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Longevity Library · Lab reference

Written by Daniel Tagge, MD
Updated October 23, 2026
Reviewed October 24, 2026
45 sources · Measured in µmol/g

System: Gut-Immune Health

Short-chain fatty acids (stool)SCFA · Fecal short-chain fatty acids · Stool butyrate · Butyrate, propionate and acetate

Short-chain fatty acids (acetate, propionate and butyrate) are what colonic bacteria make from fiber, and the biology is strong: butyrate supplied about three quarters of the oxygen consumption of isolated human colon cells, and the acids signal to gut hormones, the liver and regulatory T cells. The stool measurement is weak, because most of what is made is absorbed and used before the stool forms: transit speed alone moved stool butyrate in volunteers, higher stool levels kept company with obesity and hypertension in 441 adults, circulating rather than stool levels tracked insulin sensitivity in 160, and no stool range is tied to any outcome.

Stool short-chain fatty acids are a leftover, not a production count. The colon absorbs these acids fast and the lining burns butyrate as fuel, so a stool value reflects what escaped absorption, how fast transit was and which part of the colon the sample came from. Fiber raises stool butyrate a little on average and very differently from person to person, and antibiotics and laxatives move it within days. The number is a rough clue about fiber and transit, read beside other markers; it is not a target.

01 · The scale

Where the laboratory range and the evidence sit.

The biology is strong and the stool number is weak. Butyrate fuels the colon lining, the acids signal through their own receptors to gut hormones, the liver and, in mice, regulatory T cells; propionate delivered to the colon of 60 overweight adults for 24 weeks reduced weight gain and liver fat; and a genetic study of 952 people tied butyrate production to a better insulin response. But stool measures what was left: faster transit raised stool butyrate and slower transit lowered it in volunteers, higher stool levels went with obesity and hypertension in 441 adults and with obesity across case-control studies, circulating rather than stool levels tracked insulin sensitivity in 160 adults, and an expert review found insufficient evidence to use stool metabolite changes as markers of benefit. No stool range is tied to any outcome.

050100150200

  1. Total stool short-chain fatty acids in 20 healthy adults, wet weight (a distribution, not a target; laboratory ranges are laboratory-specific and none is outcome-derived)

    28 to 188 µmol/g · Høverstad 1984

  2. Stool butyrate alone in 46 healthy adults on their usual diet (a distribution, not a target)

    3.5 to 32.6 µmol/g · McOrist 2011

  3. Inside the colon itself, from the descending colon to the cecum, at autopsy: physiology, not a stool target

    80 to 131 µmol/g · Cummings 1987

  • Laboratory range
  • Guideline goal or unstudied
Scale in µmol/g. Micromoles per gram of stool, the same number as mmol/kg. Laboratories report on wet or dry weight, which are not interchangeable, some add a percentage of the total for each acid, and panels differ in what they list: acetate, propionate and butyrate on all, valerate and the branched-chain acids (isobutyrate, isovalerate) on some. None of these ranges is derived from outcomes. Bands show where studies found something, not a recommendation for any one person.

02 · What it is

What Short-chain fatty acids (stool) measures.

Short-chain fatty acids are the end products of fermentation of dietary fiber by the anaerobic bacteria of the colon: mainly acetate, propionate and butyrate, produced in ratios that run from about 75:15:10 to 40:40:20 across species and diets. They act in three ways: as fuel, as signals through their own G-protein-coupled receptors, and by inhibiting histone deacetylases, enzymes that control how tightly genes are packed. Reviews in this field note that a coherent understanding is hampered by a lack of quantitative data on how much is actually made and where it goes.1,2,3Grade C

Where they are made and where they go has been measured in people. In the colonic contents of sudden-death victims sampled within four hours, total short-chain fatty acids were 13 µmol/g in the terminal ileum, 131 in the cecum and 80 in the descending colon, highest where fermentation starts and falling toward the rectum; blood concentrations were 375 µmol/L in the portal vein, 148 in the hepatic vein and 79 in peripheral veins, and the changing ratios showed the colon lining taking up butyrate and the liver taking up propionate. When isotope-labeled acids were delivered to the colon of 12 healthy people, only 36 percent of the acetate, 9 percent of the propionate and 2 percent of the butyrate reached the general circulation, about 6 percent of the propionate was turned into glucose, most was breathed out as carbon dioxide after being burned, and less than 0.05 percent appeared in urine.4,5Grade B

A stool test measures what is left. Short-chain fatty acids are the main dissolved substance in normal stool water, and in colonic perfusion studies in volunteers the colon absorbed them in proportion to their concentration, taking sodium and water with them. In 20 healthy adults measured by gas chromatography, total stool short-chain fatty acids had a median of 76.8 µmol/g wet weight with a range from 27.9 to 187.7, butyrate 12.4 (4.0 to 53.0), and the authors concluded that the wide differences between people were real biological variation, not laboratory noise.6,7Grade C

03 · Origins

Where it came from, and where it sits in the network.

Fermentation is the old deal between an animal and its microbes: the animal eats plant carbohydrate it has no enzymes to digest, and the bacteria turn it into fatty acids the animal can burn. A 1990 review estimated that these acids supply about 70 percent of the energy needs of cattle and sheep, which ferment in a forestomach, about 20 to 30 percent in several other omnivores and herbivores, and about 10 percent in humans, who ferment in the colon like pigs and some monkeys, the species the review named as closest to us. An analysis of 31 foods most commonly eaten by western lowland gorillas found them to be about 74 percent fiber by dry weight, and estimated that fermentation could supply about 57 percent of the energy in such a diet; its authors suggested that humans also evolved on high-fiber plant diets in which the colon played a major role in nutrition. That is a hypothesis about ancestry, not a measurement of it.3,8Grade C

The colon lining runs on its bacteria's waste. In isolated human colon cells, butyrate, made only by anaerobic bacteria in the lumen, accounted for 73 percent of oxygen consumption in cells from the ascending colon and 75 percent from the descending colon when it was the only fuel, and it displaced glucose when both were offered. In germ-free mice, which have no bacteria to make butyrate, colon cells were in an energy-deprived state with low ATP and turned to autophagy, digesting their own components; adding butyrate rescued their respiration, and it did so as fuel rather than through its effect on gene packing.9,10Grade C

The acids are also signals, with receptors of their own. GPR43 (also called FFAR2) binds them: mice lacking it had exaggerated or unresolving inflammation in models of colitis, arthritis and asthma, and germ-free mice showed similar disordered responses. Mice lacking GPR43 were obese on a normal diet, mice overexpressing it in fat tissue stayed lean on a high-fat diet, and neither effect appeared without gut bacteria; activation suppressed insulin signaling in fat cells. The hormone-secreting L cells of the gut carry both GPR43 and GPR41 (FFAR3), short-chain fatty acids triggered GLP-1 release from colonic cultures, and mice lacking either receptor released less GLP-1 and handled glucose worse. In human colonic cells, propionate stimulated release of both PYY and GLP-1, the appetite and insulin-related hormones.11,12,13,14Grade C

In the network, the liver and the immune system are the main destinations beyond the colon wall. The liver clears most of the propionate that leaves the colon and turns part of it into glucose, and acetate passes through to fat and muscle, a little of it built into cholesterol and fatty acids. In mice, butyrate drove the differentiation of colonic regulatory T cells, the cells that hold back inflammatory and allergic responses, by acetylating histones at the Foxp3 gene, and it eased an experimental colitis; short-chain fatty acids set the size and function of the colonic regulatory T cell pool through GPR43; and butyrate and propionate, but not acetate, promoted the generation of these cells outside the thymus. The immune findings are mouse biology, consistent and elegant, and have not been shown to depend on the level a stool test reports.3,5,15,16,17Grade C

Modern diets changed the deal. Children in a rural village in Burkina Faso, eating a high-fiber diet resembling that of early farming communities, carried bacteria with genes for digesting cellulose and xylan that European children lacked entirely, and had significantly more short-chain fatty acids in their stool. That comparison is one of the few places a stool measurement tracks something real across populations, because the difference in fiber intake was very large.18Grade C

04 · The laboratory range

What a laboratory calls normal.

Laboratory-specific and not outcome-derived: each laboratory prints its own range for total short-chain fatty acids and for each acid, on wet or dry weight or as a percentage of the total, from its own reference population; in one study of 20 healthy adults, total stool short-chain fatty acids ran from about 28 to 188 µmol/g wet weight.

What a healthy range looks like is wide. In 20 healthy adults, total stool short-chain fatty acids spanned 27.9 to 187.7 µmol/g wet weight, nearly sevenfold; in 46 healthy adults aged 31 to 66, stool butyrate at entry ran from 3.5 to 32.6 µmol/g, and body mass index explained 27 percent of the differences in butyrate between people while fiber intake explained 4 percent. A laboratory's reference interval is a distribution of the people it happened to test.7,19Grade C

No range is tied to an outcome. An expert review of microbial fermentation markers that set out, among other things, to determine normal concentration ranges concluded that measuring short-chain fatty acids in stool is insufficient to assess their dynamics in the body, and that there is insufficient evidence to use changes in stool metabolite concentrations as markers of a benefit. A review of the physiology a decade and a half earlier had already noted that measuring colonic fermentation in humans is difficult, which is why stool samples were used as an indirect measure.20,21Grade C

05 · The evidence

What the studies support.

Stool levels partly reflect absorption, not production. In 10 healthy people given rectal infusions of the three acids, about 30 percent of the butyrate and 24 percent of the acetate was absorbed in 30 minutes, and the share of acetate in each person's stool was strongly inversely related to how well that person absorbed acetate (r = minus 0.834); the authors concluded that stool acetate may reflect absorption rather than production. A later study measuring absorption with a rectal dialysis bag found the opposite in one comparison: 11 overweight and obese adults had higher stool short-chain fatty acids than 11 lean adults (81.3 against 64.1 µmol/g) with similar absorption (24.4 against 24.7 percent), and its authors read the difference as greater production. Both production and absorption move the number, and a single stool value cannot say which.22,23Grade C

Transit time moves the number without any change in production. In 13 healthy adults who took wheat bran, senna and loperamide in turn for nine days each on an unchanged diet, stool short-chain fatty acids including butyrate rose with senna and fell with loperamide, and at baseline the slower a person's whole-gut transit, the lower their stool total (r = minus 0.511) and butyrate (r = minus 0.577). In 8 volunteers on a controlled diet, transit time was inversely related to stool total short-chain fatty acids, propionate and butyrate, a drug that sped transit raised them and one that slowed it reversed the change.24,25Grade C

Higher is not healthier in the observational data. Among 441 community-dwelling adults, higher stool short-chain fatty acids went with lower microbial diversity, a measure of gut permeability, markers of metabolic dysregulation, obesity and hypertension, after adjustment for measured confounders; the authors proposed less efficient absorption as the explanation and called for studies measuring stool and blood together. A meta-analysis of case-control studies found people with obesity had higher stool acetate, propionate and butyrate than people without (standardized mean differences 0.87, 0.86 and 0.78), with high heterogeneity (I² above 80 percent) that disappeared when only people with a body mass index above 30 were compared.26,27Grade C

Blood, not stool, tracked metabolism when both were measured. In 160 adults with normal or impaired glucose metabolism, 93 of them studied with a hyperinsulinemic clamp, fasting circulating acetate, propionate and butyrate were associated with GLP-1, lower whole-body fat breakdown, triglycerides and free fatty acids, and circulating acetate and propionate were related, in opposite directions, to insulin sensitivity; stool short-chain fatty acids were not. The authors concluded that circulating levels are more directly linked to metabolic health.28Grade C

Genetics supports production mattering, which is not the same as the stool number mattering. In 952 people with normal blood sugar who had genome-wide genotyping, stool metagenomes and stool short-chain fatty acids, a bidirectional Mendelian randomization analysis found that a genetically driven increase in gut butyrate production was associated with a better insulin response in a glucose tolerance test, while abnormalities in the production or absorption of propionate were causally related to a higher risk of type 2 diabetes. It is one study with instruments drawn from a modest sample, and its butyrate signal came from bacterial production pathways, not from the stool concentration.29Grade C

Delivering propionate to the colon has been tested in people. An inulin-propionate ester designed to release propionate in the colon raised PYY and GLP-1 after a meal and reduced how much people ate, and over 24 weeks 10 g a day in 60 overweight adults reduced weight gain, fat around the organs and fat in the liver, and prevented the decline in insulin sensitivity seen with inulin alone. In a crossover trial of 12 adults with overweight or obesity, 42 days of 20 g a day of either the ester or plain inulin improved insulin resistance against cellulose (HOMA2 1.23 and 1.17 against 1.59), with no difference between the ester and inulin.14,30Grade B

The counterweight is that propionate eaten as a food preservative behaves differently. In mice, propionate raised glucagon and the fat-cell protein FABP4 through the sympathetic nervous system, causing high blood sugar, and long-term exposure at a dose equivalent to food preservation caused gradual weight gain; in a randomized, double-blind, placebo-controlled study in people, a propionate-containing meal raised glucagon, FABP4 and norepinephrine after eating and caused insulin resistance with compensating high insulin, and in a weight-loss trial plasma propionate fell with weight loss and predicted improved insulin sensitivity. Propionate eaten in a meal is a different exposure from propionate made in the colon, and the two cannot be assumed to act alike.31Grade C

Butyrate delivered straight to an inflamed colon has small, mixed trials behind it. In 10 patients with distal ulcerative colitis unresponsive to standard therapy, two weeks of butyrate enemas against placebo in random order lowered stool frequency from 4.7 to 2.1 a day and the endoscopic score from 6.5 to 3.8, and bleeding stopped in 9 of 10; in 103 patients in a six-week placebo-controlled trial of rectal short-chain fatty acids, 33 percent improved against 20 percent on placebo, a difference that was not significant, with a larger response in those whose flare was under six months old (48 against 18 percent); and in 51 patients with refractory distal colitis, adding butyrate to topical mesalamine gave 6 remissions and 12 improvements against 1 and 13. These test the biology at the lining; they say nothing about what a stool level means.32,33,34Grade C

06 · What moves it

The levers with evidence behind them.

What is listed here has been tested. The size of each effect, and the size of the study, are in the sentence, so a small effect reads as a small effect.

  • Fermentable fiber

    raises stool butyrate a little on average

    Across 64 randomized studies with 2,099 healthy adults, fiber interventions raised Bifidobacterium (standardized mean difference 0.64) and Lactobacillus (0.22) and raised stool butyrate by a small margin that only just reached significance (0.24, interval 0.00 to 0.47), with no difference in the other short-chain fatty acids or in diversity. The case for eating more fiber rests on outcome evidence of its own, set out in the fiber entry; this marker is a weak witness to it.35Grade B

  • Resistant starch, with wide differences between people

    usually raises stool butyrate, depending on the starch and the person's bacteria

    In a randomized crossover study of 46 healthy adults, adding 22 g a day of resistant starch for four weeks raised stool acetate, butyrate and total short-chain fatty acids, but individual responses varied and butyrate often fell in people whose starting level was high. In 174 young adults given one of three fermentable fibers for two weeks, resistant starch from potatoes gave the largest rise in total short-chain fatty acids and butyrate, while resistant starch from maize and inulin did not significantly raise stool butyrate; people in whom particular starch-degrading species increased were the ones more likely to reach higher butyrate. In a dose-response trial of three chemically modified resistant starches, each structure pushed the bacteria toward either propionate or butyrate, consistently within each group, with effects plateauing at 35 g a day. The same food does different things in different colons.19,36,37Grade B

  • A whole high-fiber, lower-fat diet

    raises butyrate production within two weeks

    When African Americans and rural South Africans swapped diets under supervision for two weeks, the high-fiber, low-fat African-style diet produced more saccharolytic fermentation and butyrate production in the Americans, suppressed secondary bile acid synthesis and reversed mucosal markers of colon cancer risk, with the opposite changes in the Africans eating a Western-style diet. A whole diet pattern, not a single fiber, moved the fermentation.38Grade C

  • Fermented foods

    effect on this number unknown

    In a 17-week randomized study of healthy adults (18 per arm), a diet high in fermented foods steadily increased microbiota diversity and lowered inflammatory markers, while a high-fiber diet increased the bacteria's carbohydrate-digesting enzymes without changing diversity. The abstract reports no short-chain fatty acid result, so whether fermented foods move this stool number is not known from this trial.39Grade C

  • Transit speed, laxatives and antidiarrheals

    faster transit raises it, slower transit lowers it

    Senna and a prokinetic drug raised stool short-chain fatty acids and loperamide lowered them, on an unchanged diet, in two small crossover studies. Anyone taking a laxative, an antidiarrheal or a medicine that slows the gut, or with diarrhea or constipation at the time of the sample, will see that reflected in this number.24,25Grade C

  • Antibiotics

    can lower it sharply for weeks, depending on the drug

    In groups of six healthy people, six days of clindamycin cut the median total stool short-chain fatty acids from 62.9 to 7.3 µmol/g and ampicillin from 62.4 to 47.8, while metronidazole did not change them significantly; acetate rose from half to 90 percent of the total on clindamycin, and all values returned to normal within five weeks. A stool test taken within weeks of a course of antibiotics reports the antibiotic.40Grade C

  • Butyrate supplements by mouth

    not shown to change the colon's supply

    A review of short-chain fatty acids as treatments concluded that, despite a wide range of preclinical evidence, translating animal results to people is limited by the challenge of delivering enough of the acids to the colon and the circulation, and that targeted delivery is the main limitation. A capsule's effect on a stool value, or on anything the stool value is supposed to mark, has not been established.41Grade C

07 · Reading it well

Caveats, and what belongs with a physician.

A stool sample comes from the end of the colon, where fermentation is slowest. In colonic contents from two people sampled after sudden death, short-chain fatty acid production by cecal contents was up to eightfold higher than by contents from the sigmoid colon and rectum, while the products of protein fermentation, including ammonia, the branched-chain fatty acids and phenolic compounds, increased from right to left. The concentrations in the colon fell from 131 µmol/g in the cecum to 80 in the descending colon in the autopsy series. The stool is the far end of that gradient, and a raised branched-chain fraction says more about protein reaching the colon than about fiber.42,4Grade C

Wet weight, dry weight and method all change the number. The healthy distributions quoted here are on wet weight, so a result on dry weight cannot be read against them, and a wet-weight result depends on how much water the stool holds. Fiber diets raised stool weight and moisture as well as short-chain fatty acid output in the resistant starch trial, and an expert review concluded that stool concentrations cannot capture production, absorption and use. Two laboratories' results, or one laboratory's results on two methods, are not comparable.7,19,20Grade C

Most of the benefit claims come from animals and cells. A review of butyrate and colonic function found that most studies point toward benefit but that effects depend heavily on the concentrations and models used and human data are limited; a review of short-chain fatty acids in body weight and insulin sensitivity noted that most data come from animal and in vitro studies and that well-controlled human trials were awaited.43,44Grade C

The gut-brain story is earlier still. Short-chain fatty acids are speculated to play a key role in communication between the gut bacteria and the brain, but a 2019 review found the pathways not fully worked out and research directly testing them as mediators of mood or cognition sparse, especially in humans.45Grade C

In practice the stool number cannot separate its causes. A low value can mean little fiber, slow transit, efficient absorption or a recent antibiotic; a high value can mean more fiber, fast transit, poor absorption or a microbiota that produces more, and in population data high values kept company with obesity. Nothing on this page applies to anyone with inflammatory bowel disease, a recent bowel operation or a stoma, whose fermentation and absorption are altered and whose care belongs with a gastroenterologist.24,22,26,40Grade C

See a physician

  • Blood in the stool, black stool, or a lasting change in bowel habit, whatever the short-chain fatty acid result; those are questions for a colonoscopy decision, not a stool panel.
  • Diarrhea that lasts more than a few weeks, wakes you at night, or comes with weight loss, fever or a raised fecal calprotectin, which together point toward inflammation that needs a proper workup.
  • Diarrhea during or within weeks of a course of antibiotics, especially if it is frequent or watery, which needs testing for an infection rather than a fermentation panel.
  • Anyone with ulcerative colitis or Crohn's disease considering butyrate by mouth or by enema, which has been studied only as an add-on in small trials and belongs with the gastroenterologist managing the disease.
  • Anyone who has been told to take butyrate, a prebiotic or a probiotic on the strength of a stool short-chain fatty acid result alone, who should hear that no trial has shown that changing this number changes health.

This page is education, not individual medical advice, and reading it creates no physician-patient relationship.

08 · Open questions

What the literature does not settle.

  • No study has shown that a person's stool short-chain fatty acid level, high or low, predicts any health outcome over time, and none has tested whether raising it changes one.
  • Whether higher stool levels in obesity mean more production, less absorption or faster transit is unresolved: one absorption study found production, another found absorption, and most studies measured neither.
  • Circulating short-chain fatty acids tracked insulin sensitivity where stool levels did not, but no blood test is standardized for clinical use and no outcome range exists for it either.
  • Why the same resistant starch raises butyrate in one person and not another depends on which bacteria are present; whether a stool microbiome report can predict the response in advance is a research question.
  • Colonic propionate improved weight and insulin measures in trials while propionate eaten as a preservative impaired insulin action; how the route, dose and timing decide the effect is not settled.
  • The regulatory T cell, receptor and gut-brain findings come mostly from mice; how much of that biology operates at the concentrations a human colon reaches, and whether it shows up in a stool value, is unknown.
  • Isotope methods that trace labeled fiber to labeled short-chain fatty acids in blood may one day measure production directly; until then the stool value remains an indirect, leftover measure.

09 · In practice

How Dr. Tagge reads it in his own practice.

I read the short-chain fatty acid line on a stool test as a rough statement about fiber intake and transit, not as a measure of how much a person's bacteria make. Most of what the bacteria produce is absorbed and used by the colon lining and the liver before the stool forms, so what reaches the sample is the remainder, and its size depends on how fast things move and how well the lining takes them up. A low butyrate in someone who eats little fiber tells me what the food diary already did. A high value does not reassure me: it can mean fast transit or poor absorption, and in population studies higher stool levels kept company with excess weight and blood pressure rather than with health. The lever is food, which has its own evidence on the fiber page: more and more varied plant fiber, some resistant starch, legumes and fermented foods, built up gradually, with the understanding that people respond differently. I do not prescribe butyrate capsules on a stool number. I read this line beside calprotectin, bowel habit, the microbiome report and fasting insulin, because a single marker is a clue and several read together are a story. I will say plainly where I am ahead of the evidence: the biology of these acids is among the best on this shelf, but no study has shown that changing the stool number changes how anyone does, so I use it to open a conversation about food, not to set a goal.

A practice judgment, labeled as one (Grade D): it is how one physician reads the number for the people he cares for, not a recommendation for you.

10

Questions

11 · Sources

45 sources, read in full.

Numbered in the order they appear. Each line says what this page relies on from the paper; the link opens the record at PubMed or the publisher.

  1. 1.

    Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell. 2016. PMID 27259147. DOI 10.1016/j.cell.2016.05.041.

    Review · Short-chain fatty acids, a major class of bacterial metabolites, can directly activate G-protein-coupled receptors, inhibit histone deacetylases and serve as energy substrates, and through these routes affect physiology in health and disease.

  2. 2.

    den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. Journal of Lipid Research. 2013. PMID 23821742. DOI 10.1194/jlr.R036012.

    Review · Short-chain fatty acids are the end products of fermentation of dietary fibers by the anaerobic gut microbiota; a coherent understanding of their effects is hampered by the lack of quantitative data on actual fluxes, and there are many apparently contradictory results.

  3. 3.

    Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiological Reviews. 1990. PMID 2181501. DOI 10.1152/physrev.1990.70.2.567.

    Review · Acetate, propionate and butyrate are produced in ratios of about 75:15:10 to 40:40:20; most butyrate is used by the epithelium, propionate is removed by the liver and largely converted to glucose, acetate is used by peripheral tissues; they supply about 70 percent of energy in ruminants, 20 to 30 percent in several other species and about 10 percent in humans; pigs and some monkeys most closely resemble humans.

  4. 4.

    Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. 1987. PMID 3678950. DOI 10.1136/gut.28.10.1221.

    Laboratory method study · At autopsy of sudden-death victims, total short-chain fatty acids were 13 mmol/kg in the terminal ileum and 131 in the cecum falling to 80 in the descending colon; blood levels were 375 µmol/L portal, 148 hepatic and 79 peripheral; changing molar ratios indicated uptake of butyrate by the colonic epithelium and of propionate by the liver.

  5. 5.

    Boets E, Gomand SV, Deroover L, Preston T, Vermeulen K, De Preter V, et al.. Systemic availability and metabolism of colonic-derived short-chain fatty acids in healthy subjects: a stable isotope study. Journal of Physiology. 2017. PMID 27510655. DOI 10.1113/JP272613.

    Laboratory method study · In 12 healthy subjects given 13C-labeled acids in colon delivery capsules, systemic availability was 36 percent for acetate, 9 percent for propionate and 2 percent for butyrate; about 6 percent of propionate became glucose, under 1 percent of acetate became cholesterol and under 15 percent fatty acids; most was exhaled as CO2 and under 0.05 percent excreted in urine.

  6. 6.

    Ruppin H, Bar-Meir S, Soergel KH, Wood CM, Schmitt MG Jr. Absorption of short-chain fatty acids by the colon. Gastroenterology. 1980. PMID 6768637.

    Laboratory method study · Short-chain fatty acids are the major solute fraction of normal stool water; in colonic perfusion of normal volunteers their absorption was concentration-dependent and accompanied by increased sodium, potassium and water absorption.

  7. 7.

    Høverstad T, Fausa O, Bjørneklett A, Bøhmer T. Short-chain fatty acids in the normal human feces. Scandinavian Journal of Gastroenterology. 1984. PMID 6740214.

    Laboratory method study · In 20 healthy subjects, stool short-chain fatty acids (mmol/kg wet weight, median and range) were total 76.8 (27.9 to 187.7), acetic 37.4, propionic 12.5, n-butyric 12.4 (4.0 to 53.0); they are quantitatively the most important anions in feces, and the pronounced individual variations are real biological variations.

  8. 8.

    Popovich DG, Jenkins DJ, Kendall CW, Dierenfeld ES, Carroll RW, Tariq N, Vidgen E. The western lowland gorilla diet has implications for the health of humans and other hominoids. Journal of Nutrition. 1997. PMID 9311957. DOI 10.1093/jn/127.10.2000.

    Laboratory method study · The 31 most commonly eaten gorilla foods averaged 74.0 g of dietary fiber per 100 g dry weight; the authors estimated that 57.3 percent of metabolizable energy could come from short-chain fatty acids from colonic fermentation and suggested humans also evolved on similar high-fiber diets.

  9. 9.

    Roediger WE. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut. 1980. PMID 7429343. DOI 10.1136/gut.21.9.793.

    Laboratory method study · In isolated human colonocytes, n-butyrate, produced only by anaerobic bacteria, accounted for 73 percent of oxygen consumption in the ascending and 75 percent in the descending colon when it was the only substrate, and reduced glucose oxidation when both were present.

  10. 10.

    Donohoe DR, Garge N, Zhang X, Sun W, O'Connell TM, Bunger MK, Bultman SJ. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metabolism. 2011. PMID 21531334. DOI 10.1016/j.cmet.2011.02.018.

    Laboratory method study · Colonocytes from germ-free mice were energy-deprived, with lower NADH/NAD+, oxidative phosphorylation and ATP, AMPK activation and autophagy; butyrate rescued mitochondrial respiration and prevented autophagy by acting as an energy source rather than as an HDAC inhibitor.

  11. 11.

    Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, et al.. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009. PMID 19865172. DOI 10.1038/nature08530.

    Laboratory method study · Short-chain fatty acids bind GPR43 (FFAR2); GPR43-deficient mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma, and germ-free mice showed similar dysregulation.

  12. 12.

    Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, et al.. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nature Communications. 2013. PMID 23652017. DOI 10.1038/ncomms2852.

    Laboratory method study · GPR43-deficient mice were obese on a normal diet and mice overexpressing GPR43 in adipose tissue stayed lean on a high-fat diet, with normal phenotypes under germ-free conditions or antibiotics; GPR43 activation suppressed insulin signaling in adipocytes.

  13. 13.

    Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, et al.. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2012. PMID 22190648. DOI 10.2337/db11-1019.

    Laboratory method study · Short-chain fatty acids triggered GLP-1 secretion from mixed colonic cultures; GLP-1-secreting L cells were enriched in ffar2 (GPR43) and ffar3 (GPR41); mice lacking either receptor had reduced short-chain fatty acid-triggered GLP-1 secretion and impaired glucose tolerance.

  14. 14.

    Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac-Varghese SE, et al.. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 2015. PMID 25500202. DOI 10.1136/gutjnl-2014-307913.

    Randomized trial · Propionate stimulated PYY and GLP-1 release from human colonic cells; 10 g of inulin-propionate ester acutely raised postprandial PYY and GLP-1 and reduced energy intake; over 24 weeks in 60 overweight adults, 10 g a day reduced weight gain, intra-abdominal fat and intrahepatocellular lipid and prevented the deterioration in insulin sensitivity seen with inulin control.

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    Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, et al.. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013. PMID 24226770. DOI 10.1038/nature12721.

    Laboratory method study · In mice, butyrate induced the differentiation of colonic regulatory T cells in vitro and in vivo, enhanced histone H3 acetylation at the Foxp3 locus, and ameliorated T cell transfer colitis.

  16. 16.

    Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013. PMID 23828891. DOI 10.1126/science.1241165.

    Laboratory method study · In mice, short-chain fatty acids regulated the size and function of the colonic regulatory T cell pool and protected against colitis in an Ffar2-dependent manner.

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    Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, et al.. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013. PMID 24226773. DOI 10.1038/nature12726.

    Laboratory method study · In mice, butyrate facilitated extrathymic generation of regulatory T cells; propionate, also an HDAC inhibitor, did too, while acetate, which lacks HDAC-inhibitory activity, did not.

  18. 18.

    De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, et al.. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proceedings of the National Academy of Sciences of the United States of America. 2010. PMID 20679230. DOI 10.1073/pnas.1005963107.

    Cross-sectional study · Children from a rural Burkina Faso village eating a high-fiber diet had Prevotella and Xylanibacter with genes for cellulose and xylan hydrolysis, completely lacking in European children, and significantly more short-chain fatty acids in their stool (P < 0.001).

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    McOrist AL, Miller RB, Bird AR, Keogh JB, Noakes M, Topping DL, Conlon MA. Fecal butyrate levels vary widely among individuals but are usually increased by a diet high in resistant starch. Journal of Nutrition. 2011. PMID 21430242. DOI 10.3945/jn.110.128504.

    Randomized trial · In a randomized crossover study of 46 healthy adults aged 31 to 66, entry stool butyrate ranged from 3.5 to 32.6 mmol/kg; BMI explained 27 percent and fiber intake 4 percent of the variation; 22 g a day of resistant starch for four weeks raised acetate, butyrate and total short-chain fatty acids, with varied individual responses and butyrate often falling when entry levels were high.

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    Verbeke KA, Boobis AR, Chiodini A, Edwards CA, Franck A, Kleerebezem M, et al.. Towards microbial fermentation metabolites as markers for health benefits of prebiotics. Nutrition Research Reviews. 2015. PMID 26156216. DOI 10.1017/S0954422415000037.

    Review · Measuring short-chain fatty acid concentrations in feces is insufficient to assess their nutrikinetics, and there is at present insufficient evidence to use changes in fecal bacterial metabolite concentrations as markers of prebiotic effectiveness.

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    Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiological Reviews. 2001. PMID 11427691. DOI 10.1152/physrev.2001.81.3.1031.

    Review · Butyrate is a preferred substrate for colonocytes; measurement of colonic fermentation in humans is difficult, and indirect measures such as fecal samples or animal models have been used.

  22. 22.

    Vogt JA, Wolever TM. Fecal acetate is inversely related to acetate absorption from the human rectum and distal colon. Journal of Nutrition. 2003. PMID 14519799. DOI 10.1093/jn/133.10.3145.

    Laboratory method study · In 10 healthy subjects given rectal infusions, butyrate absorption (30.2 percent) exceeded acetate absorption (24.1 percent) in 30 minutes; fecal molar acetate percentage was inversely correlated with acetate absorption (r = -0.834); fecal acetate may reflect absorption rather than production.

  23. 23.

    Rahat-Rozenbloom S, Fernandes J, Gloor GB, Wolever TM. Evidence for greater production of colonic short-chain fatty acids in overweight than lean humans. International Journal of Obesity. 2014. PMID 24642959. DOI 10.1038/ijo.2014.46.

    Cross-sectional study · Age-adjusted fecal short-chain fatty acids were higher in 11 overweight or obese than 11 lean adults (81.3 against 64.1 mmol/kg) while rectal absorption (24.4 against 24.7 percent) and diet were similar; the authors read the difference as greater production.

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    Lewis SJ, Heaton KW. Increasing butyrate concentration in the distal colon by accelerating intestinal transit. Gut. 1997. PMID 9301506. DOI 10.1136/gut.41.2.245.

    Laboratory method study · In 13 healthy adults taking wheat bran, senna and loperamide for nine days each with diet unchanged, fecal short-chain fatty acids including butyrate rose with senna and fell with loperamide; baseline whole-gut transit time correlated with fecal short-chain fatty acids (r = -0.511) and butyrate (r = -0.577).

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    El Oufir L, Flourié B, Bruley des Varannes S, Barry JL, Cloarec D, Bornet F, Galmiche JP. Relations between transit time, fermentation products, and hydrogen consuming flora in healthy humans. Gut. 1996. PMID 8984026. DOI 10.1136/gut.38.6.870.

    Laboratory method study · In 8 healthy volunteers on a controlled diet, transit time was inversely related to fecal total short-chain fatty acids, propionate and butyrate; shortening transit with cisapride raised them, and loperamide gave roughly the reverse.

  26. 26.

    de la Cuesta-Zuluaga J, Mueller NT, Álvarez-Quintero R, Velásquez-Mejía EP, Sierra JA, Corrales-Agudelo V, et al.. Higher Fecal Short-Chain Fatty Acid Levels Are Associated with Gut Microbiome Dysbiosis, Obesity, Hypertension and Cardiometabolic Disease Risk Factors. Nutrients. 2019. PMID 30591685. DOI 10.3390/nu11010051.

    Cross-sectional study · In 441 community-dwelling adults, higher fecal short-chain fatty acids were associated with lower microbiota diversity, gut permeability, markers of metabolic dysregulation, obesity and hypertension after adjustment; the authors propose less efficient absorption as a hypothesis to test.

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    Kim KN, Yao Y, Ju SY. Short Chain Fatty Acids and Fecal Microbiota Abundance in Humans with Obesity: A Systematic Review and Meta-Analysis. Nutrients. 2019. PMID 31635264. DOI 10.3390/nu11102512.

    Systematic review and meta-analysis · Obese individuals had higher fecal acetate (SMD 0.87), propionate (0.86) and butyrate (0.78) than nonobese controls, with I² of 82 to 89 percent, and no heterogeneity among those with BMI above 30; phylum-level microbiota did not differ significantly.

  28. 28.

    Müller M, Hernández MAG, Goossens GH, Reijnders D, Holst JJ, Jocken JWE, et al.. Circulating but not faecal short-chain fatty acids are related to insulin sensitivity, lipolysis and GLP-1 concentrations in humans. Scientific Reports. 2019. PMID 31467327. DOI 10.1038/s41598-019-48775-0.

    Cross-sectional study · In 160 adults (93 with a hyperinsulinemic-euglycemic clamp), fasting circulating short-chain fatty acids were associated with GLP-1, lipolysis, triglycerides and free fatty acids, and circulating acetate and propionate with insulin sensitivity, while fecal short-chain fatty acids were not.

  29. 29.

    Sanna S, van Zuydam NR, Mahajan A, Kurilshikov A, Vich Vila A, Võsa U, et al.. Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nature Genetics. 2019. PMID 30778224. DOI 10.1038/s41588-019-0350-x.

    Mendelian randomization · In 952 normoglycemic individuals with genotyping, gut metagenomes and fecal short-chain fatty acids, a host-genetic-driven increase in gut butyrate production was associated with improved insulin response after an oral glucose tolerance test, and abnormalities in propionate production or absorption were causally related to increased type 2 diabetes risk.

  30. 30.

    Chambers ES, Byrne CS, Morrison DJ, Murphy KG, Preston T, Tedford C, et al.. Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised cross-over trial. Gut. 2019. PMID 30971437. DOI 10.1136/gutjnl-2019-318424.

    Randomized trial · In 12 non-diabetic adults with overweight or obesity given 20 g a day of inulin-propionate ester, inulin or cellulose for 42 days each, both the ester and inulin improved HOMA2 insulin resistance against cellulose (1.23 and 1.17 against 1.59), with no difference between them.

  31. 31.

    Tirosh A, Calay ES, Tuncman G, Claiborn KC, Inouye KE, Eguchi K, et al.. The short-chain fatty acid propionate increases glucagon and FABP4 production, impairing insulin action in mice and humans. Science Translational Medicine. 2019. PMID 31019023. DOI 10.1126/scitranslmed.aav0120.

    Randomized trial · Propionate raised glucagon and FABP4 via sympathetic activation and caused hyperglycemia in mice, with gradual weight gain on a preservative-equivalent dose; in a randomized, double-blind, placebo-controlled human study a propionate-containing meal raised postprandial glucagon, FABP4 and norepinephrine with insulin resistance and compensatory hyperinsulinemia; plasma propionate fell with weight loss in DIRECT.

  32. 32.

    Scheppach W, Sommer H, Kirchner T, Paganelli GM, Bartram P, Christl S, et al.. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology. 1992. PMID 1612357. DOI 10.1016/0016-5085(92)91094-k.

    Randomized trial · In 10 patients with distal ulcerative colitis unresponsive to standard therapy, given butyrate and placebo enemas for two weeks each in random order (single-blind), butyrate lowered stool frequency from 4.7 to 2.1 a day and the endoscopic score from 6.5 to 3.8, and bleeding ceased in 9 of 10; placebo changed nothing.

  33. 33.

    Breuer RI, Soergel KH, Lashner BA, Christ ML, Hanauer SB, Vanagunas A, et al.. Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomised, placebo controlled trial. Gut. 1997. PMID 9176076. DOI 10.1136/gut.40.4.485.

    Randomized trial · In 103 patients with distal ulcerative colitis (91 completing) in a six-week double-blind trial, 33 percent improved on rectal short-chain fatty acids against 20 percent on placebo (not significant); in those with a current episode under six months, 48 against 18 percent responded.

  34. 34.

    Vernia P, Annese V, Bresci G, d'Albasio G, D'Incà R, Giaccari S, et al.. Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial. European Journal of Clinical Investigation. 2003. PMID 12641543. DOI 10.1046/j.1365-2362.2003.01130.x.

    Randomized trial · In 51 patients with refractory distal ulcerative colitis randomized to topical 5-ASA with sodium butyrate or saline for six weeks, the butyrate group had 6 remissions and 12 improvements against 1 remission and 13 improvements (P < 0.05).

  35. 35.

    So D, Whelan K, Rossi M, Morrison M, Holtmann G, Kelly JT, et al.. Dietary fiber intervention on gut microbiota composition in healthy adults: a systematic review and meta-analysis. American Journal of Clinical Nutrition. 2018. PMID 29757343. DOI 10.1093/ajcn/nqy041.

    Systematic review and meta-analysis · Across 64 randomized studies with 2,099 healthy adults, fiber raised Bifidobacterium (SMD 0.64) and Lactobacillus (0.22) and fecal butyrate (SMD 0.24, 0.00 to 0.47, P = 0.05), with no effect on alpha diversity or other short-chain fatty acids.

  36. 36.

    Baxter NT, Schmidt AW, Venkataraman A, Kim KS, Waldron C, Schmidt TM. Dynamics of Human Gut Microbiota and Short-Chain Fatty Acids in Response to Dietary Interventions with Three Fermentable Fibers. mBio. 2019. PMID 30696735. DOI 10.1128/mBio.02566-18.

    Laboratory method study · In 174 healthy young adults supplemented for two weeks, resistant potato starch gave the greatest increase in total short-chain fatty acids including butyrate, while resistant maize starch and inulin did not significantly raise fecal butyrate; higher butyrate followed increases in Ruminococcus bromii or Clostridium chartatabidum.

  37. 37.

    Deehan EC, Yang C, Perez-Muñoz ME, Nguyen NK, Cheng CC, Triador L, et al.. Precision Microbiome Modulation with Discrete Dietary Fiber Structures Directs Short-Chain Fatty Acid Production. Cell Host and Microbe. 2020. PMID 32004499. DOI 10.1016/j.chom.2020.01.006.

    Laboratory method study · In a dose-response trial of three type-IV resistant starches in healthy humans, different starch structures produced specific microbiome shifts directing output toward either propionate or butyrate, consistent within treatment groups and dose-dependent, plateauing at 35 g a day.

  38. 38.

    O'Keefe SJ, Li JV, Lahti L, Ou J, Carbonero F, Mohammed K, et al.. Fat, fibre and cancer risk in African Americans and rural Africans. Nature Communications. 2015. PMID 25919227. DOI 10.1038/ncomms7342.

    Laboratory method study · Two-week supervised food exchanges produced reciprocal changes in mucosal biomarkers of cancer risk, best illustrated by increased saccharolytic fermentation and butyrogenesis and suppressed secondary bile acid synthesis in African Americans fed a high-fiber, low-fat African-style diet.

  39. 39.

    Wastyk HC, Fragiadakis GK, Perelman D, Dahan D, Merrill BD, Yu FB, et al.. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021. PMID 34256014. DOI 10.1016/j.cell.2021.06.019.

    Randomized trial · In a 17-week randomized study (18 per arm), a high-fermented-food diet steadily increased microbiota diversity and decreased inflammatory markers, while a high-fiber diet increased glycan-degrading enzymes with stable diversity; the abstract reports no short-chain fatty acid outcome.

  40. 40.

    Høverstad T, Carlstedt-Duke B, Lingaas E, Midtvedt T, Norin KE, Saxerholt H, Steinbakk M. Influence of ampicillin, clindamycin, and metronidazole on faecal excretion of short-chain fatty acids in healthy subjects. Scandinavian Journal of Gastroenterology. 1986. PMID 3749800. DOI 10.3109/00365528609003109.

    Laboratory method study · In groups of six healthy subjects, six days of clindamycin reduced median total fecal short-chain fatty acids from 62.9 to 7.3 mmol/kg wet weight and ampicillin from 62.4 to 47.8, metronidazole had no significant effect, and levels returned to normal within five weeks.

  41. 41.

    Gill PA, van Zelm MC, Muir JG, Gibson PR. Review article: short chain fatty acids as potential therapeutic agents in human gastrointestinal and inflammatory disorders. Alimentary Pharmacology and Therapeutics. 2018. PMID 29722430. DOI 10.1111/apt.14689.

    Review · Translating short-chain fatty acid effects from animals to human disease is limited by physiological and dietary differences and by the challenge of delivering sufficient amounts to the colon and circulation; adequate targeted delivery is the main limitation.

  42. 42.

    Macfarlane GT, Gibson GR, Cummings JH. Comparison of fermentation reactions in different regions of the human colon. Journal of Applied Bacteriology. 1992. PMID 1541601. DOI 10.1111/j.1365-2672.1992.tb04882.x.

    Laboratory method study · In colonic contents from two sudden-death victims, short-chain fatty acids were highest in the cecum and ascending colon, protein fermentation products (ammonia, branched-chain fatty acids, phenols) increased from right to left, and short-chain fatty acid production by cecal contents was up to eightfold higher than by sigmoid and rectal contents.

  43. 43.

    Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. Review article: the role of butyrate on colonic function. Alimentary Pharmacology and Therapeutics. 2008. PMID 17973645. DOI 10.1111/j.1365-2036.2007.03562.x.

    Review · Butyrate is an important energy source for intestinal epithelial cells with effects on inflammation, carcinogenesis, barrier function and oxidative stress, but observed effects largely depend on concentrations and models used and human data are still limited.

  44. 44.

    Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nature Reviews Endocrinology. 2015. PMID 26260141. DOI 10.1038/nrendo.2015.128.

    Review · Acetate, propionate and butyrate may beneficially modulate adipose tissue, skeletal muscle and liver, but most data derive from animal and in vitro studies, and the importance of short-chain fatty acids in human metabolism remains to be fully established.

  45. 45.

    Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nature Reviews Gastroenterology and Hepatology. 2019. PMID 31123355. DOI 10.1038/s41575-019-0157-3.

    Review · Short-chain fatty acids are speculated to have a key role in microbiota-gut-brain crosstalk, but the pathways have not been fully elucidated and research directly exploring them as mediators of effects on affective and cognitive functioning is sparse, especially in humans.

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