Intermittent Fasting in Type 2 Diabetes: Measure First

Intermittent fasting in type 2 diabetes starts with screening: glucose-lowering therapy, antihypertensives, disordered eating, and gout, renal or gallbladder history all come before counseling a longer gap. In clamp testing, a three-week eating window left insulin sensitivity unchanged while daily glucose control improved.

The popular windows are shallower than their reputation and weight is the least informative endpoint. Screening, a composition baseline and a measured metabolic rate change the counseling more than the schedule does.

Patients ask about intermittent fasting, usually because of type 2 diabetes, long before anyone has measured anything about them, and the counseling usually happens with no baseline and no endpoint. Two facts make that expensive. The popular schedules are shallower than their reputation, and the endpoint most patients bring — weight — is the one least able to answer the question. The Angry Gut (Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes) lays out the motility case in its chapter video, Six Meals a Day Is a Business Model. What follows is the screening and measurement version.

Does a daily eating window help type 2 diabetes?

When insulin sensitivity was measured properly rather than inferred, a three-week eating window in adults with type 2 diabetes left it unchanged: an M value of 19.6 against 17.7. Hepatic glycogen came out identical. Daily glucose control did improve, with three additional hours a day in the normal range, so the schedule was doing something real — just not the thing it is sold on. A window that never empties the hepatic tank cannot be expected to act like a fast, and pooling the two is what makes this literature look flat.

The pooled estimate carries its own warning. Across meal-timing trials, shifting calories earlier gave about 1.75 kilograms, and of the 29 randomized trials pooled, 22 raised high concerns about risk of bias and 7 raised some. The one clear twelve-month win came from a deeper protocol, 4:3 fasting, at 7.7 kilograms against 4.8. Depth is the variable. That is the tier of evidence, and it does not change the physiology; it changes how loudly you should counsel.

Does intermittent fasting work without a calorie deficit?

One trial was built to pry them apart. Lean adults were assigned daily restriction, alternate-day fasting at the same weekly deficit, or alternate-day fasting with the deficit removed. Daily restriction lost 1.91 kilograms, of which 1.75 was fat. The matched fasting arm lost a similar total but only 0.74 kilograms of fat. With no deficit at all, fasting produced 0.52 kilograms of body mass and 0.12 of fat, and the investigators found no fasting signature in gut hormones or in subcutaneous adipose gene expression. Same weight, worse composition, and nothing left when the deficit went. Twelve people per arm over three weeks, all lean and healthy, so read the direction rather than the magnitude.

Does intermittent fasting cause muscle loss?

In the trial that tested a noon-to-eight schedule against three structured meals, the between-group weight difference was 0.26 kilograms and the appendicular lean mass index fell further in the window group, by 0.16 kilograms per square meter. That is limb muscle, measured by scan, moving the wrong way in an intervention prescribed for metabolic benefit. In the alternate-day trial that reached the visceral depot under whole-body imaging, resting metabolic rate and triiodothyronine both fell in the deeper arm and not in the window arm. Deeper reaches the compartment and deeper sends a bill. Those are one finding, not two.

Adherence belongs in the same paragraph. In a one-year trial, 13 of 34 patients assigned to alternate-day fasting withdrew, and those who stayed ate more than prescribed on fast days and less on feast days, while LDL cholesterol ended 11.5 mg/dL higher than in the restriction arm. A protocol a patient cannot keep is not a protocol.

Intermittent fasting in type 2 diabetes: who to screen before a longer gap

• Glucose-lowering therapy. Insulin and secretagogues change behavior when meals move. No patient on these agents should extend a fast without the prescriber adjusting the regimen first.
• Antihypertensives. In a five-day fast followed by a structured diet, blood pressure and the requirement for antihypertensive medication were both lower three months later. That is a deprescribing conversation to plan for, not a surprise to discover in clinic.
• Disordered eating. In a survey of 2,762 adolescents and young adults, intermittent fasting in the prior year was reported by 47.7 percent of women, and the practice was significantly associated with eating-disorder psychopathology. Screen before you prescribe a schedule.
• Gout, renal disease and gallbladder history. In 1,422 supervised fasts of 4 to 21 days, mean uric acid climbed from 338.1 to 495.2 micromol/L while C-reactive protein went from 2.85 to 4.30 mg/L. Two patients were hospitalized, 0.14 percent of the group, and of those who arrived with a major complaint, 6.9 percent reported it worse afterward. No control group, one clinic, a selected population.

What to measure, and what each result changes

Measura [Cardiometabolic and Autonomic Health Analysis] measures; it does not diagnose on its own or treat, and results return to the ordering physician. It has no imaging, so the imaged visceral and subcutaneous compartments come from a different test ordered elsewhere.

• Bioimpedance body composition estimates the fat, lean and water compartments. It is an estimate, not imaging, and it cannot separate the visceral from the subcutaneous depot. Its value is serial lean mass in the same patient: a falling lean compartment stops the schedule and starts a protein and resistance conversation.
• Indirect calorimetry gives a measured resting metabolic rate rather than a predicted one, which matters precisely because rate fell in the arm that lost the most fat.
• Laboratory panels document the metabolic and inflammatory terrain, the metaflammation the first brain sits inside, and give the before-and-after that a weight log cannot.

Order the baseline before the counseling, not after, and set the repeat interval at the same visit. A standing order makes that reproducible for every patient who raises meal timing, and functional and metabolic findings fit the documentation described in annual wellness visit integration. Between-visit follow-up is covered in chronic care and between-visit monitoring. Every study above, with what it cannot show, is in the companion deep dive for The Angry Gut. The patient-facing version is the two fat compartments explained for patients, and the stool-report counterpart is when a stool finding changes care.

Frequently asked questions

References

• Andriessen, C., Fealy, C. E., Veelen, A., van Beek, S. M. M., Roumans, K. H. M., Connell, N. J., Mevenkamp, J., Moonen-Kornips, E., Havekes, B., Schrauwen-Hinderling, V. B., Hoeks, J., & Schrauwen, P. (2022). Three weeks of time-restricted eating improves glucose homeostasis in adults with type 2 diabetes but does not improve insulin sensitivity: A randomised crossover trial. Diabetologia, 65(10), 1710-1720. https://doi.org/10.1007/s00125-022-05752-z
• Liu, H. Y., Eso, A. A., Cook, N., O’Neill, H. M., & Albarqouni, L. (2024). Meal timing and anthropometric and metabolic outcomes: A systematic review and meta-analysis. JAMA Network Open, 7(11), e2442163. https://doi.org/10.1001/jamanetworkopen.2024.42163
• Catenacci, V. A., Ostendorf, D. M., Pan, Z., Kaizer, L. K., Creasy, S. A., Zaman, A., Caldwell, A. E., Dahle, J., Swanson, B., Breit, M. J., Bing, K., Wayland, L. T., Panter, S. L., Scorsone, J. J., Bessesen, D. H., MacLean, P., & Melanson, E. L. (2025). The effect of 4:3 intermittent fasting on weight loss at 12 months: A randomized clinical trial. Annals of Internal Medicine, 178(5), 634-644. https://doi.org/10.7326/ANNALS-24-01631
• Templeman, I., Smith, H. A., Chowdhury, E., Chen, Y.-C., Carroll, H., Johnson-Bonson, D., Hengist, A., Smith, R., Creighton, J., Clayton, D., Varley, I., Karagounis, L. G., Wilhelmsen, A., Tsintzas, K., Reeves, S., Walhin, J.-P., Gonzalez, J. T., Thompson, D., & Betts, J. A. (2021). A randomized controlled trial to isolate the effects of fasting and energy restriction on weight loss and metabolic health in lean adults. Science Translational Medicine, 13(598), eabd8034. https://doi.org/10.1126/scitranslmed.abd8034
• Lowe, D. A., Wu, N., Rohdin-Bibby, L., Moore, A. H., Kelly, N., Liu, Y. E., Philip, E., Vittinghoff, E., Heymsfield, S. B., Olgin, J. E., Shepherd, J. A., & Weiss, E. J. (2020). Effects of time-restricted eating on weight loss and other metabolic parameters in women and men with overweight and obesity: The TREAT randomized clinical trial. JAMA Internal Medicine, 180(11), 1491-1499. https://doi.org/10.1001/jamainternmed.2020.4153
• Trepanowski, J. F., Kroeger, C. M., Barnosky, A., Klempel, M. C., Bhutani, S., Hoddy, K. K., Gabel, K., Freels, S., Rigdon, J., Rood, J., Ravussin, E., & Varady, K. A. (2017). Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: A randomized clinical trial. JAMA Internal Medicine, 177(7), 930-938. https://doi.org/10.1001/jamainternmed.2017.0936
• Wilhelmi de Toledo, F., Grundler, F., Bergouignan, A., Drinda, S., & Michalsen, A. (2019). Safety, health improvement and well-being during a 4 to 21-day fasting period in an observational study including 1422 subjects. PLoS One, 14(1), e0209353. https://doi.org/10.1371/journal.pone.0209353
• Ganson, K. T., Cuccolo, K., Hallward, L., & Nagata, J. M. (2022). Intermittent fasting: Describing engagement and associations with eating disorder behaviors and psychopathology among Canadian adolescents and young adults. Eating Behaviors, 47, 101681. https://doi.org/10.1016/j.eatbeh.2022.101681
• Maifeld, A., Bartolomaeus, H., Löber, U., Avery, E. G., Steckhan, N., Markó, L., Wilck, N., Hamad, I., Šušnjar, U., Mähler, A., Hohmann, C., Chen, C.-Y., Cramer, H., Dobos, G., Lesker, T. R., Strowig, T., Dechend, R., Bzdok, D., Kleinewietfeld, M., … Forslund, S. K. (2021). Fasting alters the gut microbiome reducing blood pressure and body weight in metabolic syndrome patients. Nature Communications, 12(1), 1970. https://doi.org/10.1038/s41467-021-22097-0
• Derron, N., Güntner, A. T., Weber, I. C., Braun, J., Koska, İ. Ö., Othman, A., Mönch, L., von Eckardstein, A., Puhan, M. A., Beuschlein, F., Hochuli, M., Zamboni, N., Guggenberger, R., & Gerber, P. A. (2025). Alternate-day fasting elicits larger changes in fat mass than time-restricted eating in adults without obesity – A randomized clinical trial. Clinical Nutrition, 53, 212-221. https://doi.org/10.1016/j.clnu.2025.08.033

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• Blastocystis Hominis Treatment: When a Stool Finding Changes Care
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• Bioimpedance Body Composition

Blastocystis Hominis Treatment: When a Stool Finding Changes Care

Blastocystis hominis treatment changes care mainly in three groups: the immunosuppressed, the recently and repeatedly treated, and patients with objective findings rather than a symptom list.

Detection is cheap and reproducibility is poor. In an immunocompetent adult, a highlighted organism is usually a marker of the ecology you would be trying to restore, and the host is where the measurable findings are.

Requests for blastocystis hominis treatment almost always arrive with the printout already highlighted, and often with two or three antimicrobial courses behind it. The clinical question is not whether the detection is real; multiplex panels are good at detection. The question is what a detection in this particular host should change. The chapter video The Wrong Enemy on Your Stool Report, from The Angry Gut (Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes), argues the case. Here it is as a screening and workflow problem.

What a higher detection rate bought

A pediatric hospital network replaced conventional stool testing with a multiplex panel and compared the two years after against the two years before. Positivity rose to 40 percent from 11 percent, turnaround fell to 4 hours from 31, and children treated for a bacterial or parasitic pathogen were discharged two days earlier. That treated group was 3 percent of those tested, and across the whole tested population length of stay and ancillary testing did not differ. The authors’ own term for the pattern was low-value care, in a before-and-after design with a historical control.

Repeatability is the other constraint. In the Human Microbiome Project cohort, an individual’s mycobiome was no more similar to itself over time than to another person’s. A measurement that does not reproduce in the same patient cannot anchor a treatment decision, and a consensus statement with sixty-nine authors concluded that evidence for the clinical usefulness of microbiome testing remains scarce. A consensus is structured opinion rather than measurement, but no other professional benchmark exists for these panels.

When does Blastocystis hominis need treatment?

Immune status does most of the work. In an Italian survey the protozoan was found in 22.3 percent of immunocompromised patients against 6.8 percent of immunocompetent ones, and subtype 3 carriers showed higher bacterial diversity than noncarriers. Read the corollary carefully: the people without Blastocystis were the ones carrying a high share of Enterobacteriaceae. Fungal expansion follows the same logic. Among transplant patients who went on to candidemia, a single Candida species first passed 50 percent of gut fungi, riding on a substantial loss of bacterial burden and diversity after exposure to agents active against anaerobes.

So the patients in whom a detection genuinely changes management are the immunosuppressed, the recently and repeatedly treated, and those with objective findings rather than a symptom list. In an immunocompetent adult with a rich flora, the organism may be a marker of the ecology you would otherwise be trying to build.

Does clearing the organism make symptoms go away?

A primary care network outside Barcelona ran 13,983 stool examinations over three years and found Dientamoeba fragilis in 1,150 of them, or 8.2 percent, with Blastocystis hominis coinfection in 33.6 percent of those subjects. Paromomycin cleared the organism in 81.8 percent against metronidazole’s 65.4 percent, and most patients had received the weaker agent. The endpoint throughout was clearance, not symptoms, and those authors note that the pathogenic capacity of the organism has been questioned. You can win the eradication and never learn whether the patient improved. For presumed gut candida in immunocompetent adults there is no randomized antifungal trial at all; the nearest thing is a single nystatin trial from 1990. That is the evidence tier, stated once.

Are repeated antibiotic courses harmful?

In the Danish cohort, 90.9 percent of 5,551,441 people had received at least one antibiotic course, so exposure itself is not a marker of anything. Dose is. Among those with five or more courses the incidence rate ratio for inflammatory bowel disease was 1.69 at ages 10 to 40, 2.12 at 40 to 60 and 1.95 beyond 60. There is an internal control worth noticing: nitrofurantoin was the only class not associated with disease in any age band, and it is the class that barely reaches the colon. Confounding by indication is real, and the sibling comparisons are the fair correction — an in-utero exposure hazard ratio of 1.28 for infections in specialist care collapsed to 1.05 within sibling groups. Part of the early-life signal is family, not drug.

The most actionable item is rarely the panel. Colonization resistance is broken by proton pump inhibitors, antidiabetics and antipsychotics as well as by antibiotics, three of the most prescribed classes in practice and none of them labeled as a gut drug. A medication review before another antimicrobial has the best ratio of yield to harm in this situation.

What to measure in the host, and what each finding changes

Measura [Cardiometabolic and Autonomic Health Analysis] does not offer stool, microbiome or breath testing; those are ordered elsewhere. It measures the consequences in the host, with results returned to the ordering physician.

• Laboratory panels document the metabolic and inflammatory terrain (metaflammation) that a taxonomic list cannot address; an abnormal pattern redirects the visit from eradication toward metabolic management.
• Bioimpedance body composition quantifies the muscle compartment in a patient who has spent two years on restrictive elimination diets. Low lean mass changes the dietary conversation immediately.
• Indirect calorimetry replaces a predicted resting metabolic rate with a measured one before any further restriction is advised.
• Autonomic nervous system testing and heart rate variability document the regulatory arm behind motility and symptom burden; an abnormal result supports referral rather than another panel.
• Sudomotor testing measures sweat-gland function in the small fibers of the hands and feet, which is worth having when gut complaints travel with distal sensory symptoms.

Fitting it into the visit

A standing order keeps this reproducible: for a patient presenting with a consumer stool or microbiome report, attach a medication review, a course count and host measurement rather than a repeat panel. Selection criteria keep the volume sane. Functional and metabolic findings belong in the annual wellness visit, where they also support the documentation discussed under MIPS and quality reporting, and cognition and gait deserve the pairing described in cognitive assessment and fall prevention in older patients with long antimicrobial histories. Full numbers, with what each study cannot show, are in the companion deep dive for The Angry Gut. The patient-facing explanation is what a microbiome report can and cannot say, and the meal-timing counterpart is meal timing and what to measure first.

Frequently asked questions

References

• Cotter, J. M., Thomas, J., Birkholz, M., Ambroggio, L., Holstein, J., & Dominguez, S. R. (2021). Clinical impact of a diagnostic gastrointestinal panel in children. Pediatrics, 147(5), e2020036954. https://doi.org/10.1542/peds.2020-036954
• Nash, A. K., Auchtung, T. A., Wong, M. C., Smith, D. P., Gesell, J. R., Ross, M. C., Stewart, C. J., Metcalf, G. A., Muzny, D. M., Gibbs, R. A., Ajami, N. J., & Petrosino, J. F. (2017). The gut mycobiome of the Human Microbiome Project healthy cohort. Microbiome, 5(1), 153. https://doi.org/10.1186/s40168-017-0373-4
• Burgaña, A., Abellana, R., Yordanov, S. Z., Kazan, R., Pérez Ortiz, A. M., Castillo Ramos, C., Garavito Hernández, C., Molina Rivero, M., Gonçalves, A. Q., Padilla, E., Pérez, J., García-Puig, R., & Perez-Porcuna, T. M. (2019). Paromomycin is superior to metronidazole in Dientamoeba fragilis treatment. International Journal for Parasitology: Drugs and Drug Resistance, 11, 95-100. https://doi.org/10.1016/j.ijpddr.2019.10.005
• Gabrielli, S., Furzi, F., Fontanelli Sulekova, L., Taliani, G., & Mattiucci, S. (2020). Occurrence of Blastocystis subtypes in patients from Italy revealed association of ST3 with a healthy gut microbiota. Parasite Epidemiology and Control, 9, e00134. https://doi.org/10.1016/j.parepi.2020.e00134
• Zhai, B., Ola, M., Rolling, T., Tosini, N. L., Joshowitz, S., Littmann, E. R., Amoretti, L. A., Fontana, E., Wright, R. J., Miranda, E., Veelken, C. A., Morjaria, S. M., Peled, J. U., van den Brink, M. R. M., Babady, N. E., Butler, G., Taur, Y., & Hohl, T. M. (2020). High-resolution mycobiota analysis reveals dynamic intestinal translocation preceding invasive candidiasis. Nature Medicine, 26(1), 59-64. https://doi.org/10.1038/s41591-019-0709-7
• Faye, A. S., Allin, K. H., Iversen, A. T., Agrawal, M., Faith, J., Colombel, J.-F., & Jess, T. (2023). Antibiotic use as a risk factor for inflammatory bowel disease across the ages: A population-based cohort study. Gut, 72(4), 663-670. https://doi.org/10.1136/gutjnl-2022-327845
• Nakitanda, A. O., Kieler, H., Odsbu, I., Rhedin, S., Almqvist, C., Pasternak, B., & Pazzagli, L. (2023). In-utero antibiotic exposure and subsequent infections in infancy: A register-based cohort study with sibling analysis. American Journal of Obstetrics & Gynecology MFM, 5(4), 100860. https://doi.org/10.1016/j.ajogmf.2023.100860
• Ducarmon, Q. R., Zwittink, R. D., Hornung, B. V. H., van Schaik, W., Young, V. B., & Kuijper, E. J. (2019). Gut microbiota and colonization resistance against bacterial enteric infection. Microbiology and Molecular Biology Reviews, 83(3), e00007-19. https://doi.org/10.1128/MMBR.00007-19
• Porcari, S., Mullish, B. H., Asnicar, F., Ng, S. C., Zhao, L., Hansen, R., O’Toole, P. W., Raes, J., Hold, G., Putignani, L., Hvas, C. L., Zeller, G., Koren, O., Tun, H., Valles-Colomer, M., Collado, M. C., Fischer, M., Allegretti, J., Iqbal, T., … Ianiro, G. (2025). International consensus statement on microbiome testing in clinical practice. The Lancet Gastroenterology & Hepatology, 10(2), 154-167. https://doi.org/10.1016/S2468-1253(24)00311-X

Related reading

• Circadian Misalignment in Shift Workers: A Screening Framework
• Intermittent Fasting in Type 2 Diabetes: Measure First
• Laboratory Panels

Circadian Misalignment in Shift Workers: A Screening Framework

A schedule history belongs beside the medication list. Misalignment has measurable metabolic and inflammatory effects that sleep duration alone does not capture, and the patients carrying it rarely volunteer the roster.

Circadian misalignment is an exposure most charts record as an occupation at best, and the evidence says the pattern of the schedule matters more than the job title. Your Gut Has Jet Lag, the video for The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, makes the argument through a nurse with Crohn’s disease whose flares followed roster changes. For primary care, endocrinology, cardiology and pain practices, the practical questions are who to screen, what misalignment changes in measurable physiology, and how to build that screening into routine workflow.

Misalignment and short sleep are separate exposures

In a controlled laboratory protocol, eight of 17 healthy adults became truly misaligned. Chronic misalignment raised TNF-alpha, IL-10 and CRP and lowered cortisol; acute total sleep deprivation raised cortisol instead. IL-10 rose alongside TNF-alpha and the ratio barely changed, so the inflammatory reading is modest, but the endocrine divergence is clear enough that the two exposures should not be pooled.

In working night-shift staff given an alcohol challenge, colonic permeability increased only in the night workers. Lower melatonin area under the curve tracked the increase, while actigraphic sleep architecture did not differ between groups, and baseline LPS-binding protein, endotoxin and IL-6 were already elevated. The phase, not the sleep quantity, predicted the lesion.

Rotation carries the epidemiologic signal. In a cohort of 399 nurses, irritable bowel syndrome prevalence reached 48% under rotating schedules versus 31% under day schedules, P < 0.01, and persisted after adjustment for sleep quality. Pooled nursing data put rotating schedules at an odds ratio of 1.74 for IBS, with no significant association with inflammatory bowel disease or colorectal cancer.

What health risks does circadian misalignment carry?

I once treated a normal fasting glucose in a night worker as a settled question. It was not. Two nights of restricted sleep in nine normal-weight young men raised HOMA-IR from 0.72 to 1.01, near 40%, with fasting insulin up 34%; a concurrent microbiome shift did not mediate the change (P = 0.121). Pooled across 21 observational studies, shift work carried type 2 diabetes at RR 1.10 (1.05 to 1.14), in women and not in men, with health care workers at highest risk.

Appetite follows the same direction. Sleep restriction in 19 men increased snack intake by 328 kcal, mostly carbohydrate. In 80 short-sleeping adults with overweight, sleep extension reduced intake by 270 kcal a day by doubly labeled water, with change in sleep tracking change in intake at r = -0.41 and no change in expenditure.

The hard endpoints are weaker, and screening should say so. Pooled night-shift cancer risk was flat across 57 studies, and duration of rotating night work was not associated with Crohn’s disease or ulcerative colitis in the nurses’ cohort. Experimental inflammation data depend on dose: three or more nights of partial restriction raised IL-6 at d = 0.42 and CRP at d = 0.76 in a 2025 meta-analysis of 35 studies, a single night did nothing, and a larger synthesis of 72 studies found experimental sleep loss unrelated to CRP, IL-6 or TNF-alpha. The screening target is metabolic terrain under sustained rotation, not cancer.

The determinant is structural. Rosters are written to staffing budgets, and the nurses, aides, drivers and warehouse staff who cover nights rarely control the rotation. Metaflammation under that exposure is an occupational pattern, not a compliance failure.

Who should be screened for circadian misalignment?

• Rotating-shift workers, particularly schedules that swing between nights and days within a week.
• Shift workers with prediabetes, type 2 diabetes or discordant fasting insulin and triglycerides.
• Women on sustained shift work, given the sex-specific diabetes signal.
• Patients with Crohn’s disease in remission who report impaired sleep. In a prospective group of 1,291 of them, the adjusted odds ratio for progressing to active disease was 2.00 when sleep was impaired, though disease activity, depression, corticosteroids and narcotics also predicted disturbed sleep, so the arrow runs both ways.
• Patients with IBS symptoms on a rotating roster.

Take the history in clock times: habitual sleep onset and wake across two typical weeks, the rotation pattern, and the date the last run of nights ended. That history is the exposure variable every result below depends on.

What to measure, and what goes elsewhere

Measura [Cardiometabolic and Autonomic Health Analysis] performs no sleep study; suspected apnea or another sleep disorder goes to polysomnography elsewhere, which matters because long sleep and apnea, not short sleep or shift work, carried colorectal neoplasm risk in pooled observational data.

• Laboratory panels: fasting glucose and insulin for HOMA-IR, lipids and CRP, annotated with the interval since the last run of nights, since one night is noise and a sustained run is a dose.
• Indirect calorimetry: measured resting energy expenditure, which separates intake from expenditure, the distinction the sleep-extension trial turned on.
• Heart rate variability and autonomic nervous system testing: objective autonomic regulation at rest and under breathing and postural challenge. The shift-work literature above did not use them as outcomes, so they characterize the patient rather than serve as validated misalignment markers.

Stool microbiome testing adds little here. Stool consistency correlates with all major microbiome markers, and 51 staff nurses showed no diversity difference between day and night shifts while the host measures moved.

How do you correct circadian misalignment in a shift worker?

A metabolic or autonomic finding in a rotating worker moves management toward the schedule: meals anchored to consistent clock times across rotations, a fixed sleep window on days off, cognitive behavioral therapy for insomnia where insomnia is present, and an occupational conversation about rotation itself. The one Crohn’s trial of that therapy randomized 26 patients and improved insomnia severity against waitlist, with CRP only trending, so the expectation is better sleep and possibly better symptoms, not proven mucosal effects. Repeat measurement after a schedule change shows whether insulin and expenditure moved.

Documentation and workflow

A standing order can attach a fasting metabolic panel, resting metabolic rate and autonomic testing to a documented rotating schedule, so the screen runs without a physician remembering it. The annual wellness visit already collects social and occupational history where the roster can be recorded, results support MIPS quality documentation, and structured import is covered in getting results into the record. The evidence file is the companion deep dive for The Angry Gut, visceral fat screening is in visceral adiposity screening beyond BMI, and the patient explanation is night shift health risks you can measure.

Frequently asked questions

References

• Wright, K. P., Drake, A. L., Frey, D. J., Fleshner, M., Desouza, C. A., Gronfier, C., & Czeisler, C. A. (2015). Influence of sleep deprivation and circadian misalignment on cortisol, inflammatory markers, and cytokine balance. Brain, Behavior, and Immunity, 47, 24-34. https://doi.org/10.1016/j.bbi.2015.01.004
• Swanson, G. R., Gorenz, A., Shaikh, M., Desai, V., Kaminsky, T., Van Den Berg, J., Murphy, T., Raeisi, S., Fogg, L., Vitaterna, M. H., Forsyth, C., Turek, F., Burgess, H. J., & Keshavarzian, A. (2016). Night workers with circadian misalignment are susceptible to alcohol-induced intestinal hyperpermeability with social drinking. American Journal of Physiology. Gastrointestinal and Liver Physiology, 311(1), G192-G201. https://doi.org/10.1152/ajpgi.00087.2016
• Nojkov, B., Rubenstein, J. H., Chey, W. D., & Hoogerwerf, W. A. (2010). The impact of rotating shift work on the prevalence of irritable bowel syndrome in nurses. The American Journal of Gastroenterology, 105(4), 842-847. https://doi.org/10.1038/ajg.2010.48
• Benedict, C., Vogel, H., Jonas, W., Woting, A., Blaut, M., Schürmann, A., & Cedernaes, J. (2016). Gut microbiota and glucometabolic alterations in response to recurrent partial sleep deprivation in normal-weight young individuals. Molecular Metabolism, 5(12), 1175-1186. https://doi.org/10.1016/j.molmet.2016.10.003
• Gao, Y., Gan, T., Jiang, L., Yu, L., Tang, D., Wang, Y., Li, X., & Ding, G. (2020). Association between shift work and risk of type 2 diabetes mellitus: A systematic review and dose-response meta-analysis of observational studies. Chronobiology International, 37(1), 29-46. https://doi.org/10.1080/07420528.2019.1683570
• Broussard, J. L., Kilkus, J. M., Delebecque, F., Abraham, V., Day, A., Whitmore, H. R., & Tasali, E. (2015). Elevated ghrelin predicts food intake during experimental sleep restriction. Obesity, 24(1), 132-138. https://doi.org/10.1002/oby.21321
• Tasali, E., Wroblewski, K., Kahn, E., Kilkus, J., & Schoeller, D. A. (2022). Effect of sleep extension on objectively assessed energy intake among adults with overweight in real-life settings: A randomized clinical trial. JAMA Internal Medicine, 182(4), 365-374. https://doi.org/10.1001/jamainternmed.2021.8098
• Ballesio, A., Fiori, V., & Lombardo, C. (2025). Effects of experimental sleep deprivation on peripheral inflammation: An updated meta-analysis of human studies. Journal of Sleep Research, 35(1), e70099. https://doi.org/10.1111/jsr.70099
• Ananthakrishnan, A. N., Long, M. D., Martin, C. F., Sandler, R. S., & Kappelman, M. D. (2013). Sleep disturbance and risk of active disease in patients with Crohn’s disease and ulcerative colitis. Clinical Gastroenterology and Hepatology, 11(8), 965-971. https://doi.org/10.1016/j.cgh.2013.01.021
• Dun, A., Zhao, X., Jin, X., Wei, T., Gao, X., Wang, Y., & Hou, H. (2020). Association between night-shift work and cancer risk: Updated systematic review and meta-analysis. Frontiers in Oncology, 10, 1006. https://doi.org/10.3389/fonc.2020.01006

Related reading

• Visceral Adiposity: Screening for the Risk That BMI Misclassifies
• Blastocystis Hominis Treatment: When a Stool Finding Changes Care
• Laboratory Panels

Visceral Adiposity: Screening for the Risk That BMI Misclassifies

Body mass index sorts patients by size. Visceral adiposity sorts them by risk, and in patients with normal weight, diabetes or inflammatory bowel disease the two sortings disagree often enough to change the workup.

Visceral adiposity is the risk variable most primary care charts never record, because the instrument in the room is a scale. Your Immune System Is Not Confused, the video for The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, places the visceral depot inside a broader argument: fat is an immune tissue, and a chronic immune load can originate in the mesentery as readily as in the mucosa. For primary care, endocrine, cardiology and geriatric practices the screening questions are concrete. What does visceral fat add beyond body mass index, which patients carry the most misclassified risk, and what does a finding change?

Is visceral fat a better risk measure than BMI?

I spent years reading a normal weight as a normal metabolic answer. The imaging and tissue data are what corrected that. In a community cohort of 3,086 participants, 49% women with a mean age of 50.2 years, the hazard ratios attached to imaged visceral adipose tissue were 1.44 for incident cardiovascular disease and 1.43 for cancer, independent of body mass index. Adding it to a model already containing body mass index improved cardiovascular prediction modestly, net reclassification improvement 16.3%. No depot predicted all-cause mortality, but that null rests on 71 deaths over a median of 5.0 years and cannot carry a mortality conclusion.

In omental biopsies from 90 women treated surgically for endometrial cancer, adipocyte size correlated with visceral adipose tissue at r = 0.60, and crown-like structures appeared in 48% of samples, associated with diabetes rather than body mass index. In human fat, adipocyte size predicted macrophage infiltration at r² = 0.86 against 0.43 for body mass index. The position here is settled: depot beats mass. Visceral fat that expands out of proportion becomes immunogenic, and a normal-weight patient carrying it is not lean.

Why is visceral fat more harmful than subcutaneous fat?

Omental fat drains to the liver. In 25 extremely obese subjects sampled during bariatric surgery, portal vein interleukin-6 ran about 50% above radial artery levels; flow was not measured, so these are concentrations rather than delivered quantities. The causal test exists only in mice: identical fat grafts produced impaired glucose tolerance and hepatic insulin resistance when placed to drain portally, not systemically, and grafts from IL-6 knockout donors produced neither.

The cytokine that leaves fat is not the one most clinicians name. Across a subcutaneous bed in 39 subjects, venous IL-6 exceeded arterial more than 2-fold while TNF-alpha did not change. In paired explants, visceral tissue released more vascular endothelial growth factor, IL-6 and plasminogen activator inhibitor 1 than abdominal subcutaneous tissue, and the size-related rise in release came from nonfat cells.

One disagreement deserves a sentence. A study of obese women found greater CD11c-positive macrophage density in subcutaneous than omental fat; a surgical series found twice the macrophage burden in omental fat, correlated with fasting glucose, insulin and liver enzymes. The two differ in markers counted, and both support the point that matters for screening: location and cell size carry information that weight does not.

Who should be screened for visceral adiposity?

• Normal body mass index with discordant metabolic markers. Elevated fasting glucose or triglycerides, hepatic steatosis, or a strong family history of diabetes.
• South Asian patients. In 514 South Asians and 669 Europeans aged 56-86, visceral fat tracked diabetes and coronary disease while thigh muscle was protective, and neither fully explained the excess. Among 264 men assessed with the hyperinsulinemic clamp and MRI fat volumes, insulin sensitivity was lowest in the South Asian group, compared with Chinese and Malay participants, most clearly at lower body size, and fat partitioning did not account for the difference. Muscle belongs in the measurement as much as fat.
• Type 2 diabetes and fatty liver, where omental macrophage burden tracks the same laboratory values used to manage them.
• Inflammatory bowel disease, particularly Crohn’s disease, where metabolic terrain is rarely charted alongside the biologic.

The social driver belongs in the history. A subsidized food supply built on acellular carbohydrate and industrial seed oil loads this depot years before the scale moves, and the metaflammation it produces reaches the second brain and the vasculature as well as the first brain.

What should change when visceral adiposity is found?

Cytokine suppression does not repair the depot. Etanercept in 56 subjects with metabolic syndrome lowered C-reactive protein with no change in body composition or insulin sensitivity. Six months in 40 obese subjects improved fasting glucose and left body composition, lipids, CRP and IL-6 unchanged. Salsalate in 286 patients with type 2 diabetes lowered HbA1c by 0.37% while weight and LDL cholesterol rose. Canakinumab in 10,061 post-infarction patients reduced events at a hazard ratio of 0.85 without lowering mortality, and fatal infections rose. A trimmed marker is not a repaired terrain.

A finding therefore redirects management upstream, toward diet composition, sleep, activity and behavior, decided by the treating physician, with body composition and metabolic labs repeated to show whether the depot and its downstream values move. The missing human experiment is a trial that reduces visceral fat without weight loss and measures clamp insulin sensitivity; until it exists, serial measurement in the individual patient is the practical substitute.

Can visceral fat testing help in Crohn’s disease?

In Crohn’s disease the depot becomes local. Live bacteria were cultured from mesenteric fat in 9 of 11 Crohn’s patients and in 4 of 4 controls; the organisms differed, not their presence, and the creeping fat behaves as a barrier. Measura [Cardiometabolic and Autonomic Health Analysis] does not diagnose or monitor Crohn’s disease and adds nothing to calprotectin, endoscopy or drug-level monitoring. What it adds is terrain: bioimpedance body composition to separate fat mass from lean mass and follow both, and laboratory panels for glucose, insulin, lipids, liver enzymes and inflammatory markers. With anti-TNF loss of response at 20.9% per patient-year, a metabolic baseline taken while the biologic is working is worth having before it stops.

Documentation and workflow

These measurements fit existing structures. A standing order can attach body composition and a fasting metabolic panel to the triggers above, so screening does not depend on memory. The annual wellness visit is a natural point to record body composition beside weight, and serial results support value-based care documentation. The full evidence file is the companion deep dive for The Angry Gut. The patient-facing explanation is how to measure visceral fat, and schedule-driven metabolic risk is covered in screening shift workers for circadian misalignment. For older hypertensive patients, a waist-to-weight ratio has been tested directly against incident stroke; see weight-adjusted waist index and stroke risk screening.

Frequently asked questions

References

• Britton, K. A., Massaro, J. M., Murabito, J. M., Kreger, B. E., Hoffmann, U., & Fox, C. S. (2013). Body fat distribution, incident cardiovascular disease, cancer, and all-cause mortality. Journal of the American College of Cardiology, 62(10), 921-925. https://doi.org/10.1016/j.jacc.2013.06.027
• van den Bosch, A. A. S., Kooreman, L., van de Weijer, T., Romano, A., Brecheisen, R., Jin, X., Delvoux, B., Kruitwagen, R. F. P. M., Pijnenborg, J. M. A., & Werner, H. M. J. (2026). Visceral adipose tissue inflammation in endometrial cancer. Cancer Treatment and Research Communications, 48, 101273. https://doi.org/10.1016/j.ctarc.2026.101273
• Fontana, L., Eagon, J. C., Trujillo, M. E., Scherer, P. E., & Klein, S. (2007). Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes, 56(4), 1010-1013. https://doi.org/10.2337/db06-1656
• Rytka, J. M., Wueest, S., Schoenle, E. J., & Konrad, D. (2011). The portal theory supported by venous drainage-selective fat transplantation. Diabetes, 60(1), 56-63. https://doi.org/10.2337/db10-0697
• Mohamed-Ali, V., Goodrick, S., Rawesh, A., Katz, D. R., Miles, J. M., Yudkin, J. S., Klein, S., & Coppack, S. W. (1997). Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. The Journal of Clinical Endocrinology and Metabolism, 82(12), 4196-4200. https://doi.org/10.1210/jcem.82.12.4450
• Parvaresh Rizi, E., Teo, Y., Leow, M. K., Venkataraman, K., Khoo, E. Y., Yeo, C. R., Chan, E., Song, T., Sadananthan, S. A., Velan, S. S., Gluckman, P. D., Lee, Y. S., Chong, Y. S., Tai, E. S., Toh, S. A., & Khoo, C. M. (2015). Ethnic Differences in the Role of Adipocytokines Linking Abdominal Adiposity and Insulin Sensitivity Among Asians. The Journal of Clinical Endocrinology and Metabolism, 100(11), 4249-4256. https://doi.org/10.1210/jc.2015-2639
• Eastwood, S. V., Tillin, T., Wright, A., Mayet, J., Godsland, I., Forouhi, N. G., Whincup, P., Hughes, A. D., & Chaturvedi, N. (2014). Thigh fat and muscle each contribute to excess cardiometabolic risk in South Asians, independent of visceral adipose tissue. Obesity (Silver Spring, Md.), 22(9), 2071-2079. https://doi.org/10.1002/oby.20796
• Bernstein, L. E., Berry, J., Kim, S., Canavan, B., & Grinspoon, S. K. (2006). Effects of etanercept in patients with the metabolic syndrome. Archives of Internal Medicine, 166(8), 902-908. https://doi.org/10.1001/archinte.166.8.902
• Goldfine, A. B., Fonseca, V., Jablonski, K. A., Chen, Y. D., Tipton, L., Staten, M. A., & Shoelson, S. E. (2013). Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Annals of Internal Medicine, 159(1), 1-12. https://doi.org/10.7326/0003-4819-159-1-201307020-00003
• Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S. D., Kastelein, J. J. P., Cornel, J. H., Pais, P., Pella, D., Genest, J., Cifkova, R., Lorenzatti, A., Forster, T., Kobalava, Z., … Glynn, R. J. (2017). Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. The New England Journal of Medicine, 377(12), 1119-1131. https://doi.org/10.1056/NEJMoa1707914

Related reading

• Ultra-Processed Food: Measure the Host, Not the Additive
• Circadian Misalignment in Shift Workers: A Screening Framework
• Bioimpedance Body Composition

Ultra-Processed Food: Measure the Host, Not the Additive

Additive exposure has no clinical assay, so it stays an estimate from the diet history. The variable that decides the outcome in every animal model is the host, and the host can be measured.

Ultra-processed food is now a routine item in the history, and it arrives without an assay. There is no laboratory test for additive exposure, at Measura or anywhere in ordinary practice, so the exposure stays an estimate from diet records while the host it lands in can be measured directly.

The chapter video, Your Microbes Read the Label, Not the Macros, presents chapter 15 of The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes. Study-level numbers with the limits of each are in the book’s Deep Dive companion. Measura [Cardiometabolic and Autonomic Health Analysis] is a testing service; it performs no stool, microbiome, additive or endoscopic testing.

Is ultra-processed food linked to diabetes, cancer and IBD?

The population signal does not point at the compounds the laboratory studies. Following 104,139 adults for incident type 2 diabetes, guar gum reached 1.11 for each extra 500 mg a day and xanthan gum 1.08, with carrageenans, phosphates and citrate also significant. Carboxymethylcellulose and polysorbate 80, which carry nearly the whole rodent literature, are absent from that list.

In the cancer analysis of 92,000 adults, the hazard for any cancer was 1.15 with mono- and diglycerides of fatty acids and for breast cancer 1.32 with carrageenans, while no association was detected between any emulsifier and colorectal cancer. For whole categories, each 10% increment of intake from ultra-processed sources carried type 2 diabetes at 1.17 across 311,892 people, and those authors recommended targeting specific foods rather than the category. In 116,087 adults, five or more servings a day was associated with incident inflammatory bowel disease at 1.82, interval 1.22 to 2.72.

These are small relative differences per small increments on very large cohorts. They do not establish that guar gum causes diabetes. They indicate that the human signal lives in the mixture.

Why the exposure cannot be quantified in your patient

Two practical limits govern this workup. The exposure variable itself is unreliable: asked to classify marketed foods by processing level, expert evaluators reached a Fleiss kappa of 0.32, while trained coder pairs working from a structured database reached 0.75. The category is codable but not intuitive, which is why a diet history beats a label recalled from memory.

The second limit is compartment. The mouse work indicates the relevant microbial change sits in the mucus layer and differs markedly from what appears in feces, so stool sequencing samples the wrong room. No commercial panel measures either compartment usefully, and none is offered here.

Why do additives harm some people more than others?

This is the part that changes selection. In animals, normal mice largely shrugged the additives off, while in strains already inflamed the fecal inflammatory marker rose roughly ten-fold. In humans, the single measurement of bacterial encroachment tracked glycemic control rather than adiposity: an r-squared of 0.51 for hemoglobin A1c and 0.46 for fasting glucose against 0.16 for body mass index, with obesity alone showing nothing and the difference disappearing when subjects with diabetes were removed.

Read the null feeding trial against that background. Sixteen healthy adults, eleven days, seven receiving 15 g a day of carboxymethylcellulose, and the primary measure did not move. Its power calculation assumed a gap of 19.13 microns, the separation recorded in that colonoscopy study between subjects with diabetes and those without, set against a within-group standard deviation of 7.17 microns. In effect it looked for a difference the size of diabetes in people without diabetes, and every inflammatory readout in it was null.

Which patients should be screened?

Reasonable candidates for cardiometabolic measurement when the diet history is additive-heavy:

• Patients with dysglycemia or known type 2 diabetes, in whom the human barrier measurement tracked A1c and fasting glucose.
• Patients with obesity, where body mass index conflates fat with lean mass and was the weakest correlate of the three.
• Patients with inflammatory bowel disease considering dietary restriction, where a blinded add-back trial in 154 adults with active Crohn’s disease reported response in 49.4% on restriction against 30.7% with emulsifiers returned, adjusted relative risk 3.1, interval 1.5 to 6.6. That is a congress abstract and weighs as one, and a four-week trial in 24 patients found no difference between diets.
• Patients whose reported intake is heavily engineered, where measured markers document the baseline before any dietary change is attempted.

What should be measured instead of the additive?

Two measurements carry this pathway, with results returned to the ordering physician:

• Laboratory panels for glycemic, lipid and inflammatory markers, which establish whether the patient resembles the inflamed host the mechanism describes or the healthy volunteer the trial enrolled.
• Bioimpedance body composition for the fat and lean compartments behind a body mass index, and for tracking change when the diet actually shifts.

Neither measures additives, mucus thickness or barrier penetrability, and no test in the library does. What they document is metaflammation as a set of current numbers, which is the variable the animal work says decides the outcome. Prevalence supports a low threshold: metabolic health is uncommon, at under 12.2% of US adults on NHANES 2009-2016 and under 7% under the tighter criteria after 2021.

Standing orders and documentation

A standing order attaching a laboratory panel and body composition measurement when the diet history is additive-heavy makes the baseline reproducible rather than dependent on which clinician takes the history. Filed as discrete data in the record, those values are still there when the patient returns having changed the food, which is the only way a dietary intervention gets evaluated. Those values also feed the quality measures practices already report through MIPS and quality reporting, which is a documentation benefit rather than an indication.

What the evidence does not settle

The strongest argument against acting on the category comes from inside it. Stratify by diet quality and the category stops predicting mortality, while diet quality keeps predicting within every stratum of intake. The field’s own umbrella review grades incident Crohn’s disease as class IV, weak evidence, and ulcerative colitis as class V, no evidence. Recent review language is explicit that current evidence supports biological plausibility rather than causality, and no human trial has demonstrated the whole pathway from additive to clinical disease.

The regulatory files answer a different question again. Their endpoints were acute toxicity, genotoxicity, carcinogenicity and reproductive toxicity, not microbiota, mucus or low-grade inflammation. The polysorbate group acceptable daily intake is 25 mg per kilogram of body weight per day, and the agency’s own exposure assessment placed toddlers at the highest level at 24.5. When data were formally requested on carboxymethylcellulose, business operators did not provide them, and one infant category could not be assessed at all. An unanswered question is not a safety finding in either direction.

What survives adjudication is practical. Restriction is feasible, with emulsifier-containing food frequency falling 94.6% in patients with stable Crohn’s disease, and the measurable variable in front of you is the host rather than the label. The patient-facing version of this argument is what no test can measure about emulsifier exposure.

Frequently asked questions

References

• Chazelas, E., Druesne-Pecollo, N., Esseddik, Y., de Edelenyi, F. S., Agaesse, C., De Sa, A., Lutchia, R., Rebouillat, P., Srour, B., Debras, C., Wendeu-Foyet, G., Huybrechts, I., Pierre, F., Coumoul, X., Julia, C., Kesse-Guyot, E., Alles, B., Galan, P., Hercberg, S., … Touvier, M. (2021). Exposure to food additive mixtures in 106,000 French adults from the NutriNet-Sante cohort. Scientific Reports, 11(1), 19680. https://doi.org/10.1038/s41598-021-98496-6
• Salame, C., Javaux, G., Sellem, L., Viennois, E., de Edelenyi, F. S., Agaesse, C., De Sa, A., Huybrechts, I., Pierre, F., Coumoul, X., Julia, C., Kesse-Guyot, E., Alles, B., Fezeu, L. K., Hercberg, S., Deschasaux-Tanguy, M., Cosson, E., Tatulashvili, S., Chassaing, B., … Touvier, M. (2024). Food additive emulsifiers and the risk of type 2 diabetes: analysis of data from the NutriNet-Sante prospective cohort study. The Lancet Diabetes & Endocrinology, 12(5), 339-349. https://doi.org/10.1016/S2213-8587(24)00086-X
• Sellem, L., Srour, B., Javaux, G., Chazelas, E., Chassaing, B., Viennois, E., Debras, C., Druesne-Pecollo, N., Esseddik, Y., Szabo de Edelenyi, F., Arnault, N., Agaesse, C., De Sa, A., Lutchia, R., Huybrechts, I., Scalbert, A., Pierre, F., Coumoul, X., Julia, C., … Touvier, M. (2024). Food additive emulsifiers and cancer risk: Results from the French prospective NutriNet-Sante cohort. PLoS Medicine, 21(2), e1004338. https://doi.org/10.1371/journal.pmed.1004338
• Dicken, S. J., Dahm, C. C., Ibsen, D. B., Olsen, A., Tjonneland, A., Louati-Hajji, M., Cadeau, C., Marques, C., Schulze, M. B., Jannasch, F., Baldassari, I., Manfredi, L., Santucci de Magistris, M., Sanchez, M.-J., Castro-Espin, C., Rodriguez Palacios, D., Amiano, P., Guevara, M., van der Schouw, Y. T., … Batterham, R. L. (2024). Food consumption by degree of food processing and risk of type 2 diabetes mellitus: A prospective cohort analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC). The Lancet Regional Health – Europe, 46, 101043. https://doi.org/10.1016/j.lanepe.2024.101043
• Narula, N., Wong, E. C. L., Dehghan, M., Mente, A., Rangarajan, S., Lanas, F., Lopez-Jaramillo, P., Rohatgi, P., Lakshmi, P. V. M., Varma, R. P., Orlandini, A., Avezum, A., Wielgosz, A., Poirier, P., Almadi, M. A., Altuntas, Y., Ng, K. K., Chifamba, J., Yeates, K., … Yusuf, S. (2021). Association of ultra-processed food intake with risk of inflammatory bowel disease: Prospective cohort study. BMJ, 374, n1554. https://doi.org/10.1136/bmj.n1554
• Chassaing, B., Compher, C., Bonhomme, B., Liu, Q., Tian, Y., Walters, W., Nessel, L., Delaroque, C., Hao, F., Gershuni, V., Chau, L., Ni, J., Bewtra, M., Albenberg, L., Bretin, A., McKeever, L., Ley, R. E., Patterson, A. D., Wu, G. D., … Lewis, J. D. (2022). Randomized controlled-feeding study of dietary emulsifier carboxymethylcellulose reveals detrimental impacts on the gut microbiota and metabolome. Gastroenterology, 162(3), 743-756. https://doi.org/10.1053/j.gastro.2021.11.006
• Chassaing, B., Raja, S. M., Lewis, J. D., Srinivasan, S., & Gewirtz, A. T. (2017a). Colonic microbiota encroachment correlates with dysglycemia in humans. Cellular and Molecular Gastroenterology and Hepatology, 4(2), 205-221. https://doi.org/10.1016/j.jcmgh.2017.04.001
• Chassaing, B., Van de Wiele, T., De Bodt, J., Marzorati, M., & Gewirtz, A. T. (2017b). Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut, 66(8), 1414-1427. https://doi.org/10.1136/gutjnl-2016-313099
• Chassaing, B., Koren, O., Goodrich, J. K., Poole, A. C., Srinivasan, S., Ley, R. E., & Gewirtz, A. T. (2015). Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature, 519(7541), 92-96. https://doi.org/10.1038/nature14232
• EFSA Panel on Food Additives and Flavourings (FAF), Younes, M., Aquilina, G., Castle, L., Degen, G., Engel, K.-H., Fowler, P. J., Frutos Fernandez, M. J., Furst, P., Gurtler, R., Husoy, T., Manco, M., Mennes, W., Moldeus, P., Passamonti, S., Shah, R., Waalkens-Berendsen, I., Wright, M., Dusemund, B., … Gundert-Remy, U. (2022). Opinion on the re-evaluation of sodium carboxy methyl cellulose (E 466) as a food additive in foods for infants below 16 weeks of age and follow-up of its re-evaluation as food additive for uses in foods for all population groups. EFSA Journal, 20(12), e07665. https://doi.org/10.2903/j.efsa.2022.7665

Related reading

• Short-Chain Fatty Acids: Why a Fecal Panel Misleads
• Visceral Adiposity: Screening for the Risk That BMI Misclassifies
• Laboratory Panels

Short-Chain Fatty Acids: Why a Fecal Panel Misleads

Short-chain fatty acids on a fecal panel are residue, not production: colonocytes absorb 95% of what fermentation makes, so the stool value reads the 5% left over. That number supports no deficiency diagnosis and no dose.

Patients arrive with a flagged butyrate result and a supplement already started. The assay reads what the epithelium did not absorb, which makes it the wrong input for a management decision.

Short-chain fatty acids reach the exam room on direct-to-consumer stool reports, usually with butyrate flagged low and a capsule already bought. The defensible response is not to argue about the supplement but to say what the assay sampled, then measure something that changes management.

The chapter video, Full of Calories, Starving One Cell Deep, presents chapter 14 of The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes. Trial-level numbers, with the limits of each study, sit in the book’s Deep Dive companion. Measura [Cardiometabolic and Autonomic Health Analysis] is a testing service and performs no stool, breath or endoscopic studies.

What does a fecal short-chain fatty acid test measure?

Colonocytes absorb 95% of what fermentation produces, leaving 5% to exit in stool, which is the fraction any fecal assay reads. Systemic availability measured with labeled substrate delivered into the human colon runs 2% for butyrate, 9% for propionate and 36% for acetate. Butyrate is a local fuel consumed at the epithelium, not a circulating hormone.

The measurement rule follows directly: a fecal concentration is residue, not production. A low value is equally consistent with efficient absorption, and production estimates themselves carry spreads nearly as large as the point estimate. Nothing in that report supports a deficiency diagnosis or a dose.

Does butyrate supply 70% of colon cell energy?

Dr. Padda taught the line that butyrate supplies 70% of colonocyte energy for years before reading the 1980 source, and says so plainly. That experiment used colonocyte suspensions from 14 operative specimens: butyrate accounted for 73% of oxygen consumption in ascending and 75% in descending colon, falling to 59% and 72% when physiological glucose was present. The endpoint was oxygen consumption in a dish. No equivalent measurement exists in a living human, and the correct restatement is more than 70% of the oxygen consumed by colonic epithelium.

The patient in whom this matters

The presenting picture is loose stools for years, a normal colonoscopy, biopsies reported as mild nonspecific changes, and a diet with almost nothing fermentable in it. Two prescriptions usually sit alongside. Among 1,815 people, 211 of them taking a proton pump inhibitor, use was associated with reduced diversity and change in 20% of bacterial taxa, which the authors judged more prominent at population level than antibiotics.

The combination has one randomized human test. Small-bowel injury on capsule endoscopy appeared in 44.4% of volunteers given an acid blocker with an anti-inflammatory against 16.7% on placebo, a relative risk of 2.67 with an interval of 1.08 to 6.58, and the lesions were jejunal in 26% of the treated group. Healthy young volunteers, two weeks, a surrogate endpoint. It remains the only trial of a pairing carried by millions of patients.

Three drivers converge, and only two are biological: fermentable substrate absent from the plate, an acid-suppressed and reshaped luminal community, and a review structure in which a renewal takes seconds while reconsidering the indication takes a visit nobody books. The agricultural incentive that fills the plate with acellular carbohydrate is the same one that empties it of fermentable fiber.

Which has the evidence, fiber or a butyrate supplement?

Dietary fiber, not a metabolite in a capsule, carries the outcome evidence. Across 185 prospective studies and 58 clinical trials, higher fiber intake tracked with 15-30% lower all-cause and cardiovascular mortality, and the band of greatest benefit ran from 25 g to 29 g daily. For constipation, fiber produced response in 66% against 41% on control, a relative risk of 1.48 with an interval of 1.17 to 1.88, an effect carried by psyllium and pectin above 10 g a day.

Counsel the predictable adverse effect in advance. In irritable bowel syndrome prebiotics performed numerically worse than placebo, 54% against 63%, and inulin-type fructans significantly worsened flatulence. Imaged directly, 20 g of inulin produced a colonic gas area under the curve of 3145 mL.min, cut to 618 by co-administered psyllium. Habitual intake predicts response: established high-fiber eaters gained the major butyrate producer while low-fiber eaters did not, which inverts how these products are marketed.

Oral and rectal butyrate do not substitute. Four grams daily for a month in 30 adults with longstanding type 1 diabetes raised fecal butyrate and changed no prespecified outcome. Enema trials pooled across eight randomized studies and 227 patients showed no endoscopic or histologic separation from control.

What to measure instead

Stool short-chain fatty acid panels, breath testing and endoscopy are studies performed elsewhere. What can be added to this workup is the metabolic terrain the bowel sits in, reported back to the ordering physician:

• Laboratory panels for current glycemic, lipid and inflammatory markers, which is where metaflammation becomes a number rather than an adjective.
• Bioimpedance body composition to separate fat from lean mass in a patient whose weight has been stable through years of symptoms.
• Indirect calorimetry for measured resting energy expenditure when fatigue has been attributed to age or to the bowel by default.

Prevalence justifies a low threshold to test: on NHANES 2009-2016 under 12.2% of US adults were metabolically healthy, and under 7% under the tighter post-2021 criteria.

Standing orders, workflow and documentation

A standing order attaching a laboratory panel and body composition measurement to patients on chronic acid suppression with persistent bowel symptoms removes the decision from the individual encounter, which is the only way the longitudinal record gets built. Results filed as discrete data in the chart stay visible when the next refill request appears. The same values populate diabetes and body mass index measures practices already report through MIPS and quality reporting, which is a documentation benefit and never an indication on its own.

Where the evidence stops

The oxygen mechanism is mouse and cell work; no one has held a probe against living human epithelium for a week. In inflamed tissue the defect is transport, not combustion, since the butyrate transporter is downregulated by interferon-gamma and tumor necrosis factor-alpha, and across 207 people oxidation was impaired only in endoscopically active disease. And the treatment that heals pediatric Crohn’s mucosa better than steroids, at a relative risk of 2.36 with an interval of 1.22 to 4.57, is a fiber-poor formula under which fecal butyrate falls. That paradox is unresolved and stated as such.

The practice position is unchanged by it: feed the producers, revisit the prescriptions, and measure the terrain rather than the residue. The patient-facing version of the same argument is what a flagged butyrate result really samples.

Frequently asked questions

References

• den Besten, G., van Eunen, K., Groen, A. K., Venema, K., Reijngoud, D.-J., & Bakker, B. M. (2013). The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. Journal of Lipid Research, 54(9), 2325-2340. https://doi.org/10.1194/jlr.R036012
• Boets, E., Gomand, S. V., Deroover, L., Preston, T., Vermeulen, K., De Preter, V., Hamer, H. M., Van den Mooter, G., De Vuyst, L., Courtin, C. M., Annaert, P., Delcour, J. A., & Verbeke, K. A. (2017). Systemic availability and metabolism of colonic-derived short-chain fatty acids in healthy subjects: a stable isotope study. The Journal of physiology, 595(2), 541-555. https://doi.org/10.1113/JP272613
• Roediger, W. E. (1980a). Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut, 21(9), 793-798. https://doi.org/10.1136/gut.21.9.793
• Imhann, F., Bonder, M. J., Vich Vila, A., Fu, J., Mujagic, Z., Vork, L., Tigchelaar, E. F., Jankipersadsing, S. A., Cenit, M. C., Harmsen, H. J., Dijkstra, G., Franke, L., Xavier, R. J., Jonkers, D., Wijmenga, C., Weersma, R. K., & Zhernakova, A. (2016). Proton pump inhibitors affect the gut microbiome. Gut, 65(5), 740-8. https://doi.org/10.1136/gutjnl-2015-310376
• Washio, E., Esaki, M., Maehata, Y., Miyazaki, M., Kobayashi, H., Ishikawa, H., Kitazono, T., & Matsumoto, T. (2016). Proton pump inhibitors increase incidence of nonsteroidal anti-inflammatory drug-induced small bowel injury: A randomized, placebo-controlled trial. Clinical gastroenterology and hepatology, 14(6), 809-815.e1. https://doi.org/10.1016/j.cgh.2015.10.022
• Reynolds, A., Mann, J., Cummings, J., Winter, N., Mete, E., & Te Morenga, L. (2019). Carbohydrate quality and human health: a series of systematic reviews and meta-analyses. Lancet (London, England), 393(10170), 434-445. https://doi.org/10.1016/S0140-6736(18)31809-9
• van der Schoot, A., Drysdale, C., Whelan, K., & Dimidi, E. (2022). The effect of fiber supplementation on chronic constipation in adults: An updated systematic review and meta-analysis of randomized controlled trials. The American journal of clinical nutrition, 116(4), 953-969. https://doi.org/10.1093/ajcn/nqac184
• de Groot, P. F., Nikolic, T., Imangaliyev, S., Bekkering, S., Duinkerken, G., Keij, F. M., Herrema, H., Winkelmeijer, M., Kroon, J., Levin, E., Hutten, B., Kemper, E. M., Simsek, S., Levels, J. H. M., van Hoorn, F. A., Bindraban, R., Berkvens, A., Dallinga-Thie, G. M., Davids, M., … Nieuwdorp, M. (2020). Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial. Diabetologia, 63(3), 597-610. https://doi.org/10.1007/s00125-019-05073-8
• Thibault, R., De Coppet, P., Daly, K., Bourreille, A., Cuff, M., Bonnet, C., Mosnier, J.-F., Galmiche, J.-P., Shirazi-Beechey, S., & Segain, J.-P. (2007). Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation. Gastroenterology, 133(6), 1916-1927. https://doi.org/10.1053/j.gastro.2007.08.041
• Ding, Z., Ninan, K., Johnston, B. C., Moayyedi, P., Sherlock, M., & Zachos, M. (2023). Microbiota signatures and mucosal healing in the use of enteral nutrition therapy versus corticosteroids for the treatment of children with Crohn’s disease: A systematic review and meta-analysis. The British Journal of Nutrition, 130(8), 1385-1402. https://doi.org/10.1017/S0007114523000405

Related reading

• Psychogastroenterology in Practice: Measuring the Autonomic Side
• Ultra-Processed Food: Measure the Host, Not the Additive
• Laboratory Panels

Psychogastroenterology in Practice: Measuring the Autonomic Side

Autonomic testing gives psychogastroenterology its objective record: stress-driven gut dysmotility registers on heart rate variability while pulse and blood pressure stay normal, and that is the physiology a psychotherapy referral otherwise leaves undocumented.

Brain-gut behavioral therapies carry randomized evidence that most gut-directed products lack. What is usually missing is an objective autonomic record beside the symptom score.

Psychogastroenterology has a referral problem written into its own guidance. The American College of Gastroenterology conditionally suggests gut-directed psychotherapies for irritable bowel syndrome, on very low quality evidence with a collective number needed to treat of 4, then advises that patients with comorbid mental health conditions, who respond less well, be referred to non-gastrointestinal mental health professionals (Lacy et al., 2021). The patient with the most autonomic load is the one most likely to leave the building.

In The Angry Gut, Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes frame that gap, and the companion video Two Doctors, One Bowel, Nobody in Charge follows it through a patient with biopsy-proven Crohn’s disease and a trauma history. Measura [Cardiometabolic and Autonomic Health Analysis] is a testing service that returns findings to the ordering physician. Its contribution here is narrow and specific: an objective autonomic record beside the symptom score.

How does stress change gut motility?

Dr. Padda concedes he spent years using stress as a closing diagnosis after a clean endoscopy. The motility literature argues against that habit. In healthy volunteers with colonic manometry, psychological stress produced more propagated contractions and physical stress more simultaneous ones, with no regional differences; only the physical stressor raised pulse and blood pressure, and colonic activity stayed elevated after the psychological stressor ended (Rao et al., 1998).

Electrogastrography adds the autonomic link. Stress abolished the postprandial rise in gastric myoelectrical activity and dropped the percentage of normal slow waves from 82.0% to 66.0%, while spectral heart rate variability showed vagal inhibition and rising sympathetic activity at the same time (Yin et al., 2004). Acute auditory stress lengthened gastric half-emptying from 105.0 to 130.8 minutes with accommodation preserved (Lee et al., 2013), in eight subjects, seven of them men. In 18 healthy subjects, vagal stimulation raised cardiac vagal tone against sham, p = 0.009, along with antral contraction frequency, p = 0.004 (Frøkjaer et al., 2016).

The clinical reading: pulse and blood pressure are too coarse to register stress-driven dysmotility, while HRV-level measures tracked it under laboratory conditions. None of these studies enrolled patients, and the patient trial the vagal authors requested has not been run.

Which GI patients carry the most autonomic load?

Across 8 studies and 648,375 subjects, PTSD and IBS associated at a pooled odds ratio of 2.80 (Ng et al., 2019). Post-infectious cohorts identify the host state as the predictor. In Walkerton, prior anxiety or depression predicted persistent IBS, with odds of 3.12 against unexposed residents at eight years (Marshall et al., 2010). After the German outbreak, somatization and anxiety scores survived the model and acute disease severity did not (Andresen et al., 2016). In two tertiary IBS samples of 231 and 141, somatization mediated most visceral sensitivity on barostat testing, though abuse history retained an independent effect on some parameters (Grinsvall et al., 2018).

Two biological drivers converge. One is vagal withdrawal with sympathetic predominance, the state the motility studies captured. The second is an inflammatory threshold: in 2,555 Marines, pre-deployment CRP predicted whether PTSD symptoms emerged, with an odds ratio of 1.51 per 10-fold increment, but not their severity (Eraly et al., 2014), and in a metabolically loaded population metaflammation is a common source of that baseline. The third driver is organizational. Gastroenterology and psychiatry run separate schedules, and a patient shared between them is owned by neither.

Practical selection criteria for autonomic testing in a GI or primary care population:

• Functional GI symptoms that persist after a structural and inflammatory workup is negative.
• Inflammatory bowel disease with pain between flares despite normal markers.
• Symptom onset after an enteric infection.
• A documented trauma history, PTSD, anxiety or depression alongside GI symptoms.

What can autonomic tests measure in a GI patient, and what can’t they?

Heart rate variability quantifies beat-to-beat variation as an index of vagal and sympathetic balance. Cardiac autonomic reflex tests record heart rate and blood pressure responses to standardized maneuvers such as paced breathing and standing. Autonomic nervous system testing extends the assessment of autonomic regulation more broadly.

None of these diagnoses IBS, distinguishes functional from inflammatory disease, or substitutes for Rome criteria and a gastroenterology workup. An abnormal result describes the autonomic state of a patient who already carries a GI diagnosis; a normal result does not exclude a brain-gut disorder. Stool microbiome profiling and blood permeability panels are different tests performed elsewhere, and both carry validity problems: host variables such as bowel movement quality confound microbiome case-control comparisons (Vujkovic-Cvijin et al., 2020), and the most widely used commercial zonulin ELISA did not detect its named target (Scheffler et al., 2018).

Because the adversity-to-inflammation path in adult women ran through body weight (Hantsoo et al., 2026), bioimpedance body composition is a reasonable metabolic companion measure where adiposity is in question.

What does an autonomic finding change in GI management?

It does not change disease-directed GI therapy. A patient with Crohn’s disease stays on the biologic that controls flares. What it changes is the case for delivering brain-gut behavioral care early and in the same practice. A network meta-analysis of 67 randomized trials (7,441 patients) found behavioral therapies, including CBT and gut-directed hypnotherapy, outperformed waiting-list control on global IBS symptoms (Thakur et al., 2025). Telephone CBT lowered symptom severity by 61.6 points against usual care at 12 months in 558 patients (Everitt et al., 2019). Gut-directed hypnotherapy matched the low FODMAP diet on symptoms and alone improved trait anxiety and depression (Peters et al., 2016).

Body-based methods sit at a lower tier: no breath-based or somatic trial has reported a primary bowel endpoint, and those trials have not enrolled the patient with inflammatory disease, trauma and pain. The practice position uses them on mechanism. A documented autonomic baseline gives the treating team an objective reference before therapy begins and a comparison point afterward, without implying that the value itself is the treatment target. The cortisol and HPA side is covered in HPA axis dysfunction in chronic pain.

Psychogastroenterology workflow and documentation

A standing order keyed to a negative GI workup plus persistent symptoms makes autonomic testing reproducible rather than clinician-dependent. Results should land in the chart as structured data; see getting results into the record. The metabolic and cognitive counterpart is screening the drivers of blood-brain barrier dysfunction, the patient version is written for the person with the symptoms, and the full evidence with its limits is in the Chapter 13 Deep Dive.

Frequently asked questions

References

• Lacy, B. E., Pimentel, M., Brenner, D. M., Chey, W. D., Keefer, L. A., Long, M. D., & Moshiree, B. (2021). ACG clinical guideline: management of irritable bowel syndrome. The American Journal of Gastroenterology, 116(1), 17-44. https://doi.org/10.14309/ajg.0000000000001036
• Rao, S. S., Hatfield, R. A., Suls, J. M., & Chamberlain, M. J. (1998). Psychological and physical stress induce differential effects on human colonic motility. The American Journal of Gastroenterology, 93(6), 985-990. https://doi.org/10.1111/j.1572-0241.1998.00293.x
• Yin, J., Levanon, D., & Chen, J. D. Z. (2004). Inhibitory effects of stress on postprandial gastric myoelectrical activity and vagal tone in healthy subjects. Neurogastroenterology and Motility, 16(6), 737-744. https://doi.org/10.1111/j.1365-2982.2004.00544.x
• Lee, H. S., An, Y.-S., Kang, J., Yoo, J. H., & Lee, K. J. (2013). Effect of acute auditory stress on gastric motor responses to a meal in healthy volunteers. Journal of Gastroenterology and Hepatology, 28(11), 1699-1704. https://doi.org/10.1111/jgh.12309
• Frøkjaer, J. B., Bergmann, S., Brock, C., Madzak, A., Farmer, A. D., Ellrich, J., & Drewes, A. M. (2016). Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity. Neurogastroenterology and Motility, 28(4), 592-598. https://doi.org/10.1111/nmo.12760
• Ng, Q. X., Soh, A. Y. S., Loke, W., Venkatanarayanan, N., Lim, D. Y., & Yeo, W.-S. (2019). Systematic review with meta-analysis: The association between post-traumatic stress disorder and irritable bowel syndrome. Journal of Gastroenterology and Hepatology, 34(1), 68-73. https://doi.org/10.1111/jgh.14446
• Andresen, V., Löwe, B., Broicher, W., Riegel, B., Fraedrich, K., von Wulffen, M., Gappmayer, K., Wegscheider, K., Treszl, A., Rose, M., Layer, P., & Lohse, A. W. (2016). Post-infectious irritable bowel syndrome (PI-IBS) after infection with Shiga-like toxin-producing Escherichia coli (STEC) O104:H4: A cohort study with prospective follow-up. United European Gastroenterology Journal, 4(1), 121-131. https://doi.org/10.1177/2050640615581113
• Grinsvall, C., Törnblom, H., Tack, J., Van Oudenhove, L., & Simrén, M. (2018). Relationships between psychological state, abuse, somatization and visceral pain sensitivity in irritable bowel syndrome. United European Gastroenterology Journal, 6(2), 300-309. https://doi.org/10.1177/2050640617715851
• Eraly, S. A., Nievergelt, C. M., Maihofer, A. X., Barkauskas, D. A., Biswas, N., Agorastos, A., O’Connor, D. T., & Baker, D. G. (2014). Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry, 71(4), 423-431. https://doi.org/10.1001/jamapsychiatry.2013.4374
• Thakur, E. R., Khasawneh, M., Moayyedi, P., Black, C. J., & Ford, A. C. (2025). Efficacy of behavioural therapies for irritable bowel syndrome: a systematic review and network meta-analysis. The Lancet Gastroenterology & Hepatology, 10(12), 1075-1088. https://doi.org/10.1016/S2468-1253(25)00238-9

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• Blood-Brain Barrier Dysfunction: Screening the Metabolic Drivers
• Short-Chain Fatty Acids: Why a Fecal Panel Misleads
• Heart Rate Variability

Blood-Brain Barrier Dysfunction: Screening the Metabolic Drivers

Blood-brain barrier dysfunction is leakage across the brain’s barrier, and it appears before inflammatory markers move: in mild impairment a pericyte injury marker was 115% higher while spinal fluid cytokines were unchanged. Screening it means documenting the correlates primary care already owns: diabetes and adiposity.

The best-replicated barrier data point at insulin load and endothelial strain, not amyloid. That moves the actionable part of a memory workup into primary care.

A patient with a borderline cognitive screen is usually scheduled for a repeat in twelve months. Blood-brain barrier dysfunction, measured in living humans, is already present before that screen fails, and its best-documented correlates are diabetes, adiposity and endothelial strain: variables a primary care chart already tracks, or should.

The video A Waistline Predicted a Leaking Brain, from The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, walks through the imaging and spinal fluid record. The screening question it raises is practical. Measura [Cardiometabolic and Autonomic Health Analysis] is a testing service that returns findings to the ordering physician; it does not diagnose or treat, and it does not measure barrier permeability. What it can document is the metabolic, vascular and cognitive terrain the permeability literature keeps implicating.

How is blood-brain barrier leakage measured, and how strong is the evidence?

Dynamic contrast MRI changed the model. Cognitively normal older adults showed hippocampal permeability 41% above young controls, 107% in CA1 and 48% in the dentate gyrus; in mild cognitive impairment the same regions rose by 24%, 53% and 27% over age-matched controls (Montagne et al., 2015). The same series found the reverse map in multiple sclerosis, with white matter changes of 32%, 26% and 23% and no hippocampal change, which argues the method is regionally specific rather than noisy.

In 245 participants imaged and 350 with spinal fluid, cognitively normal APOE4 carriers already had hippocampal and parahippocampal breakdown with no difference in amyloid or tau tracer uptake, and baseline pericyte injury predicted decline only in carriers (Montagne et al., 2020). Grade this correctly: these papers come from one group with overlapping cohorts. It is a deepening record, not independent replication, and the practice position is built on it with that label attached.

Does blood-brain barrier leakage appear before inflammation?

The underused result is temporal. In the 2015 cohort, spinal fluid cytokines (among them interleukin-6 and TNF-alpha), soluble adhesion molecules, tau and amyloid species showed no change, while soluble PDGFR-beta, a pericyte injury marker, was 115% higher in mild impairment and the albumin ratio was 30% higher. The 2019 follow-up in 161 people found no impaired-versus-unimpaired difference across 20 glial, inflammatory and degeneration biomarkers, while barrier measures still added predictive weight once amyloid and tau were in the model (Nation et al., 2019). Its enrollment deliberately left out vascular dementia and substantial cerebrovascular pathology, which partly manufactures the apparent independence from vascular risk.

The management implication is uncomfortable. A normal inflammatory panel in a patient with a memory complaint is not reassurance about the barrier. If leakage precedes the inflammatory signal, an anti-inflammatory strategy arrives late by design, and the earlier lever is whatever load is opening the door.

What causes blood-brain barrier dysfunction?

The CSF-to-serum albumin ratio, in 1,015 people, was unchanged in preclinical and prodromal Alzheimer’s disease, did not track amyloid PET or APOE genotype, and was elevated in diabetes, correlating with VEGF, ICAM-1 and VCAM-1 (Janelidze et al., 2017). In the healthy elderly arm, higher body mass index and waist-hip ratio predicted a raised ratio two decades later. Across 1,861 dementia patients, the ratio followed neurofilament light rather than Alzheimer’s biomarkers (Skillbäck et al., 2017). In type 2 diabetes, white matter permeability was raised before small vessel disease was visible on conventional imaging, independent of recent glycemic control, in a small sample of 25 patients against 12 controls (Chen et al., 2022).

Two biological drivers, then: chronic hyperinsulinemia and glucose load, the core of metaflammation, and endothelial dysfunction downstream of it. The third is structural. Memory complaints route to neurology, bowel complaints to gastroenterology, and waist circumference to no one, while the food environment keeps loading the variable nobody records. A postmortem series in CADASIL, 12 patients and 10 controls, found white matter lesion leakage inconsistent (Rajani et al., 2019), a reminder that not every hyperintensity implies an open barrier.

Who should be tested for blood-brain barrier dysfunction?

Reasonable selection criteria, consistent with Measura’s clinical selection page, include adults with a memory complaint or borderline screen plus one or more of the following:

• Type 2 diabetes, prediabetes or suspected insulin resistance with a normal-appearing glucose history.
• Central adiposity, or a BMI that underestimates fat mass.
• Long-standing constipation. In 462,327 adults, constipation came before the combined outcome of stroke, dementia or Parkinson’s disease (adjusted HR 1.35), and dementia risk alone was 50% higher (Yun et al., 2025), strongest in the first two years, which also fits reverse causation.
• Microbleeds on existing imaging in a diabetic patient. Of 4,500 candidate classification criteria tested, microbleeds were among only six that separated permeability.
• Severe periodontitis, which in a national cohort of 10,115 matched pairs carried a hazard ratio of 1.24 for vascular dementia.

Can Measura measure blood-brain barrier dysfunction?

Permeability itself belongs to research imaging and CSF studies, and those two methods disagree in early disease. Stool calprotectin, which the chapter uses to ask whether the first brain is inflamed, is a separate test done elsewhere. Within the protocol, four measurements map onto the drivers:

• Cognitive assessment converts a borderline screen into a documented baseline with a defined re-test interval, which pairs naturally with fall-risk evaluation.
• Bioimpedance body composition separates fat mass from lean mass where BMI conflates them.
• Laboratory panels quantify fasting insulin and glycemic markers.
• Arterial stiffness and endothelial function gives a systemic vascular reading. It is not a cerebral measurement, and it should not be reported as one.

What a finding changes: a patient with a documented cognitive baseline, excess fat mass and hyperinsulinemia now has a measurable target and a re-measure date instead of a year of watchful waiting. The levers are nutrition, meal timing, sleep and activity; no intervention trial has yet shown that lowering waist circumference and fasting insulin reduces hippocampal permeability, and the mechanism tier is stated as such. The insulin side of the dementia argument is developed in insulin resistance and dementia screening.

Documentation and workflow

The annual wellness visit already carries a cognitive component, which makes it the natural encounter for recording body composition and metabolic values beside the cognitive result; see annual wellness visit integration. A standing order triggered by a borderline screen plus a metabolic criterion removes the dependence on individual recall. The primary care screening sequence is in cognitive screening in primary care, the patient-facing version is here, and the study-by-study limits are in the Chapter 12 Deep Dive. The next physician piece covers autonomic measurement in psychogastroenterology.

Frequently asked questions

References

• Montagne, A., Barnes, S. R., Sweeney, M. D., Halliday, M. R., Sagare, A. P., Zhao, Z., Toga, A. W., Jacobs, R. E., Liu, C. Y., Amezcua, L., Harrington, M. G., Chui, H. C., Law, M., & Zlokovic, B. V. (2015). Blood-brain barrier breakdown in the aging human hippocampus. Neuron, 85(2), 296-302. https://doi.org/10.1016/j.neuron.2014.12.032
• Montagne, A., Nation, D. A., Sagare, A. P., Barisano, G., Sweeney, M. D., Chakhoyan, A., Pachicano, M., Joe, E., Nelson, A. R., D’Orazio, L. M., Buennagel, D. P., Harrington, M. G., Benzinger, T. L. S., Fagan, A. M., Ringman, J. M., Schneider, L. S., Morris, J. C., Reiman, E. M., Caselli, R. J., … Zlokovic, B. V. (2020). APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature, 581(7806), 71-76. https://doi.org/10.1038/s41586-020-2247-3
• Nation, D. A., Sweeney, M. D., Montagne, A., Sagare, A. P., D’Orazio, L. M., Pachicano, M., Sepehrband, F., Nelson, A. R., Buennagel, D. P., Harrington, M. G., Benzinger, T. L. S., Fagan, A. M., Ringman, J. M., Schneider, L. S., Morris, J. C., Chui, H. C., Law, M., Toga, A. W., & Zlokovic, B. V. (2019). Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nature Medicine, 25(2), 270-276. https://doi.org/10.1038/s41591-018-0297-y
• Janelidze, S., Hertze, J., Nägga, K., Nilsson, K., Nilsson, C., Wennström, M., van Westen, D., Blennow, K., Zetterberg, H., & Hansson, O. (2017). Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype. Neurobiology of Aging, 51, 104-112. https://doi.org/10.1016/j.neurobiolaging.2016.11.017
• Skillbäck, T., Delsing, L., Synnergren, J., Mattsson, N., Janelidze, S., Nägga, K., Kilander, L., Hicks, R., Wimo, A., Winblad, B., Hansson, O., Blennow, K., Eriksdotter, M., & Zetterberg, H. (2017). CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients. Neurobiology of Aging, 59, 1-9. https://doi.org/10.1016/j.neurobiolaging.2017.06.028
• Chen, Y. C., Lu, B. Z., Shu, Y. C., & Sun, Y. T. (2022). Spatiotemporal dynamics of cerebral vascular permeability in type 2 diabetes-related cerebral microangiopathy. Frontiers in Endocrinology, 12, 805637. https://doi.org/10.3389/fendo.2021.805637
• Rajani, R. M., Ratelade, J., Domenga-Denier, V., Hase, Y., Kalimo, H., Kalaria, R. N., & Joutel, A. (2019). Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL. Acta Neuropathologica Communications, 7(1), 187. https://doi.org/10.1186/s40478-019-0844-x
• Yun, Q., Wang, S., Li, B., Yang, Z., Wei, C., Yuan, J., Hu, J., Li, Y., Yang, Z., Sha, F., & Tang, J. (2025). Constipation preceding stroke, dementia and Parkinson’s disease in middle-aged and older adults: a population-based cohort study. Age and Ageing, 54(9), afaf257. https://doi.org/10.1093/ageing/afaf257
• Kim, D. H., Jeong, S. N., & Lee, J. H. (2020). Severe periodontitis with tooth loss as a modifiable risk factor for the development of Alzheimer, vascular, and mixed dementia: National Health Insurance Service-National Health Screening Retrospective Cohort 2002-2015. Journal of Periodontal & Implant Science, 50(5), 303-312. https://doi.org/10.5051/jpis.2000600030
• Cortexyme, Inc. (sponsor). ClinicalTrials.gov registry record NCT03823404. (2022). GAIN Trial: A randomized, double-blind, placebo-controlled study of COR388 in subjects with Alzheimer’s disease. https://clinicaltrials.gov/study/NCT03823404

Related reading

• HLA-B27 and Ulcerative Colitis: Screening for Spinal Involvement
• Psychogastroenterology in Practice: Measuring the Autonomic Side
• Cognitive Assessment

HLA-B27 and Ulcerative Colitis: Screening for Spinal Involvement

HLA-B27 sharply raises the risk of spinal disease in ulcerative colitis: in pooled cohorts, carriers had a relative risk of 22.17 for ankylosing spondylitis. Across 71 studies of inflammatory bowel disease, 10% of patients had sacroiliitis and 3% ankylosing spondylitis, yet axial symptoms are rarely asked about.

Axial involvement in inflammatory bowel disease is common, gene-sorted and rarely asked about. Neither the gastroenterology visit nor the spine workup is built to catch it.

HLA-B27 is the sharpest available risk marker for axial disease in ulcerative colitis, and the HLA-B27 ulcerative colitis patient is seldom screened for it. In a meta-analysis of ulcerative colitis cohorts, carriage conferred a relative risk of 22.17 for ankylosing spondylitis, and 68.29% of those who developed it were carriers against 31.71% who were not. Because just three of the pooled studies recorded carrier status, the confidence around that figure is broad.

In the video Your Gut Is Reaching Your Spine, Chapter 11 of The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, the gut-to-spine evidence is sorted into tiers: inflammatory spread that is established, and a disc microbiome hypothesis that is not. For the physician, the established tier is the actionable one. It defines whom to ask, what to order, where to refer and what to document.

How common is spine involvement in ulcerative colitis and IBD?

Across 71 studies, prevalence in inflammatory bowel disease was 10% for sacroiliitis, 3% for ankylosing spondylitis and 13% for peripheral arthritis. Only three incidence studies exist, with follow-up windows of 5 to 30 years, so prevalence is well described and rate of onset is not. A 52-study synthesis of 352,454 patients reported at least one extraintestinal manifestation in 24%, with subtype figures of 27% for ulcerative colitis and 35% for Crohn’s disease drawn from different pooled subsets, and axial involvement at comparable rates in both.

The arrow also runs in reverse. Of 108 patients with ankylosing spondylitis and no known bowel disease who underwent ileocolonoscopy, 40 had inflammatory lesions and 17 had a diagnosable disease: Crohn’s in 12, intestinal tuberculosis in 4 and ulcerative colitis in 1. Among those scoped purely as screening, 17.6% showed abnormalities, predominantly erosions and ulcers. That series was retrospective, single-center, symptom-enriched and unadjusted for NSAID exposure.

The miss is structural rather than a knowledge gap. Gastroenterology follow-up is organized around the bowel, the spine pathway around the disc, and neither visit template carries the question that links them.

How does HLA-B27 link gut and spine inflammation?

HLA-B27 transgenic rats develop gut and joint inflammation; raised without microbial colonization they develop neither, while skin and genital lesions still appear. In human ileal biopsies, interleukin-23 is overexpressed in ankylosing spondylitis without a matching rise in interleukin-17. Spondylitis gut biopsies also show inflammasome expression roughly tenfold above controls (NLRP3 fold induction 22.2 versus 2.33), with NLRP3 correlating with spinal disease activity at r = 0.28, a modest association.

The management implication is concrete. An interleukin-17A antagonist that performs in axial disease was ineffective in Crohn’s disease, with outcomes worse than placebo, in a phase II trial in which 18 of 59 patients discontinued early. In a patient carrying both diagnoses, a therapy chosen for the spine can work against the bowel, which means the axial diagnosis should be made and shared before that choice.

Imaging findings and the antibiotic request

The lumbar MRI rarely settles the question. Modic changes are present in about 6% of asymptomatic people and a median 43% of those with back pain; type 1 carries an odds ratio of 4.01 for pain, while unspecified Modic change carries 1.62 with an interval spanning one. Patients who have read about disc bacteria may request antibiotics. The Norwegian multicenter trial prespecified a minimal important difference of 4 points and found −1.6, with −2.3 in type 1 and −0.1 in type 2, and drug-related adverse events of 56% against 34%. The 2026 Australian trial found a twelve-month pain difference of 0.06 on a 0-to-10 scale, though only six of 170 participants had type 1 changes alone.

What Measura measures, and what it does not

Measura [Cardiometabolic and Autonomic Health Analysis] does not image the sacroiliac joints, scope the bowel, sequence stool or perform HLA typing; those remain with the ordering physician and specialists. What the protocol contributes is a documented terrain in the same patient:

• Laboratory panels for the metabolic markers of insulin resistance that accompany metaflammation.
• Bioimpedance body composition for fat and lean compartments that BMI conflates.
• Autonomic nervous system testing and heart rate variability for autonomic balance in patients whose nocturnal pain fragments sleep.

None of these diagnoses spondyloarthritis. They document the upstream drivers of a breached barrier: acellular carbohydrates that deplete short-chain fatty acid producers, industrial seed oils, sleep lost to night pain, and metaflammation beneath all of them. In a pilot of surgical patients with disc disease, 20 per subgroup, stool showed depleted short-chain fatty acid producers while CRP ran elevated. How results are structured for the chart is covered in interpreting the report.

A workflow for the inflammatory bowel disease panel

1. Add an inflammatory back pain screen to bowel disease visits: nocturnal pain in the second half of the night, morning stiffness beyond half an hour, improvement with activity and worsening with rest.
2. For positive screens, order HLA-B27 and route to rheumatology for sacroiliac assessment rather than repeating lumbar imaging.
3. Communicate an axial diagnosis to gastroenterology before biologic selection.
4. Document the metabolic and autonomic terrain at baseline and at reassessment.
5. Build the screen into standing orders so it does not depend on which specialist the patient saw that day.

The same malabsorbing bowel drives the deficiency discussed in vitamin D screening and falls risk. Specialty-specific uses are outlined in specialty applications, and the complete evidence file is the Chapter 11 Deep Dive.

Frequently asked questions

References

• Lin, A., Tan, Y., Chen, J., Liu, X., & Wu, J. (2023). Development of ankylosing spondylitis in patients with ulcerative colitis: A systematic meta-analysis. PLoS One, 18(8), e0289021. https://doi.org/10.1371/journal.pone.0289021
• Karreman, M. C., Luime, J. J., Hazes, J. M. W., & Weel, A. E. A. M. (2017). The prevalence and incidence of axial and peripheral spondyloarthritis in inflammatory bowel disease: A systematic review and meta-analysis. Journal of Crohn’s & Colitis, 11(5), 631–642. https://doi.org/10.1093/ecco-jcc/jjw199
• Kilic, Y., Kamal, S., Jaffar, F., Sriranganathan, D., Quraishi, M. N., & Segal, J. P. (2024). Prevalence of extraintestinal manifestations in inflammatory bowel disease: A systematic review and meta-analysis. Inflammatory Bowel Diseases, 30(2), 230-239. https://doi.org/10.1093/ibd/izad061
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• Taurog, J. D., Richardson, J. A., Croft, J. T., Simmons, W. A., Zhou, M., Fernández-Sueiro, J. L., Balish, E., & Hammer, R. E. (1994). The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. The Journal of Experimental Medicine, 180(6), 2359–2364. https://doi.org/10.1084/jem.180.6.2359
• Hueber, W., Sands, B. E., Lewitzky, S., Vandemeulebroecke, M., Reinisch, W., Higgins, P. D. R., Wehkamp, J., Feagan, B. G., Yao, M. D., Karczewski, M., Karczewski, J., Pezous, N., Bek, S., Bruin, G., Mellgard, B., Berger, C., Londei, M., Bertolino, A. P., Tougas, G., & Travis, S. P. L. (2012). Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut, 61(12), 1693–1700. https://doi.org/10.1136/gutjnl-2011-301668
• Guggino, G., Mauro, D., Rizzo, A., Alessandro, R., Raimondo, S., Bergot, A.-S., Rahman, M. A., Ellis, J. J., Milling, S., Lories, R., Elewaut, D., Brown, M. A., Thomas, R., & Ciccia, F. (2021). Inflammasome activation in ankylosing spondylitis is associated with gut dysbiosis. Arthritis & Rheumatology, 73(7), 1189-1199. https://doi.org/10.1002/art.41644
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Vitamin D Screening: Who Has an Indication and What Falls Risk Adds

Vitamin D screening has an indication in malabsorption (inflammatory bowel disease, prior bowel surgery, celiac disease, post-bariatric anatomy), in darker skin at high latitude and in adiposity. Fall risk adds a documented balance baseline before any dosing schedule is chosen, because the harm signal in the dosing trials is falls.

Routine vitamin D testing is out of favor for the general population. Patients with malabsorption, dyslipidemia and fall risk were never the population that recommendation addressed.

Vitamin D screening in primary care has a clear guideline answer for the general population and almost none for the patients who generate the most questions. The 2024 Endocrine Society panel recommends against routine testing of 25-hydroxyvitamin D across the populations it reviewed, and against dosing above the dietary reference intake for disease prevention. Its scope statement is the operative line: it addresses people without an established indication.

In the video Vitamin D Is a Hormone, Not a Vitamin, Chapter 10 of The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, the argument is endocrine: a governed axis adapts to excess and punishes bolus dosing. For the physician the operational questions are narrower. Who has an indication, what distorts the value before interpretation, and why fall-risk assessment belongs in the same order set.

Is vitamin D screening necessary?

The systematic review behind the guideline screened 37,007 citations and retained 151 studies. It identified no trials of screening itself. The recommendation against testing therefore reflects a test-and-treat strategy that has never been trialed, not a negative trial of one. The same panel names four groups for empiric supplementation without testing (ages 1 to 18, adults over 75, pregnancy and high-risk prediabetes), prefers daily over intermittent high doses in adults over 50 with an indication, and concedes that optimal doses remain unclear.

That leaves the indicated patient to clinical judgment, which is exactly where a structured screen earns its place in the chart.

Who should be screened for vitamin D deficiency?

• Malabsorption. Across 25 observational studies and 5,826 patients with inflammatory bowel disease, active disease raised deficiency odds to 1.85, prior surgery to 1.61, biologic exposure to 1.78, and the Crohn’s phenotype to 1.38 relative to ulcerative colitis. Steroid exposure also carried 1.61. Short bowel, celiac disease and post-bariatric anatomy share the mechanism.
• Ancestry and latitude. Non-Caucasian ancestry carried an odds ratio of 3.79 in that same analysis, larger than any disease variable. Keeping 97.5% of dark-skinned adults at high latitude above 50 nmol/L in winter required 66.8 µg daily, roughly 2,672 IU, well above standard intake tables.
• Adiposity. Adipose tissue sequesters the molecule and lowers the circulating level, and BMI does not quantify the compartment responsible.
• Fall risk. Not an indication to supplement, but a reason to document balance status before a dosing schedule is chosen, because the harm signal in the dosing literature is falls.

How accurate is the vitamin D blood test?

Two error sources precede interpretation. Restandardization moved the American prevalence below 50 nmol/L from 22% to 31%, and the methods authors estimated that a single patient’s apparent level could range from 20 to 35 ng/mL by method. In the Canadian biobank comparison, the immunoassay carried an overall negative bias of 5.5 nmol/L against mass spectrometry, limits of agreement -23.8 to 12.7. The bias was 4.0 nmol/L below the non-HDL cholesterol threshold and 10.2 above it, and assay standardization did not eliminate it.

The consequence is directional. Dyslipidemic patients, the ones carrying insulin resistance and metaflammation, are biased toward a falsely low value, and the reference interval printed beside it was drawn from a largely indoor population. Recording the assay method with the value changes what a borderline number means and makes serial values comparable.

Can vitamin D dosing increase falls?

Trials that failed on benefit are informative on harm, and the harm concentrates in falls.

• Annual bolus. In 2,256 older women given 500,000 IU once a year, the fall rate was 83.4 versus 72.7 per 100 person-years, a rate ratio of 1.15, and fractures rose with a rate ratio of 1.26, the excess concentrated in the first three months after dosing. Median baseline was 49 nmol/L; fewer than 3% were below 25. These women were largely replete.
• Higher daily dose in fall-prone adults. Compared with 200 IU, 1000 IU or more yielded a hazard ratio of 1.87 for serious falls and 2.48 for falls requiring hospitalization, with no improvement in gait speed, grip strength, chair-stand performance or six-minute walk distance.
• Sustained high dose. Over three years, 10,000 IU daily reduced radial volumetric density by 7.5 mg HA/cm3 against 400 IU. Serum levels peaked at 188 nmol/L at three months and declined to 144.4 on an unchanged dose, consistent with catabolic adaptation. Bone strength did not differ.

For a practice, that moves fall prevention from a separate program into the vitamin D decision. A documented baseline from vestibular and balance testing, obtained before a schedule is set and repeated at reassessment, turns a trial signal into something observable in the individual patient. The pairing with cognition, which shares the same older population, is laid out in cognitive assessment and fall prevention.

Building vitamin D screening into workflow

An indication-driven order set is more defensible than either routine testing or none. One workable sequence:

1. Flag indications at intake: bowel resection, inflammatory bowel disease, celiac disease, bariatric surgery, chronic steroid or biologic exposure, darker skin at northern latitude, obesity.
2. Order the level with the metabolic blood work so the context from laboratory panels sits beside it, and record the assay method.
3. Add bioimpedance body composition where adiposity is part of the indication.
4. Document balance status before dosing and at reassessment.
5. Document schedule, daily rather than bolus, and a stop point once the deficit is corrected.

Measura [Cardiometabolic and Autonomic Health Analysis] measures and reports; the ordering physician interprets and manages. Protocolizing the screen is covered in standing orders for screening, and the documentation maps to the quality frameworks described in quality measures that cardiometabolic testing supports. The gastrointestinal patient who needs this screen often carries a second missed problem, addressed in screening IBD patients for spinal involvement. Full study data are in the Chapter 10 Deep Dive.

Frequently asked questions

References

• Demay, M. B., Pittas, A. G., Bikle, D. D., Diab, D. L., Kiely, M. E., Lazaretti-Castro, M., Lips, P., Mitchell, D. M., Murad, M. H., Powers, S., Rao, S. D., Scragg, R., Tayek, J. A., Valent, A. M., Walsh, J. M. E., & McCartney, C. R. (2024). Vitamin D for the prevention of disease: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism, 109(8), 1907–1947. https://doi.org/10.1210/clinem/dgae290
• Shah, V. P., Nayfeh, T., Alsawaf, Y., Saadi, S., Farah, M., Zhu, Y., Firwana, M., Seisa, M., Wang, Z., Scragg, R., Kiely, M. E., Lips, P., Mitchell, D. M., Demay, M. B., Pittas, A. G., & Murad, M. H. (2024). A systematic review supporting the Endocrine Society clinical practice guidelines on vitamin D. The Journal of Clinical Endocrinology and Metabolism, 109(8), 1961-1974. https://doi.org/10.1210/clinem/dgae312
• Shi, S., Feng, J., Zhou, L., Li, Y., & Shi, H. (2021). Risk factors for vitamin D deficiency in inflammatory bowel disease: A systematic review and meta-analysis. The Turkish Journal of Gastroenterology, 32(6), 508–518. https://doi.org/10.5152/tjg.2021.20614
• Cashman, K. D., Kiely, M. E., Andersen, R., Grønborg, I. M., Tetens, I., Tripkovic, L., Lanham-New, S. A., Lamberg-Allardt, C., Adebayo, F. A., Gallagher, J. C., Smith, L. M., Sacheck, J. M., Huang, Q., Ng, K., Yuan, C., Giovannucci, E. L., Rajakumar, K., Patel, S., Vanstone, C. A., … Weiler, H. A. (2022). Individual participant data (IPD)-level meta-analysis of randomised controlled trials to estimate the vitamin D dietary requirements in dark-skinned individuals resident at high latitude. European Journal of Nutrition, 61(2), 1015–1034. https://doi.org/10.1007/s00394-021-02699-6
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• Appel, L. J., Michos, E. D., Mitchell, C. M., Blackford, A. L., Sternberg, A. L., Miller, E. R., Juraschek, S. P., Schrack, J. A., Szanton, S. L., Charleston, J., Minotti, M., Baksh, S. N., Christenson, R. H., Shade, D. M., Shiferaw, W. F., Walston, J. D., Guralnik, J. M., Cai, T., & Tonascia, J. (2021). The effects of four doses of vitamin D supplements on falls in older adults: A response-adaptive, randomized clinical trial. Annals of Internal Medicine, 174(2), 145–156. https://doi.org/10.7326/M20-3812
• Burt, L. A., Billington, E. O., Rose, M. S., Raymond, D. A., Hanley, D. A., & Boyd, S. K. (2019). Effect of high-dose vitamin D supplementation on volumetric bone density and bone strength: A randomized clinical trial. JAMA, 322(8), 736–745. https://doi.org/10.1001/jama.2019.11889
• Lund-Nielsen, J., Vedel-Krogh, S., Kobylecki, C. J., Brynskov, J., Afzal, S., & Nordestgaard, B. G. (2018). Vitamin D and inflammatory bowel disease: Mendelian randomization analyses in the Copenhagen studies and UK Biobank. The Journal of Clinical Endocrinology and Metabolism, 103(9), 3267–3277. https://doi.org/10.1210/jc.2018-00250

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