresholds but consistent in direction. In 67 dose-reduction studies, pain, function and quality of life improved in every fair-quality study measuring them, although only 3 studies were rated good and 51 poor.

The practice position links these through metaflammation: a stagnant first brain feeding systemic inflammation that amplifies central pain. That bridge rests on tissue and animal work. A pilot comparing 18 long-term users with 22 opioid-naive back pain patients found only minor plasma cytokine differences, and plasma is downstream of the mucosa. The social layer compounds it, since patients who avoid eating before going out withdraw, and isolation drives chronic pain.

What to measure beyond the bowel

Transit scintigraphy, antroduodenal manometry and breath testing are gastroenterology studies performed elsewhere, not part of Measura [Cardiometabolic and Autonomic Health Analysis]. Breath tests warrant caution here: in 525 consecutive glucose breath tests, post-surgical patients on more motility-depressing drugs were less likely to test positive (HR 0.752), suggesting the test may track transit speed. What Measura can add in the same patient:

• Cognitive assessment. In the same pilot, long-term users performed significantly worse on attention and reported lower pain self-efficacy. A documented baseline makes later change interpretable and supports fall-risk and functional decisions.
• Laboratory panels and bioimpedance body composition. The diabetes, fatty liver and depression that remove patients from trials are the terrain long-term opioid patients carry; measuring it gives the metabolic side of a pain plan a number.
• Autonomic nervous system testing. The duodenal effect is cholinergic, but cardiovascular and sudomotor autonomic studies do not assess enteric function, and no cited study connects them to constipation. Order them for independent autonomic indications, not as a bowel surrogate.

Documentation and workflow

Move opioid-induced constipation from the side-effect field to the problem list, record stool frequency and straining at each renewal, and document any patient-initiated dose changes. A standing order for screening can attach a cognitive baseline to long-term therapy, and between-visit monitoring carries the bowel question forward. Falls and cognition pair in cognitive assessment and fall prevention, and staffing and workflow covers who asks. The trial-level detail is in The Angry Gut deep dive on the narcotic bowel. The patient version is narcotic bowel syndrome for patients, and PPI and B12 deficiency screening covers acid suppression.

Frequently asked questions

References

• Davies, A., Fagan, N., Gonzalez-Barboteo, J., Chelazzi, C., Economos, G., Elsner, F., Leach, C., Monsen, R. E., Oldenmenger, W. H., Remi, C., van den Beuken-van Everdingen, M., & Wüstefeld, M. (2024). Inadequate management of opioid-induced constipation in European cancer pain patients: Results of a real-world, multicentre, observational study (“E-StOIC”). Supportive Care in Cancer, 32(10), 701. https://doi.org/10.1007/s00520-024-08898-1
• Bell, T. J., Panchal, S. J., Miaskowski, C., Bolge, S. C., Milanova, T., & Williamson, R. (2009). The prevalence, severity, and impact of opioid-induced bowel dysfunction: Results of a US and European patient survey (PROBE 1). Pain Medicine, 10(1), 35-42. https://doi.org/10.1111/j.1526-4637.2008.00495.x
• Yimer, B. B., Soomro, M., McBeth, J., Medina, C. R. R., Lunt, M., Dixon, W. G., & Jani, M. (2025). Comparative risk of severe constipation in patients treated with opioids for non-cancer pain: A retrospective cohort study in Northwest England. BMC Medicine, 23(1), 288. https://doi.org/10.1186/s12916-025-04118-7
• Snyder, D. L., Crowell, M. D., Horsley-Silva, J., Ravi, K., Lacy, B. E., & Vela, M. F. (2019). Opioid-induced esophageal dysfunction: Differential effects of type and dose. The American Journal of Gastroenterology, 114(9), 1464-1469. https://doi.org/10.14309/ajg.0000000000000369
• Hale, M., Wild, J., Reddy, J., Yamada, T., & Arjona Ferreira, J. C. (2017). Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): Two multicentre, phase 3, double-blind, randomised, parallel-group trials. The Lancet Gastroenterology & Hepatology, 2(8), 555-564. https://doi.org/10.1016/S2468-1253(17)30105-X
• Luthra, P., Burr, N. E., Brenner, D. M., & Ford, A. C. (2019). Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: Systematic review and network meta-analysis. Gut, 68(3), 434-444. https://doi.org/10.1136/gutjnl-2018-316001
• Drossman, D., & Szigethy, E. (2014). The narcotic bowel syndrome: A recent update. American Journal of Gastroenterology Supplements, 2(1), 22-30. https://doi.org/10.1038/ajgsup.2014.6
• Albrecht, E., Grape, S., Frauenknecht, J., Kilchoer, L., & Kirkham, K. R. (2020). Low- versus high-dose intraoperative opioids: A systematic review with meta-analyses and trial sequential analyses. Acta Anaesthesiologica Scandinavica, 64(1), 6-22. https://doi.org/10.1111/aas.13470
• Frank, J. W., Lovejoy, T. I., Becker, W. C., Morasco, B. J., Koenig, C. J., Hoffecker, L., Dischinger, H. R., Dobscha, S. K., & Krebs, E. E. (2017). Patient outcomes in dose reduction or discontinuation of long-term opioid therapy: A systematic review. Annals of Internal Medicine, 167(3), 181-191. https://doi.org/10.7326/M17-0598
• Richards, G. C., Lluka, L. J., Smith, M. T., Haslam, C., Moore, B., O’Callaghan, J., & Strong, J. (2018). Effects of long-term opioid analgesics on cognitive performance and plasma cytokine concentrations in patients with chronic low back pain: A cross-sectional pilot study. Pain Reports, 3(4), e669. https://doi.org/10.1097/PR9.0000000000000669

Related reading

• PPI and B12 Deficiency: Screening Long-Term Acid Suppression
• Pesticide Exposure Testing: What to Measure When You Cannot
• Cognitive Assessment

PPI and B12 Deficiency: Screening Long-Term Acid Suppression

Check B12 in patients past two years of continuous PPI use or on high dose, adding magnesium and iron where the history warrants: two or more years of supply raised the odds of B12 deficiency to 1.65, and to 1.95 above 1.5 pills daily.

Acid suppression outlives its indication in a large share of patients. The absorption cost is dose-graded, the rebound is predictable, and both belong on the record before the next medication review.

PPI and B12 deficiency is a dose-graded association that most medication reviews never check, in a drug class that routinely outlives its indication. Estimates of inappropriate proton pump inhibitor prescribing run between 25% and 70%. The clinical argument is laid out in The Heartburn Pill You Can’t Quit, the chapter video for The Angry Gut (Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes). For the treating physician the operational questions are narrower: which long-term users to screen, what a finding changes in management, and how to document it so the review happens again next year.

Retire the hypochlorhydria model of reflux first

I taught the low-acid explanation of reflux for years, and it does not survive human testing. Under a week of twice-daily omeprazole, impedance-measured reflux episodes did not decline; acid reflux fell from 45% to 3% while non-acid reflux rose from 55% to 97%. In a separate series of 100 patients with manometry and pH studies, gastrin correlated with neither the DeMeester score nor sphincter pressure.

The drivers are mechanical. Transient sphincter relaxation rate tracks intragastric pressure at r = 0.91. Across 84 subjects in three weight categories, relaxation rates were 2.1, 3.8 and 7.3 an hour and the gastroesophageal pressure gradient climbed from 4.5 to 10.0 mm Hg, while resting sphincter pressure and length stayed comparable. After a meal, the acid pocket sat at or above the diaphragm during 22% of relaxations in healthy volunteers, 54% with a small hiatal hernia and 77% with a large one. Counsel on pressure and hernia anatomy, not on acid.

The age assumption fails as well. In 248 volunteers aged 65 and over, weighted prevalence of consistent hyposecretion was 11%, and across 41 healthy adults age independently raised acid output while H. pylori lowered it. Atrophic gastritis carries a global prevalence of 25.4% with no difference between symptomatic and asymptomatic individuals, so genuine hypochlorhydria is found by H. pylori testing and pepsinogens rather than by history. Gastric pH, impedance and acid output studies are not part of Measura [Cardiometabolic and Autonomic Health Analysis]; the autoimmune side is covered in intrinsic factor antibody screening.

Can a PPI such as omeprazole cause B12 deficiency?

Acid releases cobalamin from dietary protein, and the deficiency signal behaves like a dose response. The odds of B12 deficiency rose to 1.65 (95% CI, 1.58-1.73) with two or more years of PPI supply, compared with 1.25 for H2 receptor antagonists, rising to 1.95 above 1.5 pills daily. Mineral data are thinner and population-bound: hypomagnesemia at 2.16 (95% CI 1.46-3.20) in kidney transplant recipients, and iron deficiency at 1.57, or 2.30 on high dose, in renal transplant recipients. Protein handling shifts too, because pepsin requires an acid environment, which matters for the first brain as a whole and not only for one vitamin.

Keep the rest proportionate. The randomized safety trial of 17,598 participants over three years separated on enteric infection alone, 1.4% versus 1.0% (odds ratio 1.33), with dementia, fractures, pneumonia, chronic kidney disease and diabetes prespecified and null. Pooled randomized data put C. difficile at RR 1.19 across 29,880 participants, and fracture evidence is graded very low to low certainty. The screening case rests on absorption, not on headline harms.

What happens when a long-term PPI is stopped?

Withdrawal symptoms are pharmacology. In 120 healthy volunteers given eight weeks of a PPI or placebo, 44% (26/59) reported a clinically relevant acid-related symptom within four weeks of withdrawal versus 15% (9/59); a second trial found 11 of 25 versus 2 of 23. Onset clusters at day 5 to 14 with a mean duration of 4 to 5 days, 38% start later at week 3 or 4, and measured hypersecretion lasts more than 8 and under 26 weeks. Rebound tracks depth of suppression, not brand, and patients who are warned about it misread it less often as relapse.

Set expectations from the trials. A year after a structured discontinuation attempt, 27% of long-term users were off the drug; tapering and abrupt stopping did not differ (31% versus 22%), patients with reflux disease succeeded less often (21% versus 48%), and baseline gastrin predicted resumption. Expert guidance offers a discontinuation trial to patients without a definite indication and steps twice-daily dosing to once daily first. Barrett’s esophagus, severe erosive esophagitis, esophageal ulcer, stricture, eosinophilic esophagitis and idiopathic pulmonary fibrosis stay on therapy. Alginate gives patients a non-suppressant option through the rebound window. Whether and how to discontinue remains the prescriber’s decision, made with the patient on the basis of indication.

What to measure, and what each result changes

• Laboratory panels. B12 in patients past two years of continuous suppression or on high dose, with magnesium and iron where the history warrants. A low value is a management finding in its own right and a prompt to revisit the indication.
• Bioimpedance body composition. Weight loss and head-of-bed elevation were the only lifestyle measures supported on systematic review, so a documented abdominal fat burden gives the reflux plan a mechanical target and a follow-up metric. Visceral adiposity is also the metaflammation substrate that a subsidized acellular-carbohydrate food supply keeps rebuilding.
• Vestibular and balance testing. In older users where fracture concern enters the conversation, fall risk measured directly is actionable in a way a low-certainty drug association is not.
• Cognitive assessment. The observational dementia hazard ratio of 1.44 did not reproduce under randomization. A memory complaint in a long-term user deserves its own measurement rather than attribution to the drug.

Measura reports to the ordering physician. It does not diagnose reflux, measure gastric acid or manage medication.

Documentation and standing orders

Suppression outlives indication because renewal is frictionless and review is not. A standing order can attach a B12-inclusive panel to documented PPI use of two years or more and require an indication field at each renewal. The medication review fits the annual wellness visit, and fall-risk findings pair with the approach in cognitive assessment and fall prevention. Results flow into the chart as described in getting results into the record. Supporting evidence, study by study, is in the companion deep dive for The Angry Gut; the patient explanation is long-term PPI use for patients, and opioid-induced constipation screening follows the next drug class that stalls the gut.

Frequently asked questions

References

• Vela, M. F., Camacho-Lobato, L., Srinivasan, R., Tutuian, R., Katz, P. O., & Castell, D. O. (2001). Simultaneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology, 120(7), 1599-606. https://doi.org/10.1053/gast.2001.24840
• Wu, J. C. Y., Mui, L. M., Cheung, C. M. Y., Chan, Y., & Sung, J. J. Y. (2006). Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology, 132(3), 883-9. https://doi.org/10.1053/j.gastro.2006.12.032
• Hurwitz, A., Brady, D. A., Schaal, S. E., Samloff, I. M., Dedon, J., & Ruhl, C. E. (1997). Gastric acidity in older adults. JAMA, 278(8), 659-62. https://pubmed.ncbi.nlm.nih.gov/9272898/
• Mulder, D. T., Hahn, A. I., Huang, R. J., Zhou, M. J., Blake, B., Omofuma, O., Murphy, J. D., Gutierrez-Torres, D. S., Zauber, A. G., O’Mahony, J. F., Camargo, M. C., Ladabaum, U., Yeh, J. M., Hur, C., Lansdorp-Vogelaar, I., Meester, R., & Laszkowska, M. (2024). Prevalence of Gastric Precursor Lesions in Countries With Differential Gastric Cancer Burden: A Systematic Review and Meta-analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 22(8), 1605-1617.e46. https://doi.org/10.1016/j.cgh.2024.02.023
• Lam, J. R., Schneider, J. L., Zhao, W., & Corley, D. A. (2013). Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA, 310(22), 2435-42. https://doi.org/10.1001/jama.2013.280490
• Mohammadi, K., Yaribash, S., Razi, B., & Dashti-Khavidaki, S. (2021). Comparing safety of proton-pump inhibitors versus H2-receptor antagonists in kidney transplant recipients: A systematic review and meta-analysis. Journal of clinical pharmacy and therapeutics, 47(5), 567-574. https://doi.org/10.1111/jcpt.13589
• Moayyedi, P., Eikelboom, J. W., Bosch, J., Connolly, S. J., Dyal, L., Shestakovska, O., Leong, D., Anand, S. S., Stork, S., Branch, K. R. H., Bhatt, D. L., Verhamme, P. B., O’Donnell, M., Maggioni, A. P., Lonn, E. M., Piegas, L. S., Ertl, G., Keltai, M., Bruns, N. C., … Yusuf, S. (2019). Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin. Gastroenterology, 157(3), 682-691.e2. https://doi.org/10.1053/j.gastro.2019.05.056
• Reimer, C., Søndergaard, B., Hilsted, L., & Bytzer, P. (2009). Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology, 137(1), 80-87, 87.e1. https://doi.org/10.1053/j.gastro.2009.03.058
• Björnsson, E., Abrahamsson, H., Simrén, M., Mattsson, N., Jensen, C., Agerforz, P., & Kilander, A. (2006). Discontinuation of proton pump inhibitors in patients on long-term therapy: a double-blind, placebo-controlled trial. Alimentary Pharmacology & Therapeutics, 24(6), 945-954. https://doi.org/10.1111/j.1365-2036.2006.03084.x
• Targownik, L. E., Fisher, D. A., & Saini, S. D. (2022). AGA Clinical Practice Update on de-prescribing of proton pump inhibitors: Expert review. Gastroenterology, 162(4), 1334-1342. https://doi.org/10.1053/j.gastro.2021.12.247

Related reading

• Intermittent Fasting in Type 2 Diabetes: Measure First
• Opioid-Induced Constipation: Screening in Long-Term Therapy
• Laboratory Panels