Background Microscopic colitis (MC) is a common cause of chronic diarrhea, predominantly among older adults. Emerging evidence suggests that perturbations of gut microbiome and metabolome may play an important role in MC pathogenesis. Objective To comprehensively characterize alterations of the gut microbial and metabolic composition in MC. Design We established a longitudinal cohort of adult patients with MC and two control groups of individuals — chronic diarrhea controls and age– and sex– matched controls without diarrhea. Using stool samples, gut microbiome was analyzed by whole–genome shotgun metagenomic sequencing, and gut metabolome was profiled by ultra–high performance liquid chromatography–mass spectrometry. Per–feature enrichment analyses of microbial species, metabolic pathways, and metabolites were done using multivariable linear models both cross-sectionally comparing MC to controls and longitudinally according to disease activity. Lastly, we performed multi–omics association analyses to assess the relationship between microbiome and metabolome data. Results We included 683 participants, 131 with active MC (66 with both active and remission samples), 159 with chronic diarrhea, and 393 age– and sex–matched controls without diarrhea. The stool microbiome in active MC was characterized by a lower alpha diversity as compared to controls and the remission phase of MC. Compared to controls, we identified eight enriched species in MC, most of which were pro–inflammatory oral–typical species, such as Veillonella dispar and Haemophilus parainfluenzae. In contrast, 11 species, including anti–inflammatory microbes such as Blautia glucerasea and Bacteroides stercoris, were depleted in MC. Similarly, pro–inflammatory metabolites, including lactosylceramides, ceramides, lysophospholipids, and lysoplasmalogens were enriched in active MC as compared to controls or MC cases in remission. Multi–omics association analyses revealed strong and concordant links between microbes, their metabolic pathways, and metabolomic profiles, supporting the tight interplay between disturbances in stool microbiome and metabolome in MC. Conclusion We observed a significant shift in stool microbial and metabolomic composition in MC. Our findings could be used in the future for development of non–invasive biomarkers for diagnosing and monitoring MC and developing novel therapeutics.

HKh has received consulting fees from Aditium Bio and serve on clinical advisory board for Cylinder. KS has served as a consultant to Ardelyx, Gemelli Biotech, Laborie, Mahana, Salix, and Takeda and has received research support from Ardelyx, and ReStalsis.

This study was funded by R01AG068390 and P30 DK043351. Funding sources did not participate in study design, analysis, interpretation, drafting of manuscript, or submission process.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Partners Human Research Committee and the Institutional Review Board of Mass General Brigham gave ethical approval for this work (Protocol # 2015P001333 and # 2015P000275).

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All data produced in the present study are available upon reasonable request to the authors.