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Cited by 120Gut microbiota and healthGastrointestinal motility and disordersDiabetes Treatment and Management

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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

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Masse, Karly E., Lu, Van B.·2023·Frontiers in Endocrinology
DOI 10.3389/fendo.2023.1169624PMC PMC10407565
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Abstract

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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Crossref · 10.3389/fendo.2023.1169624

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Figure 1 Schematic representation of the bidirectional relationship between the host-gut microbiota equilibrium and metabolic health. Cells lining the distal gastrointestinal tract are in direct contact with bacterial metabolites produced by the gut microbiota, and thus can contribute to host health. In a healthy state, the gut microbiota produces metabolites that activate receptors on distal EECs to mediate insulinotropic effects by the release of secretory vesicles containing GLP-1. Gut dysbiosis alters the intestinal composition and metabolites produced and is associated with the development of T2DM and obese-related diseases. Research has proposed that the dysregulation of metabolism in metabolic diseases releases molecules that can reduce the abundance of intestinal bacteria and alter the function of the ecosystem. EEC, enteroendocrine cell; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus.
Figure 1 Schematic representation of the bidirectional relationship between the host-gut microbiota equilibrium and metabolic health. Cells lining the distal gastrointestinal tract are in direct contact with bacterial metabolites produced by the gut microbiota, and thus can contribute to host health. In a healthy state, the gut microbiota produces metabolites that activate receptors on distal EECs to mediate insulinotropic effects by the release of secretory vesicles containing GLP-1. Gut dysbiosis alters the intestinal composition and metabolites produced and is associated with the development of T2DM and obese-related diseases. Research has proposed that the dysregulation of metabolism in metabolic diseases releases molecules that can reduce the abundance of intestinal bacteria and alter the function of the ecosystem. EEC, enteroendocrine cell; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus.CC BY · PubMed Central
Figure 2 SCFA-triggered intracellular signaling mechanisms in GLP-1 releasing EEC L-cells. Schematic of an L-cell (white) surrounded by enterocytes (grey). Complex carbohydrates are substrates for resident gut bacteria to produce SCFAs in the distal gastrointestinal tract. SCFAs can signal through multiple receptors on both the apical (top) and basolateral membranes (bottom) of L-cells. Uptake of SCFAs by SMCT and MCT across the intestinal epithelium to the basolateral side shown in enterocytes. SCFAs inhibit HDACs or activate G-protein coupled receptors FFA2, FFA3 and OR51E1/2 in L-cells. Unresolved mechanisms are marked with a question mark. EEC, enteroendocrine cell; SCFAs, short-chain fatty acids; FFA2/3, free fatty acid receptor 2 or 3; OR51E1/2, olfactory receptor subfamily 5E1 or 2; GLP-1, glucagon-like peptide-1; Ca2+, calcium ions; SMCT, sodium-dependent monocarboxylate transporter; MCT, H+-dependent monocarboxylate transporter; Na+, sodium ions; HDACs, histone deacetylases; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PLCβ, phospholipase C beta; ERK1/2, extracellular signal-regulated kinases; IP3, inositol triphosphate.
Figure 2 SCFA-triggered intracellular signaling mechanisms in GLP-1 releasing EEC L-cells. Schematic of an L-cell (white) surrounded by enterocytes (grey). Complex carbohydrates are substrates for resident gut bacteria to produce SCFAs in the distal gastrointestinal tract. SCFAs can signal through multiple receptors on both the apical (top) and basolateral membranes (bottom) of L-cells. Uptake of SCFAs by SMCT and MCT across the intestinal epithelium to the basolateral side shown in enterocytes. SCFAs inhibit HDACs or activate G-protein coupled receptors FFA2, FFA3 and OR51E1/2 in L-cells. Unresolved mechanisms are marked with a question mark. EEC, enteroendocrine cell; SCFAs, short-chain fatty acids; FFA2/3, free fatty acid receptor 2 or 3; OR51E1/2, olfactory receptor subfamily 5E1 or 2; GLP-1, glucagon-like peptide-1; Ca2+, calcium ions; SMCT, sodium-dependent monocarboxylate transporter; MCT, H+-dependent monocarboxylate transporter; Na+, sodium ions; HDACs, histone deacetylases; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PLCβ, phospholipase C beta; ERK1/2, extracellular signal-regulated kinases; IP3, inositol triphosphate.CC BY · PubMed Central
Figure 3 Secondary bile acid-triggered intracellular signaling mechanisms in GLP-1 releasing EEC L-cells. Schematic as in Figure 2. Primary bile acids are converted to secondary bile acids by intestinal gut bacteria. Secondary bile acids passively diffuse or are transported across the intestinal epithelium via ASBT and activate the G-protein coupled receptor, GPBAR1 and nuclear receptor, FXR. Activation of GPBAR1 by secondary bile acids results in GLP-1 secretion. FXR regulates SHP and FGF19 expression and may regulate GPBAR1 gene transcription (marked by a question mark). EEC, enteroendocrine cell; GPBAR1, G-protein coupled bile acid receptor; FXR, Farnesoid-X receptor; GLP-1, glucagon-like peptide-1; ASBT, apical sodium-dependent bile acid transporter; Ca2+, calcium ions; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; ATP, adenosine triphosphate; SHP, short heterodimer protein; FGF19, fibroblast growth factor 19; Na+, sodium ions.
Figure 3 Secondary bile acid-triggered intracellular signaling mechanisms in GLP-1 releasing EEC L-cells. Schematic as in Figure 2. Primary bile acids are converted to secondary bile acids by intestinal gut bacteria. Secondary bile acids passively diffuse or are transported across the intestinal epithelium via ASBT and activate the G-protein coupled receptor, GPBAR1 and nuclear receptor, FXR. Activation of GPBAR1 by secondary bile acids results in GLP-1 secretion. FXR regulates SHP and FGF19 expression and may regulate GPBAR1 gene transcription (marked by a question mark). EEC, enteroendocrine cell; GPBAR1, G-protein coupled bile acid receptor; FXR, Farnesoid-X receptor; GLP-1, glucagon-like peptide-1; ASBT, apical sodium-dependent bile acid transporter; Ca2+, calcium ions; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; ATP, adenosine triphosphate; SHP, short heterodimer protein; FGF19, fibroblast growth factor 19; Na+, sodium ions.CC BY · PubMed Central
Figure 4 Indole-triggered intracellular signaling mechanisms in GLP-1 releasing EEC L-cells. Schematic as in Figure 2. Tryptophan is a substrate for resident gut bacteria to produce the metabolites tryptamine, IPyA and indoles. IPyA is a precursor to the metabolites IAA, IAld, skatole and IPA. Indole and other metabolites passively diffuse across the intestinal epithelium and activate the transcription factors AhR and PXR to regulate gene transcription. Indole may mediate effects through a yet to be determined receptor. There are dual and opposing effects on GLP-1 release by acute and chronic exposure to indoles. Acute indole stimulates release of secretory vesicles containing GLP-1 by a voltage-gated potassium channel blockade. Chronic indole exposure suppresses mitochondrial activity to produce ATP. IPyA, indole-3-pyruvic acid; IAA, indole-3-acetic acid; IAld, indole-3-aldehyde; IPA, indole-3-propionic acid; EEC, enteroendocrine cell; AhR, Aryl hydrocarbon receptor; PXR, Pregnane-X-receptor; ψ, membrane potential; K+, potassium ions; Ca2+, calcium ions; ATP, adenosine triphosphate.
Figure 4 Indole-triggered intracellular signaling mechanisms in GLP-1 releasing EEC L-cells. Schematic as in Figure 2. Tryptophan is a substrate for resident gut bacteria to produce the metabolites tryptamine, IPyA and indoles. IPyA is a precursor to the metabolites IAA, IAld, skatole and IPA. Indole and other metabolites passively diffuse across the intestinal epithelium and activate the transcription factors AhR and PXR to regulate gene transcription. Indole may mediate effects through a yet to be determined receptor. There are dual and opposing effects on GLP-1 release by acute and chronic exposure to indoles. Acute indole stimulates release of secretory vesicles containing GLP-1 by a voltage-gated potassium channel blockade. Chronic indole exposure suppresses mitochondrial activity to produce ATP. IPyA, indole-3-pyruvic acid; IAA, indole-3-acetic acid; IAld, indole-3-aldehyde; IPA, indole-3-propionic acid; EEC, enteroendocrine cell; AhR, Aryl hydrocarbon receptor; PXR, Pregnane-X-receptor; ψ, membrane potential; K+, potassium ions; Ca2+, calcium ions; ATP, adenosine triphosphate.CC BY · PubMed Central

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Metadata

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)
DOI
10.3389/fendo.2023.1169624
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
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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