Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease
Open accessAbstract
The gastrointestinal tract hosts the largest ecosystem of microorganisms in the body. The metabolism of ingested nutrients by gut bacteria produces novel chemical mediators that can influence chemosensory cells lining the gastrointestinal tract. Specifically, hormone-releasing enteroendocrine cells which express a host of receptors activated by these bacterial metabolites. This review will focus on the activation mechanisms of glucagon-like peptide-1 releasing enteroendocrine cells by the three main bacterial metabolites produced in the gut: short-chain fatty acids, secondary bile acids and indoles. Given the importance of enteroendocrine cells in regulating glucose homeostasis and food intake, we will also discuss therapies based on these bacterial metabolites used in the treatment of metabolic diseases such as diabetes and obesity. Elucidating the mechanisms gut bacteria can influence cellular function in the host will advance our understanding of this fundamental symbiotic relationship and unlock the potential of harnessing these pathways to improve human health.
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Gut microbiota-derived metabolites, including SCFAs, secondary BAs, and indoles, modulate gut hormone secretion from enteroendocrine cells.
“the gut microbiota-derived metabolites, including SCFAs, secondary BAs, and indoles, have been demonstrated to modulate gut hormone secretion from EECs.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [547]
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BackgroundIdentification of membrane-type receptor for bile acids (M-BAR)
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BackgroundFXR is a molecular target for the effects of vertical sleeve gastrectomy
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BackgroundInfluentialEndoplasmic reticulum stress, obesity and diabetes
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BackgroundIntestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction
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BackgroundSCFAs strongly stimulate PYY production in human enteroendocrine cells
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BackgroundFarnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells
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BackgroundImmune regulation by microbiome metabolites
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BackgroundThe Landscape of Genetic Content in the Gut and Oral Human Microbiome
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BackgroundMechanisms underlying weight loss after bariatric surgery
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BackgroundInfluentialExpression of the short-chain fatty acid receptor, GPR43, in the human colon
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BackgroundCharacteristics of gut microbiota in people with obesity
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BackgroundMolecular mechanisms underlying bile acid‐stimulated glucagon‐like peptide‐1 secretion
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“EECs express HDACs and SCFA-responsive GPCRs (85–89), except HCAR2 which is primarily localized in adipose and immune tissue (83).”
BackgroundInfluentialGut microbiome alterations in high-fat-diet-fed mice are associated with antibiotic tolerance
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BackgroundTGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice
McGavigan, A. K., Garibay, D., Henseler, Z. M., Chen, J. C., Bettaieb, A., Haj, F. G., Ley, R. E., Chouinard, M. L., & Cummings, B. P. (2015) · Gut · doi:10.1136/gutjnl-2015-309871 · Cited by 210 · see citing works
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“EECs express HDACs and SCFA-responsive GPCRs (85–89), except HCAR2 which is primarily localized in adipose and immune tissue (83).”
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Tryptophan Metabolic Pathways Are Altered in Obesity and Are Associated With Systemic Inflammation
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TGR5 potentiates GLP-1 secretion in response to anionic exchange resins
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“Secondary bile acids, specifically LCA and the taurine conjugate TLCA, are the most potent stimulants of GPBAR1 activation (127, 133, 134).”
BackgroundBile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery
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BackgroundPrevention and Treatment of Obesity, Insulin Resistance, and Diabetes by Bile Acid–Binding Resin
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BackgroundHepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate
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“For instance, complex carbohydrates undergo bacterial fermentation to produce short-chain fatty acids (SCFAs) (10–12) and the amino acid tryptophan is further metabolized by gut bacteria to produce indole and other indole-derivatives (13, 14).”
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“More than 85 different Gram-positive and Gram-negative bacterial species express tryptophanase (67), the enzyme that catalyzes the hydrolytic b-elimination of tryptophan to indole, pyruvate, and ammonia (68).”
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A Surgical Model in Male Obese Rats Uncovers Protective Effects of Bile Acids Post-Bariatric Surgery
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BackgroundThe Pharmacology of Bile Acids and Their Receptors
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“FXR expression has also been identified in immune cells, adipose tissue, and skeletal muscle (138).”
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
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“57 Moreover, EECs are enriched for FFAR2 and TGR5 compared to other epithelial cell subtypes (Figures S7B–S7C).”
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Mapping pesticide-induced metabolic alterations in human gut bacteria
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GLP‐1 agonists and the gut microbiome: A bidirectional relationship
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“20,60,61 These interactions extend beyond glycaemic control, embedding GLP-1 within a broader host – microbe metabolic network that governs insulinotropic responses, energy balance and neuroendocrine regulation.”
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“Short-chain fatty acids, secondary bile acids, and tryptophan catabolites have emerged as key mediators of microbiota–transporter interactions [37,38].”
Unraveling the Pathophysiology of Irritable Bowel Syndrome: Mechanisms and Insights
Aggeletopoulou, I., Papantoniou, K., Pastras, P., & Triantos, C. K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262110598 · Cited by 23 · see citing works
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Harnessing Bacterial Extracellular Vesicle Immune Effects for Cancer Therapy
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“For instance, acetate produced by Bifidobacterium bifidum [25] and the short-chain fatty acid butyrate [26] were shown to enhance anti-tumor immunity by increasing tumor-infiltrating IFNγ secreting CD8+ T cells.”
BackgroundEffect of Gut Dysbiosis on Onset of GI Cancers
Kumari, S., Srilatha, M., & Nagaraju, G. P. (2024) · Cancers · doi:10.3390/cancers17010090 · Cited by 19 · see citing works
Maternal Nutrition, Toxicants, and Epigenetic Programming of Obesity Across Generations
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“156 For example, butyrate-mediated HDAC inhibition in fetal liver promotes histone acetylation at lipid oxidation genes, improving metabolic efficiency.”
Lu, C., Liu, D., Wu, Q., Zeng, J., Xiong, Y., & Luo, T. L. (2024) · npj Biofilms and Microbiomes · doi:10.1038/s41522-024-00585-7 · Cited by 12 · see citing works
“Gutmicrobial metabolites,suchastrimethylamineN-oxide,asourpreviousreport, acceleratestheprogressionofatherosclerosis 15 , whereas short-chain fatty acids and secondary bile acids (SBAs) confer cardioprotective effects 16,17 .”
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“More importantly, microbially derived SCFAs, secondary bile acids, and indole derivatives can activate enteroendocrine cells, promoting the secretion of glucagon-like peptide-1 (GLP-1) and thereby influencing host neuroendocrine regulation and energy metabolism [12].”
Gut microbiome dysbiosis in PCOS: from pathogenesis to microbiome-targeted therapies
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Magnesium and LongevityPreprint
Chambers, P. W. (2024) · Qeios · doi:10.32388/n1scbr.3 · Cited by 8 · see citing works
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Magnesium and LongevityPreprint
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Biomarkers in wearables, ingestible, and implantable sensors for health monitoring
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Design and Characterization of a Generalist Biosensor for Indole Derivatives
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“These metabolites profoundly influence host metabolism and maintain immune homeostasis by modulating immune cell functions [277, 286, 287].”
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“These secondary bile acids are exclusively produced by intestinal bacteria, and their levels are influenced by the composition of the gut microbiota [115].”
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BackgroundMetabolic crosstalk: Exploring the dynamic interactions between gut microbiota and metabolism
Akash, M. S. H., & Rehman, K. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-36312-2.00017-6 · Cited by 1 · see citing works
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Peptidomics: A New Dimension in Microbiome Research
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“This enhances insulin secretion [93 ].”
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“When this dialogue is functioning properly, it maintains metabolic and immune health, but any break in communication can lead to inflammatory or metabolic disorders (Bonaz et al. 2018; Overby and Ferguson 2021; Masse and Lu 2023).”
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“These metabolites not only maintain intestinal homeostasis but also regulate the reproductive tract microenvironment and immune responses at distant sites (62, 63).”
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InfluentialHuang, Q., Liang, Z., Zeng, Y., Yao, C., He, J. S., Cao, Y., & Chen, Y. (2026) · Food Frontiers · doi:10.1002/fft2.70337
- Authors
- Masse, K. E., & Lu, V. B.
- Affiliations
- Western University (CA)
- Corresponding author
- Lu, Van B.
- ORCID
- Lu, Van B.
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2023-07-25
- Volume
- 14
- Pages
- 1169624-1169624
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC10407565
- OpenAlex
- W4385251361
- Cited by
- 120
- References
- 272
- Citations by year
- 2026: 66 · 2025: 23 · 2024: 29 · 2023: 2
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- short-chain fatty acids, secondary bile acids, indole, gut microbiota metabolites, enteroendocrine cells, glucagon-like peptide-1, glucose homeostasis, food intake regulation, diabetes mellitus, obesity, metabolic disease treatment, gut microbiota, host-microbe symbiosis
- MeSH terms
- Gastrointestinal Microbiome, Bacteria, Bile Acids and Salts, Fatty Acids, Volatile, Humans, Indoles, Metabolic Diseases, Ecosystem, Enteroendocrine Cells
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