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Donor Gut MicrobialDrives Fecal Microbiota Transplantation Efficacy in ulcerative colitis

ABSTRACT:

Fecal microbiota transplantation (FMT) has emerged as a promising therapeutic strategy for Inflammatory Bowel Disease (UC), though its clinical success appears contingent upon donor microbiota engraftment degree. While microbial colonization dynamics remain poorly understood, our study identifies metabolism as a critical determinant of gut community assembly under UC nutrient-limiting intestinal conditions. Using an model, we demonstrate that microbial competence in influences engraftment outcomes. Building on this mechanistic insight, we engineered a novel probiotic-metabolite consortium (G-MIX) designed to synergistically enhance gut ecosystems. Through multi-step catalytic conversion G-MIX facilitates L-glutamate biosynthesis and ATP generation, thereby alleviating RNS-mediated barriers to donor microbiota colonization. In murine UC models, G-MIX supplementation during FMT significantly improved microbial engraftment fidelity, correlating with enhanced anti-inflammatory responses and attenuated colonic pathology. Network meta-analysis of clinical datasets further substantiated the prognostic value of donorin UC remission. Our findings utilisation as an ecological driver of microbiota engraftment and present a rationally designed microbial therapy that optimises FMT efficacy through targeted metabolic reprogramming.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12531 | MetaboLights | 2026-01-11

REPOSITORIES: MetaboLights

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Project description:Background and aims. The etiopathology of inflammatory bowel diseases is still poorly understood. To date, only few little data are available on the microbiota composition in ulcerative colitis (UC), representing a major subform of inflammatory bowel diseases. Currently, one of the main challenges is to unravel the interactions between genetics and environmental factors in the onset or during the progression and maintenance of the disease. The aim of the present study was to analyse twin pairs discordant for UC for both gut microbiota dysbiosis and host expression profiles at a mucosal level and to get insight into the functional genomic crosstalk between microbiota and mucosal epithelium in vivo. Methods. Biopsies were sampled from the sigmoid colon of both healthy and diseased siblings from UC discordant twin pairs but also from healthy twins. Microbiota profiles were assessed by 16S rDNA libraries while mRNA expression profiles were analysed from the same volunteers using Affymetrix microarrays. Results. UC patients showed a dysbiotic microbiota with lower diversity and more species belonging to Actinobacteria and Proteobacteria phyla. On the contrary, their healthy siblingsM-bM-^@M-^Y microbiota contained more bacteria from the Lachnospiracea and Ruminococcaceae family than did healthy individuals . Sixty-three host transcripts significantly correlated with bacterial genera in healthy individuals whereas only 43 and 32 correlated with bacteria in healthy and UC siblings from discordant pairs, respectively. Several transcripts related to oxidative and immune responses were differentially expressed between unaffected and UC siblings. Conclusion. A loss of crosstalk between gut microbiota and host was highlighted in UC patients. This defect was also striking in healthy siblings from discordant pairs, as was the lower biodiversity within the microbiota. Our results suggest disease-relevant interactions between host transcriptome and microbiota. Moreover, unusual aerobic bacteria were noticed in UC mucosal microbiota, whereas healthy siblings from discordant pairs had higher percentages of potentially beneficialusual commensal bacterial species. Paired samples (twins) were analyzed to obtain data independent of genetic variation

Project description:The aims of the multi-center Ulcerative Colitis Human Microbiome Project (UCHMP) are to examine the role of the enteric microbiome in causing human ulcerative colitis, specifically the development of pouchitis. Pouchitis is an inflammatory condition of the surgically-created ileoanal pouch that serves as a pseudo-rectum in patients with ulcerative colitis who have undergone a total colectomy. It is a condition unique to ulcerative colitis (UC), as it rarely occurs in non-UC patients who have the same procedure. Within one year, about 50% of patients will develop pouchitis. The condition is almost certainly due to aspects of the pouch microbiota on a background of genetic susceptibility, as most patients respond to treatment with antibiotics. While there have been reports on the microbiota in pouchitis patients, all have been performed after the inflammatory process is initiated, rendering interpretation of the results difficult, as the inflammatory process itself will change the microbiota. Our project is therefore unique and possibly the only opportunity in the role of the enteric microbiome in IBD in a prospective manner, thereby establishing potentially important causal relationships between microbiota structure or function and development of UC.The studies also offer two additional advantages. First, the development of the pouch microbiota can be observed prospectively. Second, the cause of antibiotic treatment failure in some patients with pouchitis may be revealed. The two aims are (1) to identify causal factors in the structure and/or function of the enteric microbiota in the development of pouchitis, and (2) to determine the basis of treatment failure in UC pouchitis patients. Our analyses will include serial measurements of enteric microbial structure (16S rRNA gene-based), function (metagenomics and functional candidate genes), and cultivation, the latter to enhance interpretation of gene sequences derived from metagenomes and targeted gene surveys (either functional or 16S genes). The insights gained from these studies will help us understand the fundamental and causative roles of the enteric microbiome in human inflammatory bowel diseases (IBD). This information will be the basis for developing strategies to restore host-microbial relationships to prevent and treat IBD.

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Donor Gut MicrobialDrives Fecal Microbiota Transplantation Efficacy in ulcerative colitis

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