Multi-omics Analysis: Mechanisms Revealed by Microbiome and Metabolome in Relation to Crohn's Disease Activity

Crohn's disease (CD) is a slowly relapsing inflammatory disease of the gastrointestinal tract. The pathogenesis of the disease is suggested to be driven by complex interactions of genetic, environmental, immune, and microbial factors. The inherent complexity of the disease is reflected in its widely varying clinical course, making it difficult to dissect disease mechanisms and predict disease progression based on the patient's initial diagnosis. The metabolic activity of the microbiome plays a central role in maintaining vital host physiological processes, including energy harvest, pathogen resistance, and host immune regulation.

Researchers have achieved drug-free remission in some severe and highly refractory CD patients using autologous hematopoietic stem cell transplantation (HSCT), with some patients relapsing over time. To functionally link changes in the fecal microbiome and metabolome with clinical responses following HSCT treatment in 29 CD patients, researchers employed an integrated multi-omics approach, further validated through experimental testing in humanized gnotobiotic mice. Using this approach in a phenotypically defined cohort of HSCT patients, it was possible to identify functional signatures associated with treatment failure or success during disease progression, enhancing the understanding of gut microbial dysbiosis's contribution to severe CD pathology.

s6

Journal: Nature Communications

Impact Factor: 12.121

Publication Date: August 2020

Link: https://www.nature.com/articles/s41467-020-17956-1

Abstract

Alterations in gut microbiota and metabolites are associated with the pathogenesis of inflammatory bowel disease. In this study, researchers conducted a multi-omics microbiome and metabolite analysis of a longitudinal cohort of CD patients undergoing HSCT and pursued an investigational treatment to induce drug-free remission. By comparing patients with responsive remission and maintained remission, those who relapsed, and treatment non-responders, shared functional characteristics related to disease activity were identified despite taxonomic differences in gut microbiota. When these microbiota were transplanted into gnotobiotic mice, their characteristics reflected the disease state. Overall, integrating human cohort and mouse microbiome and metabolite profiles improved predictive models of disease outcomes and identified bacterial metabolite interaction networks involved in sulfur metabolism as key mechanisms associated with disease activity in Crohn's disease.

Main Results

Researchers characterized the fecal microbiome features of 29 CD patients at different time points within 5 years post-HSCT, conducting 16S rRNA sequencing on 133 collected fecal samples. Stratifying the microbiome profile by disease activity showed reduced community richness and α-diversity in CD patients with active disease (non-remission or relapsed). Beta diversity analysis revealed significant separation in microbiome distribution between patients with active disease (before and after HSCT) and those with inactive disease (post-HSCT remission). Observing differences in functional component abundance among patients, pathways involved in sulfur transport systems and other ion transport systems (e.g., molybdate and nickel) were enriched in active disease (post-HSCT), while fundamental biosynthetic processes were enriched in inactive disease (post-HSCT). To characterize the functional consequences of microbiome composition changes during active disease post-HSCT, metabolite analysis was performed. Patients with active or inactive disease had 332 and 119 differentially abundant metabolic features, respectively. The untargeted metabolomics of the gut microbiota in humanized mice found dysregulated sulfur metabolism associated with inflammation in humanized mice, consistent with observations in CD patients.

Changes in the gut microbiome of individuals with Crohn's disease

Sulfur metabolism in humanized mice links disease activity to the human microbiome

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