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Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome
Open accessAbstract
The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT.
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“However, an integrated longitudinal multi-omics analysis of the gut microbiome, metabolome, host epigenome and transcriptome, in the context of host symptoms and physiology in patients with IBS-D and IBS-C, identified subtype-specific and symptom-related variations in microbial composition and function.76”
From British Society of Gastroenterology guidelines on the management of irritable bowel syndrome (2021) · cites this paper as [76]
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“tate), alterations in luminal bile acids, and dysregulation of the purine salvage pathway.(90) Finally, the utility of gut microbiome manipulation by means of dietary measures,(93) probiotics, and fecal microbiome transplantation(43,94) have”
BackgroundGut microbiota supports male reproduction via nutrition, immunity, and signaling
Cai, H., Cao, X., Qin, D., Liu, Y., Liu, Y., Hua, J., & Peng, S. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.977574 · Cited by 75
“With the establishment of gene expression profiles and metabolomics, researchers can now locate the transverse spatial organization and longitudinal phase states of GM (Tropini et al., 2017; Mars et al., 2020).”
BackgroundHost-microbial interactions in the metabolism of different dietary fats
Chadaideh, K. S., & Carmody, R. N. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.04.011 · Cited by 63
Multi-Omics Analyses Show Disease, Diet, and Transcriptome Interactions With the Virome
Mihindukulasuriya, K. A., Mars, R. A. T., Johnson, A. J., Ward, T., Priya, S., Lekatz, H. R., Kalari, K. R., Droit, L., Zheng, T., Blekhman, R., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2021.06.077 · Cited by 63
Self-citationXiao, K., Liang, X., Lu, H., Li, X., Zhang, Z., Lu, X., Wang, H., Meng, Y., Roy, A., Luo, W., et al. (2022) · The ISME Journal · doi:10.1038/s41396-022-01247-2 · Cited by 59
Xu, Y., Wang, J., Wu, X., Jing, H., Zhang, S., Hu, Z., Rao, L., Chang, Q., Wang, L., & Zhang, Z. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2168101 · Cited by 61
“Gut microbiota are being recognized as vital masters in maintaining host health, especially normal gastrointestinal functions, and fecal microbiome alterations are being accepted as essential etiological causes for numerous gastroenteric disorders, such as inflammatory bowel disease (IBD) and irritable bowel syndrome…”
BackgroundRengarajan, S., Knoop, K. A., Rengarajan, A., Chai, J. N., Grajales‐Reyes, J. G., Samineni, V. K., Russler-Germain, E. V., Ranganathan, P., Fasano, A., Sayuk, G. S., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100124 · Cited by 63
“44 Notably, IBS-D patients displayed significantly higher IgA-bound fecal bacteria than healthy individuals (Figure 5A), as well as patients with intestinal (celiac sprue) and non-intestinal (rheumatoid arthritis) immune disorders (Figure S5A).”
Self-citationWei, L., Singh, R., & Ghoshal, U. C. (2022) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm22008 · Cited by 71
“Gut microbiota dysbiosis induces alternations in the bile acid (BA) pool.67,68 On the contrary, reduction in BA levels influences gut microbial diversity leading to gut microbiota dysbiosis.69 A higher amount of BAs results in increased intestinal fluid secretion.10 Excess fecal BAs in diarrhea-predominant IBS (IBSD)…”
BackgroundInfluentialOmics and Multi-Omics in IBD: No Integration, No Breakthroughs
Fiocchi, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914912 · Cited by 64
Microbiota dysbiosis in primary Sjögren’s syndrome and the ameliorative effect of hydroxychloroquine
Wang, X., Pang, K., Wang, J., Zhang, B., Liu, Z., Lu, S., Xu, X., Zhu, L., Zhou, Z., Niu, M., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111352 · Cited by 55
Huang, Z., Liu, K., Ma, W., Li, D., Mo, T., & Liu, Q. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1018594 · Cited by 68
“The biomarkers detected by these -omics technologies could help to elucidate potential mechanisms of these commensals in health and disease (LloydPrice et al., 2019; Zhou et al., 2019; Mars et al., 2020).”
BackgroundLow FODMAP diet for treatment of irritable bowel syndrome
Young, E., Vasquez, L. S. R., Lim, A. H. W., & Philpott, H. (2022) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd014029 · Cited by 55
Microbiome and Allergy: New Insights and Perspectives
Zubeldia‐Varela, E., Barker‐Tejeda, T. C., Obeso, D., Villaseñor, A., Barber, D., & Pérez‐Gordo, M. (2022) · Journal of Investigational Allergology and Clinical Immunology · doi:10.18176/jiaci.0852 · Cited by 60
Shang, Z., Pai, L., & Patil, S. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1395664 · Cited by 57
“The fermentation of fiber by these bacteria produces short-chain fatty acids (SCFAs)—which are organic acids produced by gut bacteria during the fermentation of dietary fiber (Table 1), which possess anti-inflammatory properties and contribute to gut health (15, 16).”
BackgroundMars, R. A. T., Frith, M., & Kashyap, P. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.10.058 · Cited by 53
Self-citationXie, C., Teng, J., Wang, X., Xu, B., Niu, Y., Ma, L., & Yan, X. (2021) · Animal nutrition · doi:10.1016/j.aninu.2021.10.010 · Cited by 55
IgA in human health and diseases: Potential regulator of commensal microbiota
Takeuchi, T., & Ohno, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1024330 · Cited by 53
“In addition to IBD, it has been recognized that irritable bowel syndrome (IBS) is also associated with altered gut microbiota and their metabolites (101, 102), which is characterized by an increase in pathobionts such as the family Enterobacteriaceae (101).”
BackgroundWhat Has Longitudinal ‘Omics’ Studies Taught Us about Irritable Bowel Syndrome? A Systematic Review
Ng, Q. X., Yau, C. E., Yaow, C. Y. L., Chong, R. I. H., Chong, N. Z.-Y., Teoh, S. E., Lim, Y. L., Soh, A. Y. S., Ng, W. K., & Thumboo, J. (2023) · Metabolites · doi:10.3390/metabo13040484 · Cited by 53
Chang, D., Gupta, V. K., Hur, B., Cobo-López, S., Cunningham, K. Y., Han, N. S., Lee, I., Kronzer, V. L., Teigen, L. M., Karnatovskaia, L. V., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51651-9 · Cited by 50
Iribarren, C., Magnusson, M. K., Vigsnæs, L. K., Aziz, I., Amundsen, I. D., Šuligoj, T., Juge, N., Patel, P., Sapnara, M., Johnsen, L. G., et al. (2021) · Nutrients · doi:10.3390/nu13113836 · Cited by 49
“Patients with IBS may present alterations in the gut microbiota composition [4,5] and function [6,7], or activation of the mucosal immune system [8,9], in some cases correlated to severity [4] or psychological symptoms [10].”
Microbiota of the gastrointestinal tract: Friend or foe?
Senchukova, M. A. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i1.19 · Cited by 56
Tryptophan metabolites get the gut moving
Benech, N., Rolhion, N., & Sokol, H. (2021) · Cell Host & Microbe · doi:10.1016/j.chom.2021.01.009 · Cited by 49
Gut microbiome-metabolome interactions predict host condition
Shtossel, O., Koren, O., Shai, I., Rinott, E., & Louzoun, Y. (2024) · Microbiome · doi:10.1186/s40168-023-01737-1 · Cited by 49
“Longitudinal samples fecal microbiome and metabolites (over 6 months) from patients with irritable bowel syndrome (IBS) and controls [90].”
BackgroundGut microbial structural variation associates with immune checkpoint inhibitor response
Liu, R., Zou, Y., Wang, W.-Q., Chen, J.-H., Zhang, L., Feng, J., Yin, J.-Y., Mao, X.-Y., Li, Q., Luo, Z.-Y., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42997-7 · Cited by 45
“Speci fi cally, associations have been reported between bile acids and microbial SVs, and bacterial genes linked to host bile acid metabolism or indirectly involved in the alteration of primary bile acids have been identi fi ed 26,27 .”
BackgroundJin, C., Wu, S., Liang, Z., Zhang, J., Lei, X., Bai, H., Liang, G., Su, X., Chen, X., Wang, P., et al. (2024) · Microbiome · doi:10.1186/s40168-024-01760-w · Cited by 53
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“64 We observed a significant reduction in the level of 5-HTP in Group A, suggesting that Trp was involved in the Trp-5-HT pathway.”
BackgroundAmelio, I., Bertolo, R. G., Bove, P., Candi, E., Chiocchi, M., Cipriani, C., Daniele, N. D., Ganini, C., Juhl, H. H., Mauriello, A., et al. (2020) · Biology Direct · doi:10.1186/s13062-020-00274-3 · Cited by 45
Environmental perception and control of gastrointestinal immunity by the enteric nervous system
Schneider, K. M., Kim, J., Bahnsen, K., Heuckeroth, R. O., & Thaiss, C. A. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.09.005 · Cited by 44
Dothel, G., Barbaro, M. R., Vito, A. D., Ravegnini, G., Gorini, F., Monesmith, S., Coschina, E., Benuzzi, E., Fuschi, D., Palombo, M., et al. (2023) · Journal of Gastroenterology · doi:10.1007/s00535-023-01997-6 · Cited by 49
Targeting the human gut microbiome with small-molecule inhibitors
Woo, A. Y. M., Aguilar Ramos, M. A., Narayan, R., Richards-Corke, K. C., Wang, M. L., Sandoval-Espinola, W. J., & Balskus, E. P. (2023) · Nature Reviews Chemistry · doi:10.1038/s41570-023-00471-4 · Cited by 42
Older, E. A., Zhang, J., Ferris, Z. E., Xue, D., Zhong, Z., Mitchell, M. K., Madden, M., Wang, Y., Chen, H., Nagarkatti, P. S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53670-y · Cited by 49
“…focused on the association of certain microbes with speci fi c diseases by analyzing the abundance and distribution of microbial strains 18,19,73 – 76 , we describe here an approach which leverages disease-related sequencing data to connect the bio-synthesis of functional metabolites directly to…”
Metadata
- Authors
- Mars, R. A. T., Yang, Y., Ward, T., Houtti, M., Priya, S., Lekatz, H. R., Tang, X., Sun, Z., Kalari, K. R., Korem, T., Bhattarai, Y., Zheng, T., Bar, N., Frost, G., Johnson, A. J., van Treuren, W., Han, S., Ordog, T., Grover, M., Sonnenburg, J., D’Amato, M., Camilleri, M., Elinav, E., Segal, E., Blekhman, R., Farrugia, G., Swann, J. R., Knights, D., & Kashyap, P. C.
- Affiliations
- Mayo Clinic (US)
- Imperial College London (GB)
- University of Minnesota (US)
- Canadian Institute for Advanced Research (CA)
- Monash University (AU)
- Weizmann Institute of Science (IL)
- Stanford University (US)
- German Cancer Research Center (DE)
- University of Southampton (GB)
- Corresponding author
- Knights, Dan
- Kashyap, Purna C.
- ORCID
- Mars, Ruben A.T.
- Houtti, Mo
- Priya, Sambhawa
- Tang, Xiaojia
- Sun, Zhifu
- Kalari, Krishna R.
- Korem, Tal
- Bhattarai, Yogesh
- Zheng, Tenghao
- Frost, Gary
- Johnson, Abigail J.
- Han, Shuo
- Ordog, Tamas
- Grover, Madhusudan
- Sonnenburg, Justin
- D’Amato, Mauro
- Camilleri, Michael
- Elinav, Eran
- Segal, Eran
- Blekhman, Ran
- Farrugia, Gianrico
- Swann, Jonathan R.
- Knights, Dan
- Kashyap, Purna C.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 182
- Issue
- 6
- Pages
- 1460-1473.e17
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8109273
- OpenAlex
- W3084404023
- Cited by
- 456
- References
- 49
- Citations by year
- 2026: 59 · 2025: 69 · 2024: 99 · 2023: 78 · 2022: 92 · 2021: 53 · 2020: 5
- FWCI
- 18.48
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-11-12)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- Foundation for the National Institutes of Health
- 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 › Gastroenterology › Inflammatory Bowel Disease
- Keywords
- irritable bowel syndrome, gut microbiota, microbial metabolites, purine metabolism, host-microbe interactions, IBS subtypes, host transcriptome, host metabolome, chronic gastrointestinal diseases, therapeutic target
- MeSH terms
- Gastrointestinal Microbiome, Host Microbial Interactions, Animals, Bile Acids and Salts, Biopsy, Butyrates, Chromatography, Liquid, Cross-Sectional Studies, Feces, Female, Gene Expression Regulation, Humans, Longitudinal Studies, Male, Prospective Studies, Purines, Software, Hypoxanthine, Irritable Bowel Syndrome, Mice, Tandem Mass Spectrometry, Metabolome, Epigenomics, Transcriptome, Observational Studies as Topic
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