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Science · Evidence review

Bile acids as signals

What studies in people show about bile acids as messengers between the gut, the liver and gut bacteria, and what has only been seen in the lab.

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Science

Evidence review

Bile acids digest fat, and they also switch on receptors that carry messages between the gut and the liver. Here is what has been measured in people.

Written by
Dr.Primal Editorial
Fact-checked
Against primary sources
Evidence searched
October 20, 2026
Version
1.0
Contents
  1. From detergent to signal
  2. The gut–liver loop
  3. Bile acid diarrhea
  4. Gut bacteria and bile acids
  5. Bile acids and metabolism
  6. Drugs that act on the signals
  7. Where TUDCA and UDCA fit
  8. What we still don't know
  9. All 51 studies
  10. How we did this review
  11. About this review

The short version

  1. Bile acids also work as signals. Since 1999, research in cells and animals has shown that they switch on receptors, mainly FXR and TGR5, that act on the gut, the liver and metabolism.[1,2,3]
  2. The clearest signal in people is a feedback loop. After a meal, bile acids reaching the small intestine release a hormone, FGF19, and the liver then makes less bile acid. Blood tests can follow this loop through the day.[4,5]
  3. In bile acid diarrhea, the loop runs differently. FGF19 is lower and bile acid production higher, and a blood marker of that production, C4, is used as a test.[6,7]
  4. Gut bacteria reshape bile acids, and what people eat and take changes that within days. Antibiotics and a low-fiber, high-fat diet change the "secondary" bile acids that bacteria make, and those bile acids return after a fecal transplant for C. difficile.[8,9,10]
  5. Drugs built on these signals have been tested in large trials. One, obeticholic acid, improved liver tests in primary biliary cholangitis, but its outcome trial found no difference, and its US approval was withdrawn in 2025.[11,12,13]
  6. For TUDCA, FGF19, C4 and gut hormones have not yet been measured in people. One 1984 study of six men found that TUDCA did not lower bile acid production, and one 16-week placebo-controlled trial found no change in gut-bacteria diversity, with a different mix of species. UDCA, a related drug, has more data, which describe UDCA only.[14,15]

Evidence at a glance

Bile acid signals in people, topic by topic

  • 1999the year bile acids were found to switch on a receptor, FXR
  • 2daily peaks in bile acid production, at about 1 pm and 9 pm
  • 70%fewer secondary bile acids in the colon after two weeks of a high-fiber, low-fat diet
  • 0studies we found in people of TUDCA's effect on FGF19, C4 or GLP-1

What the studies in people found, and how much research stands behind it

The research grade measures how much evidence there is and how firm it is. A low grade means a finding is not yet confirmed.

  • The gut–liver loop (FGF19 and C4)Found: FGF19 rises after meals and falls when bile acids are bound; bile acid production moves the other wayMany small physiology studies and drug trials in people, consistent in directionResearchModerate
  • Low FGF19 in bile acid diarrheaFound: FGF19 lower and C4 higher than in people without itSeveral diagnostic studies of 71 to 251 people; C4 is used as a testResearchModerate
  • Gut bacteria changing bile acidsFound: Antibiotics and diet change secondary bile acids within daysRandomized antibiotic trials of 20 to 55 people over 7 days, a nine-month randomized fiber trial, and short diet studiesResearchEarly
  • Secondary bile acids in C. difficile infectionFound: Low during recurrent infection; they recover after a fecal transplant and in people who do not relapseBefore-and-after studies and cohorts; an associationResearchEarly
  • Bile acid binders and blood sugarFound: HbA1c about 0.3% to 0.5% lower than placebo in type 2 diabetes; how it works is not knownSeveral randomized trials; an approved US use of colesevelamResearchModerate
  • Bile acids and gut hormones after weight-loss surgeryFound: Bile acids rise, but on a different timetable from GLP-1 and blood sugarTwo small studies of 14 and 18 people; associationsResearchPreliminary
  • Obeticholic acid (an FXR activator) in PBCFound: Liver tests improved; the outcome trial found no difference, and the US approval was withdrawn in 2025A 217-person trial on liver tests and a 334-person outcome trialResearchModerate
  • FXR and FGF19 drugs for bile acid diarrheaFound: The signals moved as expected; stools improved in one open study but not in two controlled onesThree studies of 20 to 31 peopleResearchEarly
  • TUDCA and gut bacteriaFound: Diversity unchanged in one 16-week trial; the mix of species differedOne placebo-controlled trial (34 people gave stool samples), one uncontrolled study and a case reportResearchEarly
  • TUDCA and the gut–liver loop and gut hormonesFound: Bile acid production did not fall in one study; FGF19, C4 and GLP-1 not yet measuredOne uncontrolled 1984 study of six men; no study of FGF19, C4 or GLP-1ResearchPreliminary
  • Strong
  • Moderate
  • Early
  • Preliminary
  • Not yet studied

Research grades are ours, made on the scale described in “How we did this review”. Sources: [1,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]

From detergent to signal

For most of the 20th century, bile acids were understood as detergents: the liver makes them, the gallbladder stores them, and in the gut they break fat into droplets small enough to digest. In 1999 three laboratories showed, in cells, that bile acids also switch on a receptor inside cells, FXR, and one showed that FXR turns down the gene for the enzyme that starts bile acid production.[1,36,37] A second, cell-surface receptor, TGR5, followed in 2002 and 2003.[2,38] Bile acids also act on other receptors, including ones that help the body clear lithocholic acid, a more toxic bile acid.[39,40]

1999

FXR

A receptor inside cells of the gut and liver. Bile acids switch it on, and it turns down the liver's bile acid production.[1,36,37]

2002–2003

TGR5

A receptor on the cell surface that responds to bile acids. The 2003 report found it most abundant in immune cells called macrophages.[2,38]

2003–2005

FGF19

A hormone the small intestine releases when FXR is switched on. It travels to the liver and slows bile acid production.[41,42]

These discoveries were made in cells and animals. The rest of this review sets out what has been measured in people: where the human studies confirm the picture, where they differ from it, and where they have not yet looked.

The gut–liver loop

Most bile acids are reabsorbed at the end of the small intestine, the ileum, and return to the liver to be used again. As they pass through the ileum they switch on FXR, which releases FGF19 into the blood. In the liver, FGF19 slows the enzyme that makes new bile acids.[3,5,41] In people this can be followed with two blood tests: FGF19 itself, and C4, a molecule made on the liver's route from cholesterol to bile acid, whose blood level rises and falls with bile acid production.[43,44]

The loop follows the day. FGF19 peaks 90 to 120 minutes after the rise in blood bile acids that comes with a meal, and the liver's production falls soon after. Fasting removes the rhythm.[5] C4 has two daytime peaks, at about 1 pm and 9 pm, and falls overnight:

Gälman 2005

The gut–liver loop · appraisal
People
8 healthy volunteers, plus some people without a gallbladder
Design
Blood sampled every 90 minutes for 24 hours
Compared with
A marker of cholesterol production
Randomized
No
Blinded
Not applicable
Dose
Not applicable
Length
24 hours
Measured
C4, a blood marker of bile acid production
Result
C4 peaked twice in the day, at 1 pm and 9 pm, at 2 to 4 times its baseline, and fell overnight. The rhythm was kept in people without a gallbladder.
Main limits
Eight volunteers; the number without a gallbladder is not stated.

Source: [4] Gälman C, Angelin B, Rudling M. Bile acid synthesis in humans has a rapid diurnal variation that is asynchronous with cholesterol synthesis. Gastroenterology. 2005;129(5):1445-1453.

Interrupting the loop shows how it works. When a bile acid binder holds bile acids in the gut, FGF19 falls, by more than 90% on cholestyramine, and the liver's production rises fivefold or more.[16,22] Children who have lost their ileum have lower FGF19.[17] At the other extreme, four children born with no working FXR developed severe liver disease from birth.[45]

The daily C4 rhythm was kept in people without a gallbladder.[4] What else changes in bile after the operation is set out in our review of life after gallbladder removal.

Bile acid diarrhea

In bile acid diarrhea, more bile acids than usual reach the colon, where they draw in water. In the common, "primary" form there is no damage to the ileum. Studies in people point to the loop: fasting FGF19 is lower, and the liver makes more bile acid.[6,23]

Bile acid diarrhea

Fasting FGF19 is lower in people with bile acid diarrhea

Walters 2009[6]

  • Bile acid diarrhea120
  • No diarrhea231

Pattni 2013, 152 people[23]

  • Bile acid diarrhea147
  • Diarrhea, normal SeHCAT225

Borup 2020, 71 people[7]

  • Bile acid diarrhea72
  • Other diarrhea119

Median fasting FGF19 in blood, in pg/mL. The groups overlap, so FGF19 alone does not diagnose the condition.

Walters 2009

Bile acid diarrhea · appraisal
People
People with bile acid diarrhea and people without diarrhea (numbers not stated)
Design
Case-control
Compared with
People without diarrhea
Randomized
No
Blinded
Not stated
Dose
Not applicable
Length
Not applicable
Measured
Fasting FGF19 and C4
Result
Median FGF19 120 vs 231 pg/mL (P<.0005) and C4 51 vs 18 ng/mL (P<.0001). Low FGF19 was also found after gallbladder removal.
Main limits
Group sizes not in the abstract; one point in time.

Source: [6] Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW. A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis. Clin Gastroenterol Hepatol. 2009;7(11):1189-1194.

Because C4 tracks the liver's production, it is used as a blood test for the condition. In a study of 71 people with chronic diarrhea, a C4 below 15 ng/mL made bile acid diarrhea unlikely and above 48 ng/mL made it likely, with 20 of the 71 in between.[7] A pooled analysis found bile acid diarrhea in between about 1 in 6 and 1 in 3 people with long-term diarrhea and no other cause, depending on the test used.[46]

Low FGF19 has also been found in people with diarrhea after gallbladder removal.[6,47] How often diarrhea follows the operation, and how it changes over time, is covered in our review of life after gallbladder removal.

Three studies, of 20 to 31 people, have tried to act on the loop directly. Obeticholic acid, which switches on FXR, raised FGF19 and eased diarrhea over two weeks in an open study of 10 people with primary bile acid diarrhea.[31] In two placebo-controlled trials, another FXR activator (tropifexor) and an FGF19-like drug (aldafermin) moved FGF19 or C4 as expected, but stool form did not change significantly.[32,33] None of these drugs is approved for bile acid diarrhea; guidelines suggest bile acid binders.[48]

Gut bacteria and bile acids

The liver makes two "primary" bile acids. In the colon, bacteria change them. Many kinds of bacteria remove the amino acid the liver attached; a much smaller group then turns them into "secondary" bile acids, mainly deoxycholic acid (DCA) and lithocholic acid (LCA).[49] UDCA is also made this way, by bacteria flipping one part of the molecule.[50]

What people take and eat changes this within days:

  • Antibiotics. Seven days of vancomycin lowered secondary bile acids in stool and blood; amoxicillin did not.[8,25]
  • Diet. Five days of an all-animal diet raised DCA in stool.[19] When 20 African Americans and 20 rural South Africans swapped diets for two weeks, a high-fiber, low-fat diet cut secondary bile acids in the colon by 70%, and a high-fat, low-fiber diet raised them by 400%.[9] In a nine-month trial, extra wheat bran lowered stool bile acids by half.[20]
  • Age. Older adults had more secondary bile acids in stool than younger ones; the authors thought this was probably because they ate less fiber.[51]

O'Keefe 2015

Gut bacteria · appraisal
People
20 African Americans and 20 rural South Africans
Design
Supervised two-week diet swap
Compared with
Own usual diet
Randomized
No
Blinded
No
Dose
Not applicable
Length
2 weeks
Measured
Colon bile acids and bacteria
Result
A high-fiber, low-fat diet cut secondary bile acids by 70%; a high-fat, low-fiber diet raised them by 400%, with matching changes in the bacterial gene that makes them.
Main limits
Two weeks; not randomized.

Source: [9] O'Keefe SJ, Li JV, Lahti L, et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun. 2015;6:6342.

C. difficile infection

C. difficile infection usually follows antibiotics that disturb the gut's bacteria. In people with repeated infections, secondary bile acids in stool were nearly undetectable; after a fecal transplant, stool held mostly secondary bile acids, like the donors'.[10] People with recurrent infection had fewer secondary and more primary bile acids than healthy controls.[21] After a first infection, secondary bile acids recovered only in the people who did not relapse.[26] Fecal transplant itself is effective for recurrent infection in randomized trials.[52] The evidence that bile acids are part of how it works comes mainly from lab and mouse experiments; in people it is an association.[53]

Bile acids and metabolism

After gastric bypass surgery, bile acids in the blood roughly double, and the gut hormone GLP-1, which helps control blood sugar, rises too.[29] The timing differs, though: GLP-1 and blood sugar improved within a week, while bile acids rose significantly only after a year.[30] So bile acids may contribute, but the early changes after surgery appear to have other causes as well.

Given directly into the gut, bile acids do release gut hormones. In 10 people with type 2 diabetes, a single large dose of a bile acid given rectally raised GLP-1 more than sevenfold and cut food intake by up to 47%.[54] CDCA infused into the small intestine of 12 healthy people raised GLP-1 only slightly, without changing blood sugar.[18]

A bile acid binder, colesevelam, is approved in the US to improve blood sugar control in type 2 diabetes. It lowered HbA1c by about 0.3% to 0.5% more than placebo, and its label says how it does this is not known.[27,28]

Editorial note

Much of what is written about bile acids and metabolism comes from mice, so here is how we read the step to people.

In mice, TGR5 drives GLP-1 release, and bile acids raise energy use in brown fat.[55,56] In people, a drug designed to switch on TGR5 was tested in 51 people with type 2 diabetes for six days, and blood sugar did not fall.[57] Oral CDCA raised brown fat activity in 12 women over two days; the link to TGR5 in that study came from cells in a dish.[58]

So the receptor findings are real, and some effects have been reproduced in people, but a mechanism shown in mice is a reason to test it in people, not evidence that it works the same way. We grade each finding on the studies in people.

Dr.Primal Editorial.

Drugs that act on the signals

The clearest test of a signal is a drug designed to change it. Several have reached large trials.

Obeticholic acid switches on FXR. In primary biliary cholangitis (PBC), 46–47% of people on it reached a target for the liver tests ALP and bilirubin, compared with 10% on placebo, and the FDA approved it in 2016 on that basis.[11,13] Its confirmatory trial, which counted deaths, transplants and serious liver events, found 28.6% on the drug and 28.9% on placebo.[12] Among people in that trial for whom the drug was approved, the FDA reported more liver transplants on it (7 of 81 vs 1 of 68) and more deaths (4 vs 1).[59] The FDA then said the trial "did not verify clinical benefit" and recommended withdrawal; at the maker's request, approval was withdrawn on November 24, 2025.[13]

In fatty liver inflammation (NASH), obeticholic acid improved liver biopsies in two trials, and FDA declined to approve it in 2020, judging that its risks outweighed a benefit measured on biopsies.[60,61,62] An FGF19-like drug, aldafermin, lowered a blood marker of liver scarring in people with NASH cirrhosis.[63] Another FXR activator, cilofexor, did not slow scarring in primary sclerosing cholangitis, and its trial was stopped early.[64]

The same side effect appeared in every large trial of an FXR drug:

Drugs that switch on FXR

Itching was more common on every one tested in large trials

Obeticholic acid in PBC, 12 months (POISE)[11]

  • 10 mg a day68%
  • Placebo38%

Obeticholic acid in NASH, 18 months (REGENERATE)[60]

  • 25 mg a day51%
  • Placebo19%

Obeticholic acid in NASH, 72 weeks (FLINT)[61]

  • 25 mg a day23%
  • Placebo6%

Cilofexor in PSC, 96 weeks (PRIMIS)[64]

  • 100 mg a day49%
  • Placebo36%

Share of people reporting itching, as each trial reported it. Obeticholic acid also raised LDL cholesterol in the NASH trials.[62]

Obeticholic acid in the US

Approved for PBC in 2016 under accelerated approval, based on liver tests. A boxed warning was added in 2018 and use was restricted in advanced cirrhosis in 2021. In December 2024, the FDA reported serious liver injury in people without cirrhosis, and approval was withdrawn on November 24, 2025, at the maker's request after the FDA recommended it. It was never approved for NASH.[13,59,62,65,66]

Where TUDCA and UDCA fit

TUDCA and UDCA are themselves bile acids, so a natural question is whether they act on these signals. Here is what has been measured in people, and what only in the lab.

TUDCA and UDCA

What has been measured in people, and what only in the lab

SignalTUDCA, in peopleUDCA, in peopleLab and animal only
FGF19 and C4 (the gut–liver loop)No study of FGF19 or C4. Bile acid production, measured another way, did not fall over 1 month in 6 healthy men[14]FGF19 down and C4 up in a randomized study of 40 people; C4 up in 8 healthy volunteers; bile acid production unchanged in 6 healthy men and in 330 people with PSC; the opposite pattern in one observational study in pregnancy[14,67,68,69,70]—
GLP-1 and gut hormonesNo study foundNo change after single doses in two crossover studies of 11 and 12 people[71,72]TUDCA switched on TGR5 in brain immune cells, and raised insulin release from mouse pancreas cells[73,74]
Insulin sensitivityRose about 30% on TUDCA and not on placebo over 4 weeks in 20 adults with obesity; no signal measured[75]——
Gut bacteriaDiversity unchanged in a 16-week trial in multiple sclerosis; species mix differed. Diversity unchanged in a 6-week ulcerative colitis study[15,34]Species mix shifted over 3 years in 401 people within a randomized trial; some groups moved toward normal in PBC[76,77]Mouse studies of fatty liver and gallstones[78,79]
What bacteria do to themPart of the TUDCA was split from its taurine and re-joined to glycine. Lithocholic acid in bile did not change, and was lower than on UDCA in a 12-person crossover (both in PBC). Blood UDCA and GUDCA rose more than on placebo in a 16-week trial[15,80,81]Bacteria turn part of oral UDCA into lithocholic acid in stool[82]—

Lab and animal studies are named, not appraised. “No study found” means our searches of PubMed, Europe PMC and ClinicalTrials.gov on October 20, 2026 found none.

For TUDCA, we found no study in people that measured FGF19, C4, GLP-1 or receptor activity. One 1984 study measured the loop's output another way: in six healthy men on a metabolic ward, a month of TUDCA did not lower the body's own bile acid production.[14] Two studies in people with PBC followed what happens to TUDCA in the gut: part of it was split from its taurine and re-joined to glycine, and lithocholic acid in bile did not rise.[80,81] The one placebo-controlled trial with gut-bacteria results was in multiple sclerosis:

Ladakis 2025

TUDCA and UDCA · appraisal
People
54 people with progressive multiple sclerosis randomized, 47 analyzed (34 gave stool samples)
Design
Randomized, double-blind
Compared with
Placebo
Randomized
Yes
Blinded
Double-blind
Dose
TUDCA 2,000 mg/day
Length
16 weeks
Measured
Safety; blood bile acids; gut bacteria
Result
Blood TUDCA, GUDCA and UDCA rose. Gut bacterial diversity did not change; the mix of species differed between groups, and bacterial bile-acid pathways did not. Side effects 38% vs 33%.
Main limits
A safety trial; small stool subgroup; not a digestive population.

Source: [15] Ladakis DC, Harrison KL, Smith MD, et al. Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease. Med. 2025;6(3):100522.

UDCA has more data. In a randomized study of 40 people it lowered FGF19 and raised C4, the opposite of what an FXR activator does, and C4 also rose in 8 healthy volunteers; the authors' reading of this as blocking FXR is an interpretation.[67,68] An observational study in cholestasis of pregnancy found the opposite pattern on UDCA.[70] Single doses did not change GLP-1.[71,72] Over three years, it shifted the mix of gut bacteria without changing their richness, and bacteria convert part of oral UDCA into lithocholic acid.[76,82] As our comparison of the two explains, UDCA results describe UDCA. The human studies of TUDCA itself are set out in our review of the TUDCA evidence.

What we still don't know

  • Whether TUDCA changes FGF19, C4 or gut hormones in people. No study has measured them; one 1984 study of six men found no fall in bile acid production.[14]
  • Whether the low FGF19 in bile acid diarrhea is a cause or a consequence, and whether drugs that raise it can improve symptoms over months.
  • How much of the benefit of fecal transplant for C. difficile runs through bile acids in people.
  • How much bile acids contribute to the changes in blood sugar after weight-loss surgery.
  • Whether changing secondary bile acids through diet changes long-term health; the diet studies ran for days to months and measured bile acids, not disease.

All 51 studies

Every study in people appraised in this review, on the same fields. “Not stated” means the published summary does not say, not that the answer is no. Cell and animal studies are cited in the text but not appraised. On a phone, scroll the table sideways.

Evidence table

51 studies in people, appraised on the same fields

StudyPeopleDesignCompared withRandomizedBlindedDoseLengthMeasuredResultMain limits
The gut–liver loop
Gälman 2005[4]8 healthy volunteers, plus some people without a gallbladderBlood sampled every 90 minutes for 24 hoursA marker of cholesterol productionNoNot applicableNot applicable24 hoursC4, a blood marker of bile acid productionC4 peaked twice in the day, at 1 pm and 9 pm, at 2 to 4 times its baseline, and fell overnight. The rhythm was kept in people without a gallbladder.Eight volunteers; the number without a gallbladder is not stated.
Lundåsen 2006[5]Healthy adults (number not stated)Physiology studies: daily rhythm, a bile acid binder, CDCA, fastingOwn baselineNot statedNot statedNot statedNot statedFGF19, bile acids and C4 in bloodFGF19 peaked 90–120 minutes after the rise in blood bile acids after meals and came before the fall in bile acid production. It fell on a binder, rose on CDCA, and its rhythm disappeared with fasting.No group sizes or effect sizes in the abstract; the link to falling production is timing, not an experiment.
Meyer-Gerspach 2013[18]12 healthy volunteersRandomized, double-blind crossoverSalineYesDouble-blindCDCA infused into the duodenumSingle infusionsFGF19, GLP-1, CCK, glucoseFGF19 and blood bile acids rose (P<.001, P=.001); GLP-1 and CCK rose slightly; glucose did not change.A short infusion; small.
Mutanen 2015[17]52 children and young people with intestinal failureCross-sectional, with liver biopsiesHealthy matched controlsNoNot statedNot applicableNot applicableFGF19 in blood; liver findingsFGF19 was lower than in controls, and lower again in those with no ileum left than in those with some: 37 vs 74 pg/mL (p=0.028). It rose with the length of ileum left.Children on or after intravenous nutrition; one point in time.
Blahová 2016[16]16 healthy menOpen pilot studyOwn baselineNoNot statedColesevelam (dose not stated)28 daysFGF19, C4, blood fatsFGF19 fell at once and C4 rose fivefold; LDL cholesterol then fell 17%.Pilot; 16 men; no placebo.
Gomez-Ospina 2016[45]4 children from 2 familiesGenetic case seriesNoneNoNot applicableNot applicableNot applicableGenes and clinical courseFaults in both copies of the FXR gene caused severe liver disease (cholestasis) from birth, progressing quickly to end-stage liver disease.Four children with a rare inherited disease; shows what complete loss of FXR does.
Sjöberg 2017[22]Healthy adults (number not stated)Cholestyramine at rising doses, and a one-day experimentOwn baselineNot statedNot statedRising doses (not stated)Long term and 1 dayFGF19, bile acid productionFGF19 fell by more than 90% and bile acid production rose up to 17-fold. After stopping, FGF19 returned to normal within 2 days.Numbers and doses not in the abstract.
Bile acid diarrhea
Walters 2009[6]People with bile acid diarrhea and people without diarrhea (numbers not stated)Case-controlPeople without diarrheaNoNot statedNot applicableNot applicableFasting FGF19 and C4Median FGF19 120 vs 231 pg/mL (P<.0005) and C4 51 vs 18 ng/mL (P<.0001). Low FGF19 was also found after gallbladder removal.Group sizes not in the abstract; one point in time.
Pattni 2013[23]152 consecutive people with chronic diarrheaProspective diagnostic studyDiarrhea with a normal SeHCAT testNoNot statedNot applicableNot applicableFasting FGF19 and C4 against SeHCATMedian FGF19 147 vs 225 pg/mL in primary bile acid diarrhea (P<0.001); lower FGF19 went with lower SeHCAT retention and higher C4.One center; one fasting sample; the groups overlapped.
Walters 2015[31]28 people with bile acid diarrhea or chronic diarrhea (10 with primary bile acid diarrhea)Open-label, no control groupOwn baselineNoNoObeticholic acid 25 mg/day2 weeksFGF19, C4, stool frequency and formIn primary bile acid diarrhea, median FGF19 rose from 133 to 237 pg/mL (P=0.007) and the diarrhea index fell 34% (P=0.005). Cholesterol rose.Unblinded; 2 weeks; 8 to 10 per group.
Borup 2020[7]71 people with chronic diarrheaProspective multicenter diagnostic studySeHCAT testNoNot statedNot applicableNot applicableHow well C4 and FGF19 identify bile acid diarrheaC4 area under the curve 0.83. Below 15 ng/mL, 85% did not have it; above 48 ng/mL, 82% did. Fasting FGF19 was lower (72 vs 119 pg/mL), area under the curve 0.71.20 of 71 fell in an in-between C4 range.
Camilleri 2020[32]20 people with primary bile acid diarrheaRandomized, double-blind crossoverPlaceboYesDouble-blindTropifexor 0.06 mg/day14 days per periodStool frequency and form; FGF19, C4FGF19 rose and C4 fell for up to 8 hours, but stool frequency and form did not differ from placebo.Small; one dose; 14 days.
Indeykina 2021[47]61 people after gallbladder removal, with or without diarrhea, and 28 healthy controlsCross-sectionalNormal stools after surgery; healthy controlsNoNot statedNot applicableNot applicableFGF19 in blood; bile acids in stoolFGF19 was lower in those with diarrhea (86.2 vs 259), and stool bile acids about twice as high.Russian article, English summary only; FGF19 units given as ng/mL, which may be an error; time since surgery varied.
BouSaba 2023[33]31 people with diarrhea-type IBS and bile acid diarrheaRandomized, double-blindPlaceboYesDouble-blindAldafermin 1 mg/day by injection28 daysC4; stool consistencyMedian C4 at day 28 was 2.2 vs 50.4 ng/mL. Stool consistency did not change significantly over the 28 days.Small; 28 days; one dose; numbers from the registry and author manuscript.
Borup 2024[24]251 people with chronic diarrhea having a SeHCAT testDiagnostic study within a randomized trialSeHCAT testParent trial randomizedTest results blindedNot applicableNot applicableC4 as a testC4 above 46 ng/mL: sensitivity 47%, specificity 92%.The decision models were checked only within the same study.
Gut bacteria
Nagengast 1988[51]Healthy adults in three age groups, mean ages 22, 48 and 67 (numbers not stated)Cross-sectionalYounger age groupsNoNot applicableNot applicableNot applicableStool bile acids, diet, transit timeSecondary bile acids were higher in the oldest group; fiber intake was lower.One point in time; numbers not in the abstract.
Alberts 1996[20]95 adults with a past colon polyp (bile acids measured in 52)Randomized, double-blind, factorialLow-dose fiber and calciumYesDouble-blindWheat bran 13.5 g/day9 monthsStool bile acidsHigh-dose fiber lowered total stool bile acids by 52% (P=.001) and DCA by 48% (P=.003).Bile acids measured in a subsample; no bacteria measured.
Vrieze 2014[8]20 men with obesity and metabolic syndromeRandomized, single-blindAmoxicillinYesSingle-blindVancomycin 1,500 mg/day7 daysGut bacteria, bile acids, insulin sensitivityVancomycin lowered secondary bile acids in stool, raised primary bile acids in blood after meals and lowered insulin sensitivity (p<0.05); amoxicillin changed none of these.Men only; 7 days; no placebo group.
David 2014[19]11 adults, one with a chronic gut disease (10 per diet)Crossover feeding studyOwn baseline; the other dietNot statedNoNot applicable5 days per dietGut bacteria and their genes; stool bile acidsAn all-animal diet raised stool DCA significantly within days and raised bacterial bile-acid enzymes; the bacteria returned to baseline 2 days after the diet ended.Small; 5 days; an extreme diet.
Weingarden 2014[10]People with recurrent C. difficile infection treated with a fecal transplant (number not stated)Before and afterOwn earlier samples; donorsNoNoNot applicableNot statedStool bile acids and bacteriaBefore the transplant secondary bile acids were nearly undetectable; afterwards stool held mostly secondary bile acids, like the donors'.Number of people and concentrations not in the abstract; uncontrolled.
O'Keefe 2015[9]20 African Americans and 20 rural South AfricansSupervised two-week diet swapOwn usual dietNoNoNot applicable2 weeksColon bile acids and bacteriaA high-fiber, low-fat diet cut secondary bile acids by 70%; a high-fat, low-fiber diet raised them by 400%, with matching changes in the bacterial gene that makes them.Two weeks; not randomized.
Allegretti 2016[21]60 people: first C. difficile infection, recurrent infection, healthy controlsCase-controlHealthy controlsNoNot applicableNot applicableNot applicableStool and blood bile acids; bacteriaSecondary bile acids in stool were higher in controls than in recurrent (P<0.0001) and first infection (P=0.0007); primary bile acids were highest in recurrent infection.One center; one point in time.
Baumgartner 2017[25]55 men with obesity and prediabetesRandomized, double-blindPlacebo; amoxicillinYesDouble-blindVancomycin or amoxicillin 1,500 mg/day7 daysBile acids and fats in bloodFasting secondary bile acids fell more on vancomycin than on placebo (−0.24 vs −0.08 µmol/L, P<0.01); blood cholesterol unchanged.Men only; 7 days.
Mullish 2022[26]56 people after a first C. difficile infectionProspective cohort, weekly stool samplesThose who relapsed vs those who did notNoNot applicableNot applicable8 weeksStool bile acids; bacterial enzyme activity20 relapsed (36%). Secondary bile acids and bacterial bile-acid enzyme activity recovered only in those who did not relapse.Markers found and tested in the same group; an association.
Metabolism
Adrian 2012[54]10 people with obesity and type 2 diabetesSingle-blind; four doses and a vehicle, each on a separate dayVehicleNot statedSingle-blindRectal taurocholate, single dosesSingle dosesGLP-1, PYY, insulin, glucose, food intakeAt the top dose, peak GLP-1 was 7.2 times that on vehicle; glucose fell by up to about 68 mg/dL (3.8 mmol/L) and food intake by up to 47%.Ten people; single doses; everyone also took sitagliptin.
Kohli 2013[29]18 people with severe obesityBefore and after two operationsGastric bandingNoNot statedNot applicableUntil 20% weight lossBlood bile acids, GLP-1, insulinFasting bile acids more than doubled after gastric bypass (1.08 to 2.28 µmol/L, P=.03). The rise tracked GLP-1 but not insulin sensitivity.Small; not randomized; an association.
Steinert 2013[30]14 people having gastric bypass or sleeve gastrectomyRandomized pilotThe other operationYesNot statedNot applicable1 yearBile acids, GLP-1, PYYGLP-1 and blood sugar control improved within a week; bile acids rose significantly only at 1 year.Pilot; 14 people.
Hodge 2013[57]51 people with type 2 diabetesRandomized, four dosesPlaceboYesNot statedSB-756050, a TGR5 activator6 daysGlucose, gut hormonesGlucose rose at the two lower doses and did not fall at the two higher ones.Short; small groups.
Broeders 2015[58]12 healthy womenBefore and afterOwn baselineNot statedNot statedOral CDCA (dose not stated)2 daysBrown fat activity, energy expenditureBrown fat activity and whole-body energy use rose.No numbers in the abstract; the TGR5 link comes from cell work in the same paper.
Drugs that act on the signals
Fonseca 2008[28]461 people with type 2 diabetes on a sulfonylureaRandomized, double-blind, multicenterPlaceboYesDouble-blindColesevelam 3,750 mg/day26 weeksHbA1cHbA1c 0.54% lower than placebo (P<0.001); LDL cholesterol 16.7% lower.26 weeks; blood measures.
Neuschwander-Tetri 2015[61]283 people with NASH without cirrhosis (FLINT)Randomized, double-blindPlaceboYesDouble-blindObeticholic acid 25 mg/day72 weeksLiver biopsy scoreBiopsies improved in 45% vs 21% (relative risk 1.9). Itching 23% vs 6%.A biopsy endpoint; final biopsies stopped early in 64 people.
Nevens 2016[11]217 people with primary biliary cholangitis not responding to or unable to take UDCA (POISE)Randomized, double-blindPlaceboYesDouble-blindObeticholic acid 5–10 or 10 mg/day12 monthsALP and bilirubin responseResponse in 46% and 47% vs 10% (P<0.001). Itching 56% and 68% vs 38%; serious side effects 16% and 11% vs 4%.A laboratory endpoint; 12 months.
Younossi 2019[60]931 people with NASH and moderate scarring (REGENERATE, interim)Randomized, double-blindPlaceboYesDouble-blindObeticholic acid 10 or 25 mg/day18 monthsFibrosis improvement; NASH resolutionFibrosis improved in 23% on 25 mg vs 12% (p=0.0002); NASH resolution did not differ significantly. Itching 51% vs 19%.An interim biopsy analysis.
Rinella 2024[63]160 people with NASH and compensated cirrhosisRandomized, double-blindPlaceboYesDouble-blindAldafermin 1 or 3 mg/day48 weeksELF, a blood fibrosis scoreELF fell 0.5 more on 3 mg than placebo (p=0.0003). Diarrhea 40% on 3 mg vs 18%.A blood-marker endpoint; no clinical outcomes.
Kowdley 2025 (COBALT)[12]334 people with primary biliary cholangitisRandomized, double-blind confirmatory trial, plus an external comparisonPlaceboYesDouble-blindObeticholic acid 5–10 mg/dayEvent-drivenDeath, transplant or liver decompensation28.6% vs 28.9% (hazard ratio 1.01, 95% CI 0.68–1.51). The authors' separate comparison with insurance-claims patients favored the drug.Terminated early; many people switched; the external comparison is observational.
Trauner 2026 (PRIMIS)[64]416 people with primary sclerosing cholangitis without cirrhosisRandomized, double-blindPlaceboYesDouble-blindCilofexor 100 mg/day96 weeksFibrosis progression on biopsy31% vs 33% (p=0.42); stopped early for futility. Itching 49% vs 36%.Stopped early; biopsies in a subset.
TUDCA and UDCA
Hardison 1984[14]6 healthy menEach bile acid for a month, then a month offUDCA; time off treatmentNot statedNot statedTUDCA 20 mg/kg/day; UDCA 15 mg/kg/day1 month on eachBile acid production, cholesterol absorptionNeither TUDCA nor UDCA lowered the body's own bile acid production; cholesterol absorption fell on both.Six men; doses differ; no numbers in the abstract.
Setchell 1996[80]People with primary biliary cholangitis (number not stated)Randomized dose groupsDose vs doseYesNot statedTUDCA 500, 1,000 or 1,500 mg/day6 monthsMakeup of bile acids in bileUDCA and its conjugates rose to 34.4%, 32.8% and 41.6% of bile acids; TUDCA was partly re-joined to glycine; the share of lithocholic acid in bile did not change.People with liver disease; number not in the abstract.
Invernizzi 1999[81]12 women with primary biliary cholangitisCrossoverUDCAYesNot stated750 mg/day, both2 months on eachAbsorption and breakdown of bile acidsTUDCA was partly split from taurine and re-joined to glycine; lithocholic acid was consistently higher on UDCA than on TUDCA.Twelve people with liver disease; bile chemistry only.
van Gorkom 2002[82]15 healthy volunteersPlacebo-controlled crossoverPlaceboIndexed as randomized; method not describedNot statedUDCA 900 mg/day4 weeks eachStool bile acidsThe share of UDCA in stool rose from 2.7% to 23.7% and of lithocholic acid from 26.2% to 49.4% (both P<0.0001), showing gut bacteria convert part of the UDCA taken.No bacteria measured; shares, not totals.
Sauter 2004[68]8 healthy volunteersBefore and after, no control groupOwn baselineNoNoUDCA 10–15 mg/kg/day40 daysC4C4 rose from 39.7 to 64.0 ng/mL (p<0.05).Eight people; no control group; FGF19 not measured.
Kars 2010[75]20 adults with obesityRandomized, placebo-controlledPlaceboYesSingle (participant)TUDCA 1,750 mg/day4 weeksInsulin sensitivity; cell-stress markers in muscle and fatLiver and muscle insulin sensitivity rose about 30% on TUDCA and not on placebo. No receptor or bile-acid signal (FGF19, C4, GLP-1) was measured.Four weeks; 20 people.
Mueller 2015[67]40 people with severe obesity and fatty liver, before bariatric surgeryRandomizedNo treatmentYesNot statedUDCA 20 mg/kg/day3 weeksFGF19, C4, liver and fat tissueUDCA lowered FGF19 and raised C4 and bile acid production; liver fat content rose.Three weeks; a high dose; no numbers in the abstract.
Nielsen 2017[71]11 people after gastric bypassPlacebo-controlled crossoverWaterNot statedNot statedUDCA 750 mg or CDCA 1,250 mg, single dosesSingle study daysGLP-1 and other gut hormones, FGF19CDCA raised GLP-1 and FGF19; UDCA left all hormone levels unchanged.Single doses; 11 people.
Tang 2018[77]60 people with primary biliary cholangitis and 80 controls; 37 followed on UDCACase-control, plus before and after UDCAHealthy controls; own baselineNoNot applicableNot stated6 months of UDCAGut bacteriaSix bacterial groups that differed from controls moved back toward normal after 6 months of UDCA.No control group for the UDCA part; dose not stated.
Pearson 2019[76]401 adults with a past colon polyp, in a randomized trialStool analysis within a randomized trialPlaceboYesNot statedUDCA 8–10 mg/kg/day3 yearsGut bacteria; polyp recurrenceUDCA shifted the mix of gut bacteria (P<0.001) without changing their richness; the shift was not linked to polyp recurrence.A secondary analysis of a cancer-prevention trial.
Ovadia 2020[70]35 pregnant women: 14 uncomplicated, 21 with cholestasis of pregnancy (17 on UDCA)ObservationalUntreated cholestasis; uncomplicated pregnancyNoNot applicableNot statedNot applicableGut bacteria, stool bile acids, FGF19 and C4On UDCA, FGF19 was higher and C4 lower; stool lithocholic acid was higher.Not randomized; UDCA use went with the bacteria mix, so cause is unclear.
McGlone 2021[72]12 healthy volunteersRandomized crossoverNo bile acidYesNot statedUDCA or CDCA, single doses before a mealSingle study daysGut hormones, FGF19, glucoseCDCA raised GLP-1; UDCA did not change gut hormones, fasting or after the meal.Single doses; healthy people.
Francini 2024[35]One 92-year-old woman on tube feeding, taking TUDCA long termCase reportHer own earlier sampleNoNoNot stated30 days between samplesGut bacteriaFirmicutes rose from 46% to 70% and Proteobacteria fell from 26% to 2%.One person; she also took an antibiotic in that period.
Ladakis 2025[15]54 people with progressive multiple sclerosis randomized, 47 analyzed (34 gave stool samples)Randomized, double-blindPlaceboYesDouble-blindTUDCA 2,000 mg/day16 weeksSafety; blood bile acids; gut bacteriaBlood TUDCA, GUDCA and UDCA rose. Gut bacterial diversity did not change; the mix of species differed between groups, and bacterial bile-acid pathways did not. Side effects 38% vs 33%.A safety trial; small stool subgroup; not a digestive population.
Lamm 2025[34]14 people with ulcerative colitis (11 assessed)Open-label, no control groupOwn baselineNoNoTUDCA 1,750–2,000 mg/day6 weeksColon-lining stress markers; disease score; bacteria; blood bile acidsDisease score fell from 9 to 4.5 (p<0.001). Stool bacterial diversity unchanged; the share of DCA, UDCA and LCA in blood rose.No comparison group; not yet peer reviewed.
Download the table (CSV)

Taken from each study's published summary, or its full text where available. Searched October 20, 2026.

How we did this review

Search. On October 20, 2026 we searched PubMed, Europe PMC and ClinicalTrials.gov for FXR, TGR5, FGF19 and C4 in people; bile acid diarrhea; gut bacteria and bile acids with antibiotics, diet, age and C. difficile; bile acids after weight-loss surgery and gut hormones; obeticholic acid, other FXR activators, FGF19-like drugs and bile acid binders; and TUDCA and UDCA with each of these, logging 111 searches in all. We read the US labels for colesevelam and cholestyramine and the FDA documents and Federal Register notices for obeticholic acid.

What we included. Studies in people for each topic: the key physiology studies, diagnostic studies, randomized trials and pooled analyses, rather than every study. For TUDCA, every study in people we found that measured these signals, bile acid production, the gut's processing of TUDCA, or gut bacteria. For UDCA, the key studies; others found no change in these markers.[69,83] The receptor discoveries and other cell and animal work are cited for context and marked as such, but not appraised. Pooled analyses, guidelines and the studies behind the C4 test are also cited for context but not appraised.

How we appraised them. For every study we recorded the same fields: who took part, the design, the comparison, whether it was randomized and blinded, the dose and length, what was measured, the result, and the main limits. We took them from the study itself and wrote “not stated” where the study does not say. Doses are given as each study reported them.

How we graded the evidence. Each topic gets two things: what the studies in people found, and a grade for how much research stands behind that finding. The grade describes the research, not the topic. A low grade means a finding has not yet been confirmed, not that it has been disproved.

  • Strong: consistent results from several well-sized randomized, blinded trials measuring outcomes that matter to patients.
  • Moderate: at least one well-sized randomized trial, with laboratory outcomes or short follow-up.
  • Early: one placebo-controlled trial, or several small controlled trials, or a licensed medical use resting on small trials.
  • Preliminary: one or two studies that were small, uncontrolled or unblinded.
  • Not yet studied: no published study in people.

Physiology and diagnostic findings are graded on the same scale by the size and consistency of the studies in people behind them.

Limits of this review. This is a selective review of a large field: for each topic we chose the key studies in people rather than every study. For several studies we could read only the summary, and some summaries do not give the number of people. We could not search Chinese-language databases or Embase.

About this review

Who wrote it. The Dr.Primal editorial team. Our editorial standards explain how we work.

Conflict of interest. Dr.Primal sells a TUDCA supplement. That is why we have kept this page free of product links and offers, stated plainly where TUDCA has not been studied, and appraised every study in the same way.

Medical review. This review has not been checked by a physician. The Dr.Primal editorial team wrote it and fact-checked every figure against its primary source. If a credentialed reviewer checks it later, we will name them here and record it in the version history.

Versions. Version 1.0, October 20, 2026: first publication. We will update this page when new studies are published, and record every change here.

Corrections. If you find an error or a study we missed, please tell us.

Cite this page Dr.Primal Editorial. Bile acids and the gut: FGF19, the microbiome and bile acid diarrhea. Version 1.0. Dr.Primal; October 20, 2026. https://drprimal.com/en-gb/pages/bile-acids-gut-microbiome

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This review describes published research. It is not medical advice and does not replace advice from your doctor. Dietary supplements are not intended to diagnose, treat, cure or prevent any disease.

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