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Differential response of patient-derived intestinal organoids to site-specific mucosal bacteria in pediatric inflammatory bowel disease

ABSTRACT: Objective: Inflammatory bowel disease (IBD) is secondary to an abnormal immune response to the microbiota. There is evidence of impaired stem cell signatures in IBD contributing to impaired epithelial repair. We therefore aimed to study the role of the microbiome in the intestinal stem cell population in paediatric IBD cases, a group without confounding treatments or comorbidities, by directly studying the interaction between patient-isolated bacteria and the epithelium. Design: We established a unique biobank with matched intestinal organoids and cultured mucosally adherent bacteria from 36 paediatric patients. To determine the bacterial effect on host epithelial cells, closely related bacterial isolates from control and IBD patients were selected for microinjection into their corresponding organoid line. Results: Whilst no differences were observed between control and IBD-derived organoids following injury, transcriptional profiling revealed differential gene expression between uninjured control and IBD- derived organoids. Furthermore, following microinjection of an isolate originating from a control patient, there was upregulation of inflammatory signalling pathways, whereas this was not observed with a closely related isolate originating from an IBD patient. Conclusion: This demonstrates the feasibility of isolating bacteria and generating organoids from the same biopsy tissue, to explore personalised host-microbe interactions. The microinjections show the individual nature of responses, with closely related bacteria inducing very different epithelial responses, with downstream implications for immune response. This highlights the importance of understanding host-microbe interactions in a strain and site-specific manner, and developing techniques for personalised microbiome-based therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288179 | GEO | 2025/10/01

REPOSITORIES: GEO

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Project description:Genome scale metabolic model of Drosophila gut microbe Acetobacter fabarum Abstract - An important goal for many nutrition-based microbiome studies is to identify the metabolic function of microbes in complex microbial communities and their impact on host physiology. This research can be confounded by poorly understood effects of community composition and host diet on the metabolic traits of individual taxa. Here, we investigated these multiway interactions by constructing and analyzing metabolic models comprising every combination of five bacterial members of the Drosophila gut microbiome (from single taxa to the five-member community of Acetobacter and Lactobacillus species) under three nutrient regimes. We show that the metabolic function of Drosophila gut bacteria is dynamic, influenced by community composition, and responsive to dietary modulation. Furthermore, we show that ecological interactions such as competition and mutualism identified from the growth patterns of gut bacteria are underlain by a diversity of metabolic interactions, and show that the bacteria tend to compete for amino acids and B vitamins more frequently than for carbon sources. Our results reveal that, in addition to fermentation products such as acetate, intermediates of the tricarboxylic acid (TCA) cycle, including 2-oxoglutarate and succinate, are produced at high flux and cross-fed between bacterial taxa, suggesting important roles for TCA cycle intermediates in modulating Drosophila gut microbe interactions and the potential to influence host traits. These metabolic models provide specific predictions of the patterns of ecological and metabolic interactions among gut bacteria under different nutrient regimes, with potentially important consequences for overall community metabolic function and nutritional interactions with the host.IMPORTANCE Drosophila is an important model for microbiome research partly because of the low complexity of its mostly culturable gut microbiota. Our current understanding of how Drosophila interacts with its gut microbes and how these interactions influence host traits derives almost entirely from empirical studies that focus on individual microbial taxa or classes of metabolites. These studies have failed to capture fully the complexity of metabolic interactions that occur between host and microbe. To overcome this limitation, we reconstructed and analyzed 31 metabolic models for every combination of the five principal bacterial taxa in the gut microbiome of Drosophila This revealed that metabolic interactions between Drosophila gut bacterial taxa are highly dynamic and influenced by cooccurring bacteria and nutrient availability. Our results generate testable hypotheses about among-microbe ecological interactions in the Drosophila gut and the diversity of metabolites available to influence host traits.

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Differential response of patient-derived intestinal organoids to site-specific mucosal bacteria in pediatric inflammatory bowel disease

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