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Gut microbiota-derived metabolites as key actors in inflammatory bowel disease
Abstract
A key role of the gut microbiota in the establishment and maintenance of health, as well as in the pathogenesis of disease, has been identified over the past two decades. One of the primary modes by which the gut microbiota interacts with the host is by means of metabolites, which are small molecules that are produced as intermediate or end products of microbial metabolism. These metabolites can derive from bacterial metabolism of dietary substrates, modification of host molecules, such as bile acids, or directly from bacteria. Signals from microbial metabolites influence immune maturation, immune homeostasis, host energy metabolism and maintenance of mucosal integrity. Alterations in the composition and function of the microbiota have been described in many studies on IBD. Alterations have also been described in the metabolite profiles of patients with IBD. Furthermore, specific classes of metabolites, notably bile acids, short-chain fatty acids and tryptophan metabolites, have been implicated in the pathogenesis of IBD. This Review aims to define the key classes of microbial-derived metabolites that are altered in IBD, describe the pathophysiological basis of these associations and identify future targets for precision therapeutic modulation.
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“BA metabolism is defective in patients with IBD, as indicated by increased levels of primary BAs (PBAs) and/or their conjugated forms, accompanied by decreased levels of second BAs (SBAs) (Lavelle and Sokol, 2020; Biagioli et al., 2021; Gallagher et al., 2021).”
From Bacteroides dorei BDX-01 alleviates DSS-induced experimental colitis in mice by regulating intestinal bile salt hydrolase activity and the FXR-NLRP3 signaling pathway (2023) · cites this paper as Lavelle and Sokol, 2020
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Ruminococcus gnavus : friend or foe for human health
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The gut microbiota-immune-brain axis: therapeutic implications
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Feeding gut microbes to nourish the brain: unravelling the diet–microbiota–gut–brain axis
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“Microbial indole production from the bacterial metabolism of l-tryptophan derivatives further influences metabolic and gastrointestinal function in health and disease, including intestinal barrier integrity, inflammation and potentially even impacting host longevity 181,182 .”
Microbiota in inflammatory bowel disease: mechanisms of disease and therapeutic opportunities
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“The most dominant bacterial groups in the gut are Firmicutes and Bacteroides, which together constitute approximately 90% of gut microbiota 11 , and are key producers of short-chain fatty acids (SCFAs) 12 .”
Neutrophils: from IBD to the gut microbiota
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“Indeed, in addition to differences in intestinal microbial species and diversity, patients with IBD and healthy individuals present differences in microbial metabolism pathways 104 .”
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“Certain metabolites such as short-chain fatty acids (SCFAs), bile acids, and indole derivatives were found significantly changed in patients with IBD, which affect intestinal homeostasis via multiple mechanisms [9].”
BackgroundGut microbiota in overweight and obesity: crosstalk with adipose tissue
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“Bile acids are produced by the liver but are highly regulated by the activity and composition of the microbiota 178,179 .”
The Gut Microbial Bile Acid Modulation and Its Relevance to Digestive Health and Diseases
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Recipient factors in faecal microbiota transplantation: one stool does not fit all
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Self-citationThe Detrimental Impact of Ultra-Processed Foods on the Human Gut Microbiome and Gut Barrier
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“Notably, in IBD patients, three main pathways are affected: SCFA production [106], bile acid metabolism [53], and tryptophan metabolism [54].”
The role of gut microbiota in intestinal disease: from an oxidative stress perspective
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“Microbial metabolites are capable of regulating the immune system (Lavelle and Sokol, 2020) via systemic circulation (Colombo et al., 2021) or by the vagus nerve (Bluthe et al., 1996; Namgung et al., 2022; Huffman et al., 2019).”
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“Compelling evidence has demonstrated the intricate connection between the gut microbiota and its metabolites and the development and progression of IBD [5, 9, 30].”
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“10 Indole metabolites can bind and activate the aryl hydrocarbon receptor (AhR), which induces the expression of downstream cytokines to maintain gut homeostasis.”
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Bile acids activated receptors in inflammatory bowel disease
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Potential roles of gut microbiota and microbial metabolites in Parkinson’s disease
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“Alterations of other well-studied metabolites in IBD, for example, BAs and SCFAs, 44 have also been reported in several other conditions.”
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End-to-end design of ingestible electronics
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“A variety of biomarkers present in the GI tract, such as bacteria 22 , metabolites 23 , physiological gases 24 , proteins 25 and neurotransmitters 26 , can be sensed and leveraged to assess a patient’s health in real time.”
The emerging roles of bacterial proteases in intestinal diseases
Caminero, A., Guzman, M., Libertucci, J., & Lomax, A. E. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2181922 · Cited by 92
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Microbiota-derived bile acids antagonize the host androgen receptor and drive anti-tumor immunity
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Integrating multi-omics to unravel host-microbiome interactions in inflammatory bowel disease
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Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages
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Inflammatory bowel diseases: pathological mechanisms and therapeutic perspectives
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“8,9 10–12 Bile acid metabolism is also involved in the pathogenic process of NEC and a significant elevation of total bile acid (BA) levels is observed in patients with NEC.”
BackgroundLi, J., Song, J., Deng, Z.-C., Yang, J., Wang, X.-Q., Gao, B.-W., Zhu, Y.-Y., Yang, M., Long, D.-P., Luo, X., et al. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.02.033 · Cited by 70
“It involves genetic risk, lifestyle factors, environmental factors, mucosal barrier dysfunction, immune dysregulation, and microbial dysregulation [6,38].”
BackgroundLi, N., Ma, P.-G., Li, Y., Shang, X., Nan, X., Shi, L., Han, X., Liu, J., Hong, Y., Li, Q., et al. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2290315 · Cited by 76
“11 The rest can be bio-trans-formed into secondary BAs (SBAs) by 7α-dehydrox-ylation in some members of Clostridial and Bacteroidaceae species to exert diverse metabolic effects and regulate innate and adaptive immunity.”
BackgroundResultInfluentialLei, W., Cheng, Y., Liu, X., Gao, J., Zhu, Z., Ding, W., Xu, X., Li, Y., Ling, Z., Jiang, R., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1582119 · Cited by 68
Tong, Y., Guo, H., Abbas, Z., Zhang, J., Wang, J., Cheng, Q., Peng, S., Yang, T., Bai, T., Zhou, Y., et al. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1229952 · Cited by 70
Gut microbiota in regulatory T cell generation and function: mechanisms and health implications
Sharma, A., Sharma, G., & Im, S. (2025) · Gut Microbes · doi:10.1080/19490976.2025.2516702 · Cited by 68
“6,32,131,132 Additionally, the distribution and expression patterns of SCFA receptors differ between mice and humans, potentially affecting downstream signaling pathways.”
Zhu, Y., Fang, Z., Bai, J., Wang, L., Chen, J.-Q., Zhang, Z.-H., Wang, Q., Sheng, W.-W., Pan, X.-Y., Gao, Z., et al. (2025) · Advancement of science · doi:10.1002/advs.202411939 · Cited by 64
Lin, X. F., Xu, M., Lan, R., Hu, D., Zhang, S., Zhang, S., Lu, Y., Sun, H., Yang, H. J., Liu, L., et al. (2025) · mSystems · doi:10.1128/msystems.01607-24 · Cited by 67
“SCFAs can reshape the gut ecology, induce immune modulation, and mediate inflammatory signaling cascade during gut inflammation (35).”
Metabolic modeling reveals a multi-level deregulation of host-microbiome metabolic networks in IBD
Taubenheim, J., Kadibalban, A. S., Zimmermann, J., Taubenheim, C., Tran, F., Schreiber, S., Rosenstiel, P. C., Aden, K., & Kaleta, C. (2025) · Nature Communications · doi:10.1038/s41467-025-60233-2 · Cited by 64
Zhu, Y., Huang, X., Deng, Z., Bai, T., Gao, B., Xu, C., Fu, J., Zhao, Y., Zhang, Y., Zhang, M., et al. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02802-z · Cited by 59
“…** P 0.01, and ns represents no statistical difference microbiota can directly convert aromatic amino acids into indole derivatives, which can maintain intestinal homeostasis by promoting epithelial cell recovery, restoring intestinal barrier function, and modulating immune cell function [43–46].”
BackgroundInfluentialIqbal, M., Qian, Y., Tang, J., & Xiang, J. (2025) · Journal of Bacteriology · doi:10.1128/jb.00479-24 · Cited by 72
“The liver synthesizes primary bile acids, such as cholic acid and chenodeoxycholic acid (CDCA) in humans, conjugating them with glycine or taurine before storing them in the gallbladder (77–79).”
Fang, X.-Y., Liu, H.-Y., Liu, J., Du, Y., Chi, Z., Bian, Y.-Q., Zhao, X., Teng, T., & Shi, B.-M. (2025) · Research · doi:10.34133/research.0673 · Cited by 60
“SCFA levels in the feces of patients with IBD are reduced, and the administration of butyrate can alter disease status [ 24 , 25 ].”
Chen, Y., Shui, M., Li, H., Guo, M., Yuan, Q., Hao, W., Wang, T., Zhou, H., Chen, Z., & Wang, S. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123163 · Cited by 63
Pharmacological effects of ginseng and ginsenosides on intestinal inflammation and the immune system
Zhao, L., Zhang, T., & Zhang, K. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1353614 · Cited by 55
Wu, S.-M., Fang, X.-Y., Zhao, J.-F., Liu, G., & Liao, P. (2025) · Toxicon · doi:10.1016/j.toxicon.2025.108434 · Cited by 58
Jadhav, A., Jagtap, S., Vyavahare, S., Sharbidre, A. A., & Kunchiraman, B. N. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1268041 · Cited by 72
Unveiling roles of beneficial gut bacteria and optimal diets for health
Kumar, S., Mukherjee, R., Gaur, P., Leal, E. D. S., Lyu, X., Ahmad, S., Puri, P., Chang, C.-M., Raj, V. S., & Pandey, R. P. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1527755 · Cited by 63
“Several studies have focused on elucidating the specific functions and mechanisms of these microorganisms in relation to various diseases (Lavelle and Sokol, 2020; Parada Venegas et al., 2019; Liu et al., 2022).”
Precision microbiota therapy for IBD: premise and promise
Nagayama, M., Gogokhia, L., & Longman, R. (2025) · Gut Microbes · doi:10.1080/19490976.2025.2489067 · Cited by 58
“Several studies showing a distinct metabolome exists following FMT 21,54 highlight several classes of molecules that need better definition.”
Yarahmadi, A., Afkhami, H., Javadi, A., & Kashfi, M. (2024) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-024-01561-z · Cited by 61
“These AhRs function as vital transcription factors, assuming pivotal responsibilities in safeguarding and mitigating inflammation, notably through regulating natural lym-phoids and IL-22 within the GI tract [104, 193, 196].”
Jiang, L., Hao, Y., Han, D., Dong, W., Yang, A., Sun, Z., Ge, Y., Duan, S., Zhang, X., & Dai, Z. (2024) · The ISME Journal · doi:10.1093/ismejo/wrae166 · Cited by 58
“Additionally, the gut microbiome and associated metabolites are implicated in the prevention and treatment of IBD and colorectal cancer (CRC) [11]; however, their interactions with Abx require further investigation.”
Li, X., Chen, Y., Peng, X., Zhu, Y., Duan, W., Ji, R.-Y., Xiao, H., Li, X.-L., Liu, G., Yu, Y., et al. (2024) · Food Chemistry · doi:10.1016/j.foodchem.2024.140346 · Cited by 55
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“A recent study showed that GLP-1 [28 – 36], a neutral endopeptidase-generated metabolite of GLP-1, acts directly on mice through micropinocytosis [45].”
BackgroundResultInfluentialCrosstalk between gut microbiotas and fatty acid metabolism in colorectal cancer
Zhang, H., Tian, Y., Xu, C., Chen, M., Xiang, Z., Gu, L., Xue, H., & Xu, Q. R. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02364-5 · Cited by 53
Metabolic network of the gut microbiota in inflammatory bowel disease
Sugihara, K., & Kamada, N. (2024) · Inflammation and Regeneration · doi:10.1186/s41232-024-00321-w · Cited by 59
“This symbiotic relationship between gut microbiota and the host plays a vital role in maintaining intestinal homeostasis [8, 9].”
BackgroundQi, C., He, G., Qian, K., Guan, S., Li, Z., Liang, S., Liu, J., Ke, X., Zhang, S., Lu, M., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae1002 · Cited by 52
Gut microbiota and epigenetic inheritance: implications for the development of IBD
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“9 In recent years, advancements in metagenomics and metabolomics technology 8,10 have substantiated the health-promoting efficacy of probiotics, correlating it with specific genes or individual nucleotides; however, the precise control mechanisms remain inade-quately understood.”
Chen, P., Rehman, M. U., He, Y., Li, A., Jian, F.-C., Zhang, L.-X., & Huang, S.-C. (2025) · Veterinary Quarterly · doi:10.1080/01652176.2025.2452169 · Cited by 50
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Zhu, X., Zhang, C., Feng, S., He, R., & Zhang, S. (2024) · Clinical and Experimental Medicine · doi:10.1007/s10238-024-01304-4 · Cited by 52
“…biotransformation of BA that pass through the enterohepatic circulation, which plays an important role in regulating intestinal inflammation by regulating immune cell maturation and cytokine release through farnesoid X receptor (FXR) and G protein-coupled receptor 5 (TGR5) receptors [117, 118].”
BackgroundTruyens, M., Lobatón, T., Ferrante, M., Bossuyt, P., Vermeire, S., Pouillon, L., Dewint, P., Cremer, A., Peeters, H., Lambrecht, G., et al. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.07.052 · Cited by 48
Wang, Q., Huang, H., Yang, Y., Yang, X., Li, X., Zhong, W., Wen, B., He, F., & Li, J. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1491821 · Cited by 51
“In both mouse models and IBD patients, dietary tryptophan deficiency exacerbates colitis (160).”
BackgroundGut Microbiome as a Target of Intervention in Inflammatory Bowel Disease Pathogenesis and Therapy
Hetta, . F., Ramadan, Y. N., Alharbi, A. A., Alsharif, S. M., Alkindy, T. T., Alkhamali, A., Albalawi, A. S., & El‐Amin, H. (2024) · Immuno · doi:10.3390/immuno4040026 · Cited by 54
“However, some phages actively integrate their genetic element into the infected cells’ genomes, transmitting this information to the next generation of host cells (lysogenic cycle) [126,127].”
BackgroundJiang, S., Ma, W., Ma, C., Zhang, Z., Zhang, W., & Zhang, J. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2341717 · Cited by 52
“…function, and inflammation, which makes it harder to fight pathogens, 22 thereby inducing various diseases, such as inflammatory bowel diseases; 23,24 metabolic disorders, such as obesity and type 2 diabetes; 25–27 autoimmune diseases, 28,29 such as food allergies, 30 eczema, 31 and asthma; 32…”
BackgroundXing, L., Liu, X., Wu, L., Wu, J., Deng, Y., Li, Q., Zhou, Z., Li, L., & Huang, Y. (2024) · Nano Today · doi:10.1016/j.nantod.2024.102155 · Cited by 54
Epithelial regulation of microbiota-immune cell dynamics
Didriksen, B. J., Eshleman, E. M., & Alenghat, T. (2024) · Mucosal Immunology · doi:10.1016/j.mucimm.2024.02.008 · Cited by 54
Aromatic Amino Acid Metabolites: Molecular Messengers Bridging Immune-Microbiota Communication
Shin, H.-K., & Bang, Y. (2025) · Immune Network · doi:10.4110/in.2025.25.e10 · Cited by 44
“These microorganisms produce various bioactive metabolites that act as essential mediators in host-microbe communication, influencing both local and systemic immune responses (1,2).”
Yuan, M., Chang, L., Gao, P., Li, J., Xin-yuan, L., Hua, M., Li, X., Liu, X., & Lan, Y. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.133794 · Cited by 50
Inhibiting the cGAS-STING Pathway in Ulcerative Colitis with Programmable Micelles
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“It plays an essential role in human digestion, metabolism, immunity, and other processes and is closely connected with the health of the host [30].”
BackgroundGut bacteria Prevotellaceae related lithocholic acid metabolism promotes colonic inflammation
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Fucoidan modulates gut microbiota and immunity in Peyer's patches against inflammatory bowel disease
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Toward improved in vitro models of human cancer
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Metadata
- Authors
- Lavelle, A., & Sokol, H.
- Affiliations
- Inserm (FR)
- Corresponding author
- Sokol, Harry
- Venue
- Nature Reviews Gastroenterology & Hepatology
- Published
- 2020-02-19
- Volume
- 17
- Issue
- 4
- Pages
- 223-237
- ISSN
- 1759-5045 (ISSN-L)
- 1759-5053
- OpenAlex
- W3006796998
- Cited by
- 2,015
- References
- 0
- Citations by year
- 2026: 324 · 2025: 392 · 2024: 410 · 2023: 318 · 2022: 315 · 2021: 197 · 2020: 58
- FWCI
- 21.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Gastroenterology & Hepatology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- gut microbiota, microbial metabolites, inflammatory bowel disease, bile acids, short-chain fatty acids, tryptophan metabolites, host-microbe interactions, immune homeostasis, mucosal integrity, energy metabolism, IBD pathogenesis, precision therapy
- MeSH terms
- Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Animals, Bile Acids and Salts, Fatty Acids, Volatile, Humans, Tryptophan, Inflammatory Bowel Diseases, Probiotics, Gastrointestinal Tract, Metabolomics
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