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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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.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.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.CC BY · PubMed Central

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Radilla-Vázquez, R. B., Parra‐Rojas, I., Martínez-Hernández, N. E., Márquez‐Sandoval, F., Illades‐Aguiar, B., & Castro-Alarcón, N. (2016) · Obesity Facts · doi:10.1159/000442479 · Cited by 1,200
Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation
Pluznick, J. L., Protzko, R. J., Gevorgyan, H., Peterlin, Z., Sipos, A., Han, J., Brunet, I., Wan, L.-X., Rey, F., Wang, T., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1215927110 · Cited by 1,191 · cited 2×
“Originally discovered in olfactory epithelium, the olfactory receptor subfamily 51E1/2 (OR51E1/2; Olfr558/Olfr78 in mouse) are other receptors responsive to SCFAs (82).”
Background
Vitamin D Receptor As an Intestinal Bile Acid Sensor
Makishima, M., Lu, T. T., Xie, W., Whitfield, G. K., Domoto, H., Evans, R. M., Haussler, M. R., & Mangelsdorf, D. J. (2002) · Science · doi:10.1126/science.1070477 · Cited by 1,176
Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes
Nauck, M., Frid, A., Hermansen, K., Shah, N. S., Tankova, T., Mitha, I. H., Zdravkovic, M., Düring, M., Matthews, D. R., & for the LEAD-2 Study Group (2009) · Diabetes Care · doi:10.2337/dc08-1355 · Cited by 1,129
Consequences of bile salt biotransformations by intestinal bacteria
Ridlon, J. M., Harris, S. C., Bhowmik, S., Kang, D.-J., & Hylemon, P. B. (2016) · Gut Microbes · doi:10.1080/19490976.2015.1127483 · Cited by 1,128
Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome
Jones, B. V., Begley, M., Hill, C., Gahan, C. G. M., & Marchesi, J. R. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804437105 · Cited by 1,098 · cited 1×
“At the phyla level, bacterial populations encoding BSH, such as Bacillota, Bacteroidota and Actinomycetota, have been shown to play an important role in the production of secondary bile acids (61).”
Background
Indole as an intercellular signal in microbial communities
Lee, J.-H., & Lee, J. (2010) · FEMS Microbiology Reviews · doi:10.1111/j.1574-6976.2009.00204.x · Cited by 1,059 · cited 1×
“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).”
Background
Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial
Garber, A., Henry, R., Ratner, R., Garcia-Hernandez, P. A., Rodriguez-Pattzi, H., Olvera-Alvarez, I., Hale, P. M., Zdravkovic, M., & Bode, B. (2009) · The Lancet · doi:10.1016/s0140-6736(08)61246-5 · Cited by 1,057
Microglial control of astrocytes in response to microbial metabolites
Rothhammer, V., Borucki, D. M., Tjon, E. C., Takenaka, M. C., Chao, C.-C., Ardura-Fabregat, A., de Lima, K. A., Gutiérrez-Vázquez, C., Hewson, P., Staszewski, O., et al. (2018) · Nature · doi:10.1038/s41586-018-0119-x · Cited by 1,051
Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition
Kootte, R. S., Levin, E., Salojärvi, J., Smits, L. P., Hartstra, A. V., Udayappan, S. D., Hermes, G., Bouter, K. E., Koopen, A. M., Holst, J. J., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.09.008 · Cited by 1,039
Sodium butyrate inhibits histone deacetylation in cultured cells
Candido, E. (1978) · Cell · doi:10.1016/0092-8674(78)90305-7 · Cited by 1,036 · cited 1×
“SCFAs can also affect gene expression through the inhibition of histone deacetylases (HDACs) (84).”
Background
Epigenetics in Human Obesity and Type 2 Diabetes
Ling, C., & Rönn, T. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.03.009 · Cited by 1,006
Identification of membrane-type receptor for bile acids (M-BAR)
Maruyama, T., Miyamoto, Y., Nakamura, T., Tamai, Y., Okada, H., Sugiyama, E., Nakamura, T., Itadani, H., & Tanaka, K. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02550-0 · Cited by 993
Human Gut Microbiota Changes Reveal the Progression of Glucose Intolerance
Zhang, X., Shen, D., Fang, Z., Jie, Z., Qiu, X., Zhang, C., Chen, Y., & Ji, L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071108 · Cited by 946 · cited 1×
“A shift in microbiome composition away from SCFA-producing bacterial species has been linked to prediabetes (173), a key step in the progression of diabetes (202).”
Background
FXR is a molecular target for the effects of vertical sleeve gastrectomy
Ryan, K. K., Tremaroli, V., Clemmensen, C., Kovatcheva-Datchary, P., Myronovych, A., Karns, R., Wilson-Pérez, H. E., Sandoval, D. A., Kohli, R., Bäckhed, F., et al. (2014) · Nature · doi:10.1038/nature13135 · Cited by 931
Towards the human intestinal microbiota phylogenetic core
Tap, J., Mondot, S., Levenez, F., Pelletier, E., Caron, C., Furet, J., Ugarte, E., Muñoz‐Tamayo, R., Paslier, D. L. E., Nalin, R., et al. (2009) · Environmental Microbiology · doi:10.1111/j.1462-2920.2009.01982.x · Cited by 927 · cited 1×
“Actinobacteria), Pseudomonadota (aka Proteobacteria), or Verrucomicrobiota (aka Verrucomicrobia) are also represented (2).”
Background
The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents
Psichas, A., Sleeth, M. L., Murphy, K. G., Brooks, L., Bewick, G. A., Hanyaloglu, A. C., Ghatei, M. A., Bloom, S. R., & Frost, G. (2015) · International Journal of Obesity · doi:10.1038/ijo.2014.153 · Cited by 886 · cited 2×
“For example, SCFAs have been shown to stimulate the secretion of GLP-1 from intestinal L-cells (92, 95, 200) which promotes insulin release post-prandially.”
Background
Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity
Cani, P. D., Osto, M., Geurts, L., & Everard, A. (2012) · Gut Microbes · doi:10.4161/gmic.19625 · Cited by 864
Effects of gut microbes on nutrient absorption and energy regulation
Krajmalnik‐Brown, R., Ilhan, Z., Kang, D., & DiBaise, J. K. (2012) · Nutrition in Clinical Practice · doi:10.1177/0884533611436116 · Cited by 852
Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)
Zinman, B., Gerich, J., Buse, J. B., Lewin, A., Schwartz, S., Raskin, P., Hale, P. M., Zdravkovic, M., Blonde, L., & the LEAD-4 Study Investigators (2009) · Diabetes Care · doi:10.2337/dc08-2124 · Cited by 848
Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1
Koh, A., Molinaro, A., Ståhlman, M., Khan, M. T., Schmidt, C., Mannerås-Holm, L., Wu, H., Carreras, A., Jeong, H., Olofsson, L. E., et al. (2018) · Cell · doi:10.1016/j.cell.2018.09.055 · Cited by 824
Liraglutide, a once‐daily human GLP‐1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD‐1 SU)
Marre, M., Shaw, J. E., Brändle, M., Bebakar, W. M. W., Kamaruddin, N. A., Strand, J., Zdravkovic, M. D., Thi, T. D. L., Colagiuri, S., & on behalf of the LEAD‐1 SU study group (2009) · Diabetic Medicine · doi:10.1111/j.1464-5491.2009.02666.x · Cited by 821
Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity.
Courcoulas, A. P. (2013) · JAMA · doi:10.1001/jama.2013.280928 · Cited by 799
Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1
Katsuma, S., Hirasawa, A., & Tsujimoto, G. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.01.139 · Cited by 789
Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass
le Roux, C. W., Welbourn, R., Werling, M., Osborne, A., Kokkinos, A., Laurenius, A., Lönroth, H., Fändriks, L., Ghatei, M. A., Bloom, S. R., et al. (2007) · Annals of Surgery · doi:10.1097/sla.0b013e3180caa3e3 · Cited by 741
Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance
Fang, S., Suh, J. M., Reilly, S. M., Yu, E., Osborn, O., Lackey, D., Yoshihara, E., Perino, A., Jacinto, S., Lukasheva, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3760 · Cited by 738
Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine
Williams, B. B., Van Benschoten, A. H., Cimermancic, P., Donia, M. S., Zimmermann, M., Taketani, M., Ishihara, A., Kashyap, P. C., Fraser, J. S., & Fischbach, M. A. (2014) · Cell Host & Microbe · doi:10.1016/j.chom.2014.09.001 · Cited by 732 · cited 1×
“Bacteria also express decarboxylases to convert indole to tryptamine (72).”
Background
Microbes inside—from diversity to function: the case of Akkermansia
Belzer, C., & de Vos, W. M. (2012) · The ISME Journal · doi:10.1038/ismej.2012.6 · Cited by 728
Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion
Yadav, H., Lee, J.-H., Lloyd, J., Walter, P., & Rane, S. G. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.452516 · Cited by 709
Endoplasmic reticulum stress, obesity and diabetes
Cnop, M., Foufelle, F., & Velloso, L. A. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.07.010 · Cited by 705
Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity
Li, F., Jiang, C., Krausz, K. W., Li, Y., Albert, I., Hao, H., Fabre, K. M., Mitchell, J. B., Patterson, A. D., & Gonzalez, F. J. (2013) · Nature Communications · doi:10.1038/ncomms3384 · Cited by 705 · cited 2×
“Studies have shown that HFDfed mice subjected to a bile diversion procedure increased the abundance of circulating bile acids (141, 237, 238) and improved glucose homeostasis (142).”
Background
Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor
Scott, S. A., Fu, J., & Chang, P. V. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2000047117 · Cited by 696 · cited 12×
“AhR aryl hydrocarbon receptor ASBT apical sodium-dependent bile acid transporter ATP adenosine triphosphate BSH bile salt hydrolase C2/C3/C4 acetate/propionate/butyrate CA cholic acid cAMP cyclic adenosine monophosphate CAR constitutive androstane receptor CaSR calcium-sensing receptor CDCA chenodeoxycholic acid CYP45…”
BackgroundInfluential
Gut microbiota‐derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages
Krishnan, S., Ding, Y., Saedi, N., Choi, M., Sridharan, G. V., Sherr, D. H., Yarmush, M. L., Alaniz, R. C., Jayaraman, A., & Lee, K. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.109 · Cited by 679 · cited 1×
“AhR is a basic helix-loophelix (bHLH) transcription factor (157) primarily expressed in host immune cells and its activation has been shown to mediate lipid and fatty acid metabolism and intestinal homeostasis (158).”
Background
Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome
Natividad, J. M., Agus, A., Planchais, J., Lamas, B., Jarry, A. C., Martin, R., Michel, M.-L., Chong-Nguyen, C., Roussel, R., Straube, M., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.07.001 · Cited by 642 · cited 1×
“Fecal concentrations of indole, IAA and tryptamine were significantly reduced in mice fed a HFD compared with chow-fed mice (18, 243).”
Background
Short chain fatty acids prevent high-fat-diet-induced obesity in mice by regulating g protein-coupled receptors and gut microbiota
Lu, Y., Fan, C., Li, P., Lu, Y., Chang, X., & Qi, K. (2016) · Scientific Reports · doi:10.1038/srep37589 · Cited by 638
Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans
Fernandes, J., Su, W., Rahat-Rozenbloom, S., Wolever, T. M. S., & Comelli, E. M. (2014) · Nutrition & Diabetes · doi:10.1038/nutd.2014.23 · Cited by 628
The microbiota–gut–brain axis in obesity
Torres‐Fuentes, C., Schellekens, H., Dinan, T. G., & Cryan, J. F. (2017) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(17)30147-4 · Cited by 623
Whole-grain and fiber intake and the incidence of type 2 diabetes
Montonen, J., Knekt, P., Järvinen, R., Aromaa, A., & Reunanen, A. (2003) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/77.3.622 · Cited by 619
GPR41/FFAR3 and GPR43/FFAR2 as Cosensors for Short-Chain Fatty Acids in Enteroendocrine Cells vs FFAR3 in Enteric Neurons and FFAR2 in Enteric Leukocytes
Nøhr, M. K., Pedersen, M. H., Gille, A., Egerod, K. L., Engelstoft, M. S., Husted, A. S., Sichlau, R. M., Grunddal, K. V., Poulsen, S. S., Han, S., et al. (2013) · Endocrinology · doi:10.1210/en.2013-1142 · Cited by 597
Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism
Patti, M., Houten, S. M., Bianco, A. C., Bernier, R., Larsen, P. R., Holst, J. J., Badman, M. K., Maratos‐Flier, E., Mun, E. C., Pihlajamaki, J., et al. (2009) · Obesity · doi:10.1038/oby.2009.102 · Cited by 591
A metabolic pathway for bile acid dehydroxylation by the gut microbiome
Funabashi, M., Grove, T. L., Wang, M., Varma, Y., McFadden, M. E., Brown, L. C., Guo, C., Higginbottom, S., Almo, S. C., & Fischbach, M. A. (2020) · Nature · doi:10.1038/s41586-020-2396-4 · Cited by 590 · cited 1×
“The remaining bile acids that escape absorption in the small intestine (5%) act as substrates for anaerobic metabolism in the colon (15, 60) or are excreted with feces.”
Background
Fibroblast Growth Factor 19 Increases Metabolic Rate and Reverses Dietary and Leptin-Deficient Diabetes
Fu, L., John, L. M., Adams, S. H., Yu, X. X., Tomlinson, E., Renz, M. E., Williams, P. M., Soriano, R. H., Corpuz, R. T., Moffat, B., et al. (2004) · Endocrinology · doi:10.1210/en.2003-1671 · Cited by 584
Intestine farnesoid X receptor agonist and the gut microbiota activate G‐protein bile acid receptor‐1 signaling to improve metabolism
Pathak, P., Xie, C., Nichols, R. G., Ferrell, J. M., Boehme, S., Krausz, K. W., Patterson, A. D., Gonzalez, F. J., & Chiang, J. Y. L. (2018) · Hepatology · doi:10.1002/hep.29857 · Cited by 567
Quantitative Analysis of NAD Synthesis-Breakdown Fluxes
Liu, L., Su, X., Quinn, W. J., Hui, S., Krukenberg, K., Frederick, D. W., Redpath, P., Zhan, L., Chellappa, K., White, E., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.018 · Cited by 564 · cited 2×
“Following protein digestion, most of the liberated tryptophan is absorbed in the small intestine and endogenously metabolized: up to 95% of ingested tryptophan is converted to kynurenic acid or nicotinamide adenine dinucleotide (NAD) (63, 64) via the kynurenine pathway, and 1-2% of ingested tryptophan is converted to…”
Background
Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction
Jiang, C., Xie, C., Lv, Y., Li, J., Krausz, K. W., Shi, J., Brocker, C. N., Desai, D., Amin, S. G., Bisson, W. H., et al. (2015) · Nature Communications · doi:10.1038/ncomms10166 · Cited by 559
Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells
Chimerel, C., Emery, E., Summers, D. K., Keyser, U., Gribble, F. M., & Reimann, F. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.032 · Cited by 548
Modulation of intestinal barrier by intestinal microbiota: Pathological and therapeutic implications
Natividad, J. M. M., & Verdu, E. F. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2012.10.007 · Cited by 525
Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2
Gutzwiller, J., Drewe, J., Göke, B., Schmidt, H., Rohrer, B., Lareida, J., & Beglinger, C. (1999) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1999.276.5.r1541 · Cited by 518
Whole-grain intake and the risk of type 2 diabetes: a prospective study in men
Fung, T. T., Hu, F. B., Pereira, M. A., Liu, S., Stampfer, M. J., Colditz, G. A., & Willett, W. C. (2002) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/76.3.535 · Cited by 500
SCFAs strongly stimulate PYY production in human enteroendocrine cells
Larraufie, P., Martin‐Gallausiaux, C., Lapaque, N., Dore, J. M., Gribble, F. M., Reimann, F. M., & Blottière, H. M. (2018) · Scientific Reports · doi:10.1038/s41598-017-18259-0 · Cited by 484
Pathways of acetate, propionate, and butyrate formation by the human fecal microbial flora
Miller, T. L., & Wolin, M. J. (1996) · Applied and Environmental Microbiology · doi:10.1128/aem.62.5.1589-1592.1996 · Cited by 481
Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine
Karaki, S.-I., Mitsui, R., Hayashi, H., Kato, I., Sugiya, H., Iwanaga, T., Furness, J. B., & Kuwahara, A. (2006) · Cell and Tissue Research · doi:10.1007/s00441-005-0140-x · Cited by 473
Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents
Zhou, J., Martin, R. J., Tulley, R. T., Raggio, A. M., McCutcheon, K. L., Shen, L., Danna, S. C., Tripathy, S., Hegsted, M., & Keenan, M. J. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90637.2008 · Cited by 460 · cited 2×
“SCFAs are important regulators of gene expression through their actions as potent HDAC inhibitors (113).”
Background
Systemic availability and metabolism of colonic‐derived short‐chain fatty acids in healthy subjects: a stable isotope study
Boets, E., Gomand, S. V., Deroover, L., Preston, T., Vermeulen, K., De Preter, V., Hamer, H. M., Van den Mooter, G., De Vuyst, L., Courtin, C. M., et al. (2017) · The Journal of Physiology · doi:10.1113/jp272613 · Cited by 443
Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells
Trabelsi, M.-S., Daoudi, M., Prawitt, J., Ducastel, S., Touche, V., Sayin, S. I., Perino, A., Brighton, C. A., Sebti, Y., Kluza, J., et al. (2015) · Nature Communications · doi:10.1038/ncomms8629 · Cited by 426 · cited 15×
“This section examines the various signaling pathways activated by bacterial metabolites highlighted in this review, and their known effects on GLP-1 release from EEC L-cells.”
BackgroundInfluential
The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon
Christiansen, C. B., Gabe, M. B. N., Svendsen, B., Dragsted, L. O., ROSENKILDE, M. M., & Holst, J. J. (2018) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00346.2017 · Cited by 413 · cited 1×
“A study found that the selective FFA3 agonist, AR420626, promoted GLP-1 release from primary colonic cultures (88) and perfused intact colons (103).”
Background
Tauroursodeoxycholic Acid May Improve Liver and Muscle but Not Adipose Tissue Insulin Sensitivity in Obese Men and Women
Kars, M., Yang, L., Gregor, M. F., Mohammed, B. S., Pietka, T., Finck, B. N., Patterson, B. W., Horton, J. D., Mittendorfer, B., Hotamışlıgil, G. S., et al. (2010) · Diabetes · doi:10.2337/db10-0308 · Cited by 409 · cited 1×
“Other studies have shown that the administration of tauroursodeoxycholic acid, the taurine conjugated secondary bile acid of ursodeoxycholic acid, improved insulin sensitivity of obese humans (22) and obese mice (23).”
Role of Monocarboxylate Transporters in Drug Delivery to the Brain
Vijay, N., & Morris, M. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113199990462 · Cited by 408 · cited 1×
“Following production, SCFAs are almost exclusively taken up by colonocytes via H-dependent or sodium-dependent monocarboxylate transporters (MCTs and SMCTs, respectively; Figure 2) (52).”
Background
Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study
de Mello, V. D., Paananen, J., Lindström, J., Lankinen, M. A., Shi, L. S., Kuusisto, J., Pihlajamäki, J., Auriola, S. O. K., Lehtonen, M., Rolandsson, O., et al. (2017) · Scientific Reports · doi:10.1038/srep46337 · Cited by 395
Dissimilatory Amino Acid Metabolism in Human Colonic Bacteria
Smith, E. A., & Macfarlane, G. T. (1997) · Anaerobe · doi:10.1006/anae.1997.0121 · Cited by 388 · cited 1×
“Bacterial fermentation of indigestible carbohydrates yields the majority of SCFAs produced, but a small fraction of SCFAs produced (1%) stem from bacterial metabolism of dietary amino acids (50).”
Background
The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control
Pournaras, D. J., Glicksman, C., Vincent, R. P., Kuganolipava, S., Alaghband-Zadeh, J., Mahon, D., Bekker, J. H. R., Ghatei, M. A., Bloom, S. R., Walters, J. R. F., et al. (2012) · Endocrinology · doi:10.1210/en.2011-2145 · Cited by 383
Overlap of Endocrine Hormone Expression in the Mouse Intestine Revealed by Transcriptional Profiling and Flow Cytometry
Habib, A. M., Richards, P., Cairns, L. S., Rogers, G. J., Bannon, C. A. M., Parker, H. E., Morley, T. C. E., Yeo, G. S. H., Reimann, F. M., & Gribble, F. M. (2012) · Endocrinology · doi:10.1210/en.2011-2170 · Cited by 382
Microbial Modulation of Energy Availability in the Colon Regulates Intestinal Transit
Wichmann, A., Allahyar, A., Greiner, T. U., Plovier, H., Östergren‐Lundén, G., Larsson, T. P., Drucker, D. J., Delzenne, N. M., Cani, P. D., & Bäckhed, F. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.09.012 · Cited by 380 · cited 1×
“As further support, there is a reduction of GLP-1 releasing L-cells in germ-free mice lacking intestinal microbiota (115, 116).”
Background
Immune regulation by microbiome metabolites
Kim, C. H. (2018) · Immunology · doi:10.1111/imm.12930 · Cited by 375 · cited 14×
“AhR aryl hydrocarbon receptor ASBT apical sodium-dependent bile acid transporter ATP adenosine triphosphate BSH bile salt hydrolase C2/C3/C4 acetate/propionate/butyrate CA cholic acid cAMP cyclic adenosine monophosphate CAR constitutive androstane receptor CaSR calcium-sensing receptor CDCA chenodeoxycholic acid CYP45…”
BackgroundInfluential
Dietary Fiber Protects against Diabetic Nephropathy through Short-Chain Fatty Acid–Mediated Activation of G Protein–Coupled Receptors GPR43 and GPR109A
Li, Y. J., Chen, X., Kwan, T., Loh, Y. W., Singer, J., Liu, Y., Ma, J., Tan, J., Macia, L., Mackay, C. R., et al. (2020) · Journal of the American Society of Nephrology · doi:10.1681/asn.2019101029 · Cited by 373
The Anti-inflammatory Effects of Short Chain Fatty Acids on Lipopolysaccharide- or Tumor Necrosis Factor α-Stimulated Endothelial Cells via Activation of GPR41/43 and Inhibition of HDACs
Li, M., van Esch, B. C. A. M., Henricks, P. A. J., Folkerts, G., & Garssen, J. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00533 · Cited by 370 · cited 2×
“In the colon, HDACs are inhibited by both butyrate and propionate (85, 86), though butyrate is the most effective inhibitor of HDACs (110, 111).”
Background
Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein–Coupled Bile Acid Receptors
Brighton, C. A., Rievaj, J., Kuhre, R. E., Glasssmith, L. L., Schoonjans, K., Holst, J. J., Gribble, F. M., & Reimann, F. M. (2015) · Endocrinology · doi:10.1210/en.2015-1321 · Cited by 366
Mechanisms underlying weight loss after bariatric surgery
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Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR), and Benzoate X Receptor (BXR) Define Three Pharmacologically Distinct Classes of Nuclear Receptors
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Identification of a Bile Acid-responsive Element in the Human Ileal Bile Acid-binding Protein Gene
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“The functional role of FXR activation is well documented (120, 136, 137).”
Background
Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea
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“Interestingly, in epithelial cells of the human colonic mucosa, Tazoe et al. (2009), demonstrated co-localization of FFA3 with PYY, the gut hormone co-localized with GLP-1.”
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The Landscape of Genetic Content in the Gut and Oral Human Microbiome
Tierney, B. T., Yang, Z., Luber, J. M., Beaudin, M., Wibowo, M. C., Baek, C., Mehlenbacher, E., Patel, C. J., & Kostic, A. D. (2019) · Cell Host & Microbe · doi:10.1016/j.chom.2019.07.008 · Cited by 346 · cited 1×
“The gut microbiota is composed of trillions of microbes, with current estimates suggesting the collective genome of gut bacteria outnumbers the host human genome over 1000:1 (1).”
Background
Expression of the short-chain fatty acid receptor, GPR43, in the human colon
Karaki, S.-I., Tazoe, H., Hayashi, H., Kashiwabara, H., Tooyama, K., Suzuki, Y., & Kuwahara, A. (2007) · Journal of Molecular Histology · doi:10.1007/s10735-007-9145-y · Cited by 345
Different accessibilities in chromatin to histone acetylase.
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“AhR aryl hydrocarbon receptor ASBT apical sodium-dependent bile acid transporter ATP adenosine triphosphate BSH bile salt hydrolase C2/C3/C4 acetate/propionate/butyrate CA cholic acid cAMP cyclic adenosine monophosphate CAR constitutive androstane receptor CaSR calcium-sensing receptor CDCA chenodeoxycholic acid CYP45…”
BackgroundInfluential
Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort
Org, E., Blum, Y., Kasela, S., Mehrabian, M., Kuusisto, J., Kangas, A. J., Soininen, P., Wang, Z., Ala‐Korpela, M., Hazen, S. L., et al. (2017) · Genome biology · doi:10.1186/s13059-017-1194-2 · Cited by 337
Colonic infusions of short-chain fatty acid mixtures promote energy metabolism in overweight/obese men: a randomized crossover trial
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The Footprints of Gut Microbial–Mammalian Co-Metabolism
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FGF-19, A NOVEL FIBROBLAST GROWTH FACTOR WITH UNIQUE SPECIFICITY FOR FGFR4
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Akkermansia muciniphila improves metabolic profiles by reducing inflammation in chow diet-fed mice
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Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies
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Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology
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Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 therapeutically relevant GPCRs
Avet, C., Mancini, A. D., Breton, B., Gouill, C. L., Hauser, A. S., Normand, C., Kobayashi, H., Gross, F., Hogue, M., Lukasheva, V., et al. (2022) · eLife · doi:10.7554/elife.74101 · Cited by 278
Acute effects of intravenous and rectal acetate on glucagon-like peptide-1, peptide YY, ghrelin, adiponectin and tumour necrosis factor-α
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β‐Sitosterol exhibits anti‐inflammatory activity in human aortic endothelial cells
Loizou, S., Lekakis, I., Chrousos, G. P., & Moutsatsou, P. (2009) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200900012 · Cited by 270
Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia
Nøhr, M. K., Egerod, K. L., Christiansen, S. H., Gille, A., Offermanns, S., Schwartz, T. W., & Møller, M. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.01.040 · Cited by 270 · cited 1×
“Additional Ffar3 expression was described in enteric neurons and vagal afferent neurons that innervate the gastrointestinal tract (100).”
Background
Indole production by the tryptophanase TnaA in escherichia coli is determined by the amount of exogenous tryptophan
Li, G., & Young, K. D. (2013) · Microbiology · doi:10.1099/mic.0.064139-0 · Cited by 266
Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism
Pathak, P., Liu, H., Boehme, S., Xie, C., Krausz, K. W., Gonzalez, F. J., & Chiang, J. Y. L. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.784322 · Cited by 265
Microbial metabolites of tryptophan in the intestinal tract with special reference to skatole
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“The remaining ingested tryptophan that escapes absorption (46%) enters the colon and is metabolized by intestinal bacteria (13).”
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Quantitative-profiling of bile acids and their conjugates in mouse liver, bile, plasma, and urine using LC–MS/MS
Alnouti, Y., Csanaky, I. L., & Klaassen, C. D. (2008) · Journal of Chromatography B · doi:10.1016/j.jchromb.2008.08.018 · Cited by 261
Human gut bacteria as potent class I histone deacetylase inhibitors in vitro through production of butyric acid and valeric acid
Yuille, S., Reichardt, N., Panda, S., Dunbar, H., & Mulder, I. E. (2018) · PLOS ONE · doi:10.1371/journal.pone.0201073 · Cited by 257
Indole can act as an extracellular signal to regulate biofilm formation ofEscherichia coliand other indole-producing bacteria
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Effects of Diabetes Mellitus on Cholesterol Metabolism in Man
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Butyrate and propionate induced activated or non-activated neutrophil apoptosis via HDAC inhibitor activity but without activating GPR-41/GPR-43 pathways
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“This is supported by previous studies suggesting that HDAC inhibition by butyrate induces expression of many genes in various tissues and cell lines (109, 112).”
BackgroundResult
Associations of serum indolepropionic acid, a gut microbiota metabolite, with type 2 diabetes and low-grade inflammation in high-risk individuals
Tuomainen, M. H., Lindström, J., Lehtonen, M., Auriola, S. O. K., Pihlajamäki, J., Peltonen, M., Tuomilehto, J. O., Uusitupa, M. I. J., de Mello, V. D., & Hanhineva, K. (2018) · Nutrition and Diabetes · doi:10.1038/s41387-018-0046-9 · Cited by 246 · cited 2×
“Physiological levels of IPA range between 1-10 μM in human serum (70).”
Background
Dietary Calcium and Magnesium, Major Food Sources, and Risk of Type 2 Diabetes in U.S. Black Women
van Dam, R. M., Hu, F. B., Rosenberg, L. A., Krishnan, S., & Palmer, J. R. (2006) · Diabetes Care · doi:10.2337/dc06-1014 · Cited by 244
Tryptophan-kynurenine metabolism: a link between the gut and brain for depression in inflammatory bowel disease
Chen, L.-M., Bao, C., Wu, Y. H., Liang, S.-H., Wang, D., Wu, L.-Y., Huang, Y., Liu, H.-R., & Wu, H.-G. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02175-2 · Cited by 243
The regulation of K‐ and L‐cell activity by GLUT2 and the calcium‐sensing receptor CasR in rat small intestine
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“Several G-protein coupled receptors have been implicated in EEC-sensing of tryptophan including the extracellular calcium-sensing receptor (CaSR) (151) and G-protein receptor 142 (GPR142) (149).”
Background
Characteristics of gut microbiota in people with obesity
Duan, M., Wang, Y., Zhang, Q., Zou, R., Guo, M., & Zheng, H. (2021) · PLoS ONE · doi:10.1371/journal.pone.0255446 · Cited by 241
Peptide YY3–36Inhibits Food Intake in Mice through a Melanocortin-4 Receptor-Independent Mechanism
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“EEC L-cells also secrete peptide-YY (PYY), a gut hormone involved in appetite regulation (39, 40).”
Background
Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system
Poole, D. P., Godfrey, C., Cattaruzza, F., Cottrell, G. S., Kirkland, J. G., Pelayo, J. C., Bunnett, N. W., & Corvera, C. U. (2010) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2010.01487.x · Cited by 237 · cited 1×
“In the intestine, GPBAR1 is highly expressed in the ileum and colon of EECs (129, 130) and in the enteric ganglia and nerve fiber plexuses (131).”
Background
Molecular mechanisms underlying bile acid‐stimulated glucagon‐like peptide‐1 secretion
Parker, H. E., Wallis, K., le Roux, C. W., Wong, K. Y., Reimann, F. M., & Gribble, F. M. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01561.x · Cited by 234 · cited 17×
“EECs express HDACs and SCFA-responsive GPCRs (85–89), except HCAR2 which is primarily localized in adipose and immune tissue (83).”
BackgroundInfluential
Gut microbiome alterations in high-fat-diet-fed mice are associated with antibiotic tolerance
Liu, Y., Yang, K., Jia, Y., Shi, J., Tong, Z., Fang, D., Yang, B., Su, C., Li, R., Xiao, X., et al. (2021) · Nature Microbiology · doi:10.1038/s41564-021-00912-0 · Cited by 231
Distal, not proximal, colonic acetate infusions promote fat oxidation and improve metabolic markers in overweight/obese men
van der Beek, C. M., Canfora, E. E., Lenaerts, K., Troost, F. J., Olde Damink, S. W. M., Holst, J. J., Masclee, A. A. M., Dejong, C. H. C., & Blaak, E. E. (2016) · Clinical Science · doi:10.1042/cs20160263 · Cited by 230
The human NAD metabolome: Functions, metabolism and compartmentalization
Nikiforov, A. A., Kulikova, V., & Ziegler, M. (2015) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2015.1028612 · Cited by 221
TGR5 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 219
GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo
Hauge, M., Vestmar, M. A., Husted, A. S., Ekberg, J. H., Wright, M., Salvo, J. D., Weinglass, A. B., Engelstoft, M. S., Madsen, A. N., Lückmann, M., et al. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.10.002 · Cited by 213 · cited 16×
“EECs express HDACs and SCFA-responsive GPCRs (85–89), except HCAR2 which is primarily localized in adipose and immune tissue (83).”
BackgroundInfluential
Conjugated bile acid–activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression
Nagahashi, M., Takabe, K., Liu, R., Peng, K., Wang, X., Wang, Y., Hait, N. C., Wang, X., Allegood, J. C., Yamada, A., et al. (2014) · Hepatology · doi:10.1002/hep.27592 · Cited by 211 · cited 2×
“LCA/TLCA lithocholic acid/taurine conjugate of lithocholic acid LXR liver-X receptor MCA/wMCA/ TbMCA muricholic acid/omega-muricholic acid/taurine conjugate bmuricholic acid MCTs monocarboxylate transporters OR51E1/ OR51E2 human olfactory subfamily (Olfr558/Olfr78 in mouse) PXR pregnane-X receptor PYY peptide YY RYGB…”
Background
Metabolome analysis for investigating host-gut microbiota interactions
Chen, M. X., Wang, S., Kuo, C., & Tsai, I. (2018) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2018.09.007 · Cited by 206
Apoptotic cell–induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans
Shinde, R. S., Hezaveh, K., Halaby, M. J., Kloetgen, A., Chakravarthy, A., Medina, T. D. S., Deol, R., Manion, K., Baglaenko, Y., Eldh, M., et al. (2018) · Nature Immunology · doi:10.1038/s41590-018-0107-1 · Cited by 201
Improved Glycemic Control with Colesevelam Treatment in Patients with Type 2 Diabetes Is Not Directly Associated with Changes in Bile Acid Metabolism
Brufau, G., Stellaard, F., Prado, K. B., Bloks, V. W., Jonkers, E., Boverhof, R., Kuipers, F., & Murphy, E. J. (2010) · Hepatology · doi:10.1002/hep.23831 · Cited by 198
Sodium butyrate reduces insulin-resistance, fat accumulation and dyslipidemia in type-2 diabetic rat: A comparative study with metformin
Khan, S., & Jena, G. (2016) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2016.06.007 · Cited by 192
Tryptophan Metabolic Pathways Are Altered in Obesity and Are Associated With Systemic Inflammation
Cussotto, S., Delgado, I., Anesi, A., Dexpert, S., Aubert, A., Beau, C., Forestier, D., Ledaguenel, P., Magne, E., Mattivi, F., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00557 · Cited by 189
Improvements to postprandial glucose control in subjects with type 2 diabetes: a multicenter, double blind, randomized placebo-controlled trial of a novel probiotic formulation
Perraudeau, F., McMurdie, P., Bullard, J., Cheng, A., Cutcliffe, C., Deo, A., Eid, J., Gines, J., Iyer, M., Justice, N., et al. (2020) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2020-001319 · Cited by 186
Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery
Flynn, C. R., Albaugh, V. L., Cai, S. B., Cheung‐Flynn, J., Williams, P. E., Brucker, R. M., Bordenstein, S. R., Guo, Y. P., Wasserman, D. H., & Abumrad, N. N. (2015) · Nature Communications · doi:10.1038/ncomms8715 · Cited by 185
Effect of Butyrate and Inulin Supplementation on Glycemic Status, Lipid Profile and Glucagon-Like Peptide 1 Level in Patients with Type 2 Diabetes: A Randomized Double-Blind, Placebo-Controlled Trial
Roshanravan, N., Mahdavi, R., Alizadeh, E., Jafarabadi, M. A., Hedayati, M., Ghavami, A., Alipour, S., Alamdari, N. M., Barati, M., & Ostadrahimi, A. (2017) · Hormone and Metabolic Research · doi:10.1055/s-0043-119089 · Cited by 185
TGR5 potentiates GLP-1 secretion in response to anionic exchange resins
Harach, T., Pols, T. W. H., Nomura, M., Maida, A., 渡辺, 光., Auwerx, J. H., & Schoonjans, K. (2012) · Scientific Reports · doi:10.1038/srep00430 · Cited by 183 · cited 2×
“Secondary bile acids, specifically LCA and the taurine conjugate TLCA, are the most potent stimulants of GPBAR1 activation (127, 133, 134).”
Background
Final Report on the Safety Assessment of Sodium p -Chloro- m -Cresol, p -Chloro- m -Cresol, Chlorothymol, Mixed Cresols, m -Cresol, o -Cresol, p -Cresol, Isopropyl Cresols, Thymol, o -Cymen-5-ol, and Carvacrol1
Andersen, A. (2006) · International Journal of Toxicology · doi:10.1080/10915810600716653 · Cited by 176
Mediterranean diet and faecal microbiota: a transversal study
Gutiérrez-Díaz, I., Fernández-Navarro, T., Sánchez, B., Margolles, A., & González, S. (2016) · Food & Function · doi:10.1039/c6fo00105j · Cited by 176
Gut bacteria Akkermansia is associated with reduced risk of obesity: evidence from the American Gut Project
Zhou, Q., Zhang, Y., Wang, X., Yang, R., Zhu, X., Zhang, Y., Chen, C., Yuan, H., Yang, Z., & Sun, L. (2020) · Nutrition & Metabolism · doi:10.1186/s12986-020-00516-1 · Cited by 175
Microbiota‐derived tryptophan indoles increase after gastric bypass surgery and reduce intestinal permeability in vitro and in vivo
Jennis, M., Cavanaugh, C., Leo, G. C., Mabus, J. R., Lenhard, J. M., & Hornby, P. J. (2017) · Neurogastroenterology & Motility · doi:10.1111/nmo.13178 · Cited by 173
Associations between dietary habits and body mass index with gut microbiota composition and fecal water genotoxicity: an observational study in African American and Caucasian American volunteers
Mai, V., McCrary, Q. M., Sinha, R. R., & Glei, M. (2009) · Nutrition Journal · doi:10.1186/1475-2891-8-49 · Cited by 171
Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery
Larraufie, P., Roberts, G. P., McGavigan, A. K., Kay, R. G., Li, J., Leiter, A. B., Melvin, A., Biggs, E. K., Ravn, P., Davy, K., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2019.01.047 · Cited by 171
Decreased Abundance of Akkermansia muciniphila Leads to the Impairment of Insulin Secretion and Glucose Homeostasis in Lean Type 2 Diabetes
Zhang, J., Ni, Y., Qian, L., Fang, Q., Zheng, T., Zhang, M., Gao, Q., Zhang, Y., Ni, J., Hou, X., et al. (2021) · Advanced Science · doi:10.1002/advs.202100536 · Cited by 171 · cited 1×
“muciniphilia has been linked to impairments in insulin sensitivity (165) and obese-related diseases (183–185).”
Background
Physiological studies of tryptophan transport and tryptophanase operon induction in Escherichia coli
Yanofsky, C., Horn, V., & Gollnick, P. D. (1991) · Journal of Bacteriology · doi:10.1128/jb.173.19.6009-6017.1991 · Cited by 170
β-Hydroxybutyrate Modulates N-Type Calcium Channels in Rat Sympathetic Neurons by Acting as an Agonist for the G-Protein-Coupled Receptor FFA3
Won, Y., Lu, V. B., Puhl, H. L., & Ikeda, S. R. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.3102-13.2013 · Cited by 168
Self-citation
Tryptophan Metabolism and Related Pathways in Psychoneuroimmunology: The Impact of Nutrition and Lifestyle
Gostner, J. M., Geisler, S., Stonig, M., Mair, L., Sperner‐Unterweger, B., & Fuchs, D. (2019) · Neuropsychobiology · doi:10.1159/000496293 · Cited by 167
Prevention and Treatment of Obesity, Insulin Resistance, and Diabetes by Bile Acid–Binding Resin
Kobayashi, M., Ikegami, H., Fujisawa, T., Nojima, K., Kawabata, Y., Noso, S., Babaya, N., Itoi‐Babaya, M., Yamaji, K., Hiromine, Y., et al. (2006) · Diabetes · doi:10.2337/db06-0353 · Cited by 166
Butyrate enemas upregulate Muc genes expression but decrease adherent mucus thickness in mice colon
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Bile acid sequestrants: Mechanisms of action on bile acid and cholesterol metabolism
Einarsson, K., Ericsson, S., Ewerth, S., Reihnér, E., Rudling, M. J., Ståhlberg, D., & Angelin, B. (1991) · European Journal of Clinical Pharmacology · doi:10.1007/bf03216291 · Cited by 158
Generation of L Cells in Mouse and Human Small Intestine Organoids
Petersen, N., Reimann, F. M., Bartfeld, S., Farin, H. F., Ringnalda, F. C. A. S., Vries, R. G. J., van den Brink, S., Clevers, H. C., Gribble, F. M., & de Koning, E. J. P. (2013) · Diabetes · doi:10.2337/db13-0991 · Cited by 156 · cited 1×
“SCFAs have also increased the number of L-cells in the intestinal epithelium and increased endogenous secretion of GLP-1 in both mouse and human organoids in vitro (114).”
Background
Intestinal adaptation after ileal interposition surgery increases bile acid recycling and protects against obesity-related comorbidities
Kohli, R., Kirby, M., Setchell, K. D. R., Jha, P., Klustaitis, K. M., Woollett, L. A., Pfluger, P. T., Balistreri, W. F., Tso, P., Jandacek, R. J., et al. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00221.2010 · Cited by 155
Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate
Banoğlu, E., Jha, G. G., & King, R. J. (2001) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/bf03226377 · Cited by 153 · cited 1×
“detoxification by enzymes in the liver (73).”
Mechanisms controlling glucose-induced GLP-1 secretion in human small intestine
Sun, E. W., de Fontgalland, D., Rabbitt, P., Hollington, P., Sposato, L., Due, S. L., Wattchow, D. A., Rayner, C. K., Deane, A. M., Young, R. L., et al. (2017) · Diabetes · doi:10.2337/db17-0058 · Cited by 152
Rectal taurocholate increases L cell and insulin secretion, and decreases blood glucose and food intake in obese type 2 diabetic volunteers
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Gut Microbiota of Obese, Type 2 Diabetic Individuals is Enriched in Faecalibacterium prausnitzii, Akkermansia muciniphila and Peptostreptococcus anaerobius after Weight Loss
Remely, M., Hippe, B., Zanner, J., Aumueller, E., Brath, H., & Haslberger, A. G. (2016) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530316666160831093813 · Cited by 143
A Surgical Model in Male Obese Rats Uncovers Protective Effects of Bile Acids Post-Bariatric Surgery
Kohli, R., Setchell, K. D. R., Kirby, M., Myronovych, A., Ryan, K. K., Ibrahim, S. H., Berger, J., Smith, K., Toure, M. H., Woods, S. C., et al. (2013) · Endocrinology · doi:10.1210/en.2012-2069 · Cited by 131
Fecal skatole and indole and breath methane and hydrogen in patients with large bowel polyps or cancer
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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: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
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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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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