The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice
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Background & aims Abnormal delivery of bile acids (BAs) to the colon as a result of disease or therapy causes constipation or diarrhea by unknown mechanisms. The G protein-coupled BA receptor TGR5 (or GPBAR1) is expressed by enteric neurons and endocrine cells, which regulate motility and secretion.Methods We analyzed gastrointestinal and colon transit, as well as defecation frequency and water content, in wild-type, knockout, and transgenic mice (trg5-wt, tgr5-ko, and tgr5-tg, respectively). We analyzed colon tissues for contractility, peristalsis, and transmitter release.Results Deoxycholic acid inhibited contractility of colonic longitudinal muscle from tgr5-wt but not tgr5-ko mice. Application of deoxycholic acid, lithocholic acid, or oleanolic acid (a selective agonist of TGR5) to the mucosa of tgr5-wt mice caused oral contraction and caudal relaxation, indicating peristalsis. BAs stimulated release of the peristaltic transmitters 5-hydroxytryptamine and calcitonin gene-related peptide; antagonists of these transmitters suppressed BA-induced peristalsis, consistent with localization of TGR5 to enterochromaffin cells and intrinsic primary afferent neurons. tgr5-ko mice did not undergo peristalsis or transmitter release in response to BAs. Mechanically induced peristalsis and transmitter release were not affected by deletion of tgr5. Whole-gut transit was 1.4-fold slower in tgr5-ko than tgr5-wt or tgr5-tg mice, whereas colonic transit was 2.2-fold faster in tgr5-tg mice. Defecation frequency was reduced 2.6-fold in tgr5-ko and increased 1.4-fold in tgr5-tg mice compared with tgr5-wt mice. Water content in stool was lower (37%) in tgr5-ko than tgr5-tg (58%) or tgr5-wt mice (62%).Conclusions The receptor TGR5 mediates the effects of BAs on colonic motility, and deficiency of TGR5 causes constipation in mice. These findings might mediate the long-known laxative properties of BAs, and TGR5 might be a therapeutic target for digestive diseases.
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ECs express TGR5, and administration of deoxycholic acid increased 5-HT secretion in colonic tissue of wild-type, but not Tgr5 transgenic mice.
“ECs were shown to express TGR5, and administration of deoxycholic acid increased 5-HT secretion in colonic tissue of the wild-type, but not Tgr5 transgenic mice (Alemi et al., 2013).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Alemi et al., 2013
Figure 5 reports TGR5 in enterochromaffin (EC) cells. The section “BAs Stimulate the Release of 5-HT and CGRP From the Colon via TGR5” reports that deoxycholic acid stimulated 5-HT release in wild-type colon tissue, but that release was absent or blunted in Tgr5 knockout mice—not transgenic mice. Page numbers were not provided in our copy. (LLM, conf=0.93)
Experimental — accuracy not yet measuredProkinetic effects of bile acids can be mediated by TGR5 expressed by enteric neurons and enteroendocrine cells, based on animal models.
“Prokinetic effects of bile acids can be mediated by the G protein-coupled bile acid receptor TGR5 (or GPBAR1), expressed by enteric neurons and enteroendocrine cells based on findings from animal models55.”
From The gut Microbiome in adult and pediatric functional gastrointestinal disorders (2019) · cites this paper as [55]
Secondary BAs have a unique signaling profile in the GI tract compared with primary bile moieties.
“Secondary BAs, produced by gut bacteria, have a unique signaling profile in the GI tract as compared with primary bile moieties.”
From Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism (2017) · cites this paper as Alemi et al., 2013
Secondary BAs activate colonic motility by stimulating the release of intestinal 5-HT and CGRP.
“For example, secondary BAs were shown to activate colonic motility by stimulating the release of intestinal 5-HT and CGRP (Alemi et al., 2013).”
From Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism (2017) · cites this paper as Alemi et al., 2013
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- Authors
- Alemi, F., Poole, D. P., Chiu, J., Schoonjans, K., Cattaruzza, F., Grider, J. R., Bunnett, N. W., & Corvera, C. U.
- Affiliations
- University of California, San Francisco (US)
- The University of Melbourne (AU)
- École Polytechnique Fédérale de Lausanne (CH)
- Virginia Commonwealth University (US)
- Monash University (AU)
- San Francisco VA Medical Center (US)
- Corresponding author
- Bunnett, Nigel W.
- Corvera, Carlos U.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 144
- Issue
- 1
- Pages
- 145-154
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC6054127
- OpenAlex
- W2003525898
- Cited by
- 362
- References
- 44
- Citations by year
- 2026: 38 · 2025: 25 · 2024: 32 · 2023: 24 · 2022: 46 · 2021: 45 · 2020: 22 · 2019: 22 · 2018: 23 · 2017: 20 · 2016: 16 · 2015: 16 · 2014: 24 · 2013: 9
- FWCI
- 15.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Northern California Institute for Research and Education
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (125487)
- Monash University
- National Institutes of Health (DK39957, DK-34153, DK43207)
- Medical Research Council
- National Health and Medical Research Council (63303)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK034153, DK-39957, R37DK039957, DK 57840, DK 43207, R01DK057840, R01DK043207, R56DK034153, DK-34153, R01DK039957, R56DK043207)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Keywords
- TGR5, bile acids, colonic motility, peristalsis, defecation, constipation, deoxycholic acid, enterochromaffin cells, serotonin, calcitonin gene-related peptide, colonic transit, laxative effect, enteric neurons, G protein-coupled receptors, stool water content
- MeSH terms
- Animals, Colon, Defecation, Deoxycholic Acid, Enterochromaffin Cells, Feces, Gastrointestinal Transit, Intestinal Mucosa, Lithocholic Acid, Mice, Inbred C57BL, Mice, Transgenic, Muscle Contraction, Muscle Relaxation, Neurons, Afferent, Oleanolic Acid, Peristalsis, Serotonin, Water, Calcitonin Gene-Related Peptide, Mice, Knockout, Receptors, G-Protein-Coupled, Mice
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