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Responses of intestinal organoids to infection by Mycobacterium avium resemble symptoms observed in Crohn’s disease

ABSTRACT: Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) in humans. Mycobacterium avium, which causes Johne’s disease in ruminants, has been suggested as a potential CD trigger due to similar pathology. However, early epithelial responses to M. avium and their relevance to CD remain unclear. This study aimed to establish a mouse small intestinal organoid (mSIO) model of M. avium infection and assess whether the resulting epithelial and immune responses resemble CD-related inflammation. M. avium-infected mSIOs were analyzed using confocal microscopy, serial block-face scanning electron microscopy, and a macrophage co-culture system to observe bacterial localization and immune cell behavior. RNA-seq and Gene Set Enrichment Analysis (GSEA) were performed to assess transcriptional changes. Comparative transcriptomic analysis was performed against a previous published RNA-seq dataset from gut tissues of germ-free mice colonized with microbiota from CD patients. M. avium efficiently infected mSIOs, disseminated through the tissue and triggered macrophage migration and clustering around infected organoids. Transcriptomic profiling revealed strong upregulation of inflammatory genes and enrichment of pro-inflammatory pathways such as TNF-α signaling. Comparative analysis revealed significant overlap in gene expression profile between M. avium-infected mSIOs and intestinal tissues of CD-humanized mice, including shared enrichment of the IBD signaling pathway. Notably, Mmp7, involved in epithelial remodeling and inflammation, emerged as a common marker in both models. This study presents a robust mSIO model of M. avium infection that replicates key features of CD-associated inflammation. The model presents a useful tool for studying host-pathogen interactions and identifies Mmp7 as a molecular link between bacterial infection and CD-like pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE305886 | GEO | 2025/09/01

REPOSITORIES: GEO

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Project description:Inflammatory bowel disease (IBD) patients are generally at an increased risk for viral diseases. Viral infections of tissue affected by chronic IBD are insufficiently understood, especially in the context of flare-ups; while some studies have confidently shown aggravation of symptoms in large cohorts, others found no association. Although not considered at an increased risk of Coronavirus Disease 2019 (COVID-19), IBD patients suffer more frequent gastrointestinal symptoms during COVID-19 and a worse outcome has been associated with certain IBD medications and disease activity. For this reason, we generated intestinal epithelial organoids from ileum with Crohn’s disease (CD) and colon with ulcerative colitis (UC) together with healthy controls. Each group included five to six patients. Using RNA sequencing we showed that IBD organoids were not more susceptible to infection. The highest viral load two days after infection was in healthy ileum and is correlated to the expression of SARS-CoV-2 entry receptor ACE2 and proteases CTSL/B. Pathway analyses determined an apparently weaker defense reaction in CD organoids to SARS-CoV-2 which could simply be due to the lower viral load compared to the healthy group. In contrast to CD, there was an activation of viral defense in infected UC colon, especially interferon signaling, resembling highly infected healthy ileum. This was not seen in healthy colon and was unexpected since UC and healthy colon did not differ in viral load. In uninfected IBD organoids compared to healthy, there was an already stronger basal expression of genes implicated in viral defense, for example, of viral sensors OAS1 and OASL in CD and interferon regulatory transcription factor IRF7 in UC. Some were further influenced by SARS-CoV-2 infection with notable differences between CD and UC. To conclude, infection with SARS-CoV-2 did not lead to higher viral numbers in IBD organoids providing reassurance for patients in remission. Still, we observed a more pronounced epithelial defense reaction to the virus in UC colon, prompting further investigations on whether this could be the reason for stronger gastrointestinal symptoms of COVID-19 seen in IBD patients or if it could lead to a consequent IBD flare.

Project description:Inflammatory bowel disease (IBD) is a complex multi-factorial inflammatory disease with Crohn’s disease (CD) and ulcerative colitis (UC) being the two most common forms. A number of transcriptional profiling studies have provided compelling evidence that describe the role of protein-coding genes and microRNAs in modulating the immune responses in IBD. In the present study, we performed a genome-wide transcriptome profiling of lncRNAs and protein-coding genes in inflamed and non-inflamed colon pinch biopsies from the IBD patients using expression microarrays platform. In this study, we identified widespread dysregulation of lncRNAs and protein-coding genes in both inflamed and non-inflamed CD and UC compared to the healthy controls. In case of inflamed CD and UC (iCD and iUC), we identified 438 and 745 differentially expressed lncRNAs, respectively, while in case of the non-inflamed CD and UC (niCD and niUC), we identified 12 and 19 differentially expressed lncRNAs, respectively. We also observed significant enrichment (p-value < 0.001, Pearson’s Chi-squared test) for 96 differentially expressed lncRNAs and 154 protein-coding genes within the IBD susceptibility loci. Furthermore, we found strong positive expression correlations for the intersecting and cis-neighboring differentially expressed IBD loci-associated lncRNA-protein-coding gene pairs. The functional annotation analysis of differentially expressed genes revealed that they are involved in immune response, pro-inflammatory cytokine activity and MHC protein complex. The lncRNA expression profiling in both inflamed and non-inflamed CD and UC, successfully stratified IBD patients from the healthy controls. Taken together, the identified lncRNA transcriptional signature along with clinically relevant parameters suggests their potential as biomarkers in IBD. A total of 96 biopsy samples (including 6 samples used as technical replicates) extracted from different colonic locations from 45 patients (CD=13, UC=20, Controls=12) were profiled using Agilent Custom 8x60K format lncRNA expression microarray. In Gencode v15 lncRNA microarray design, each lncRNA transcript is targeted by two probes covering 22,001 lncRNA transcripts corresponding to 12,963 lncRNA genes. In addition, each array contains 17,535 randomly-selected protein-coding targets, of which 15,182 (unique 12,787) correspond to protein-coding genes.

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Responses of intestinal organoids to infection by Mycobacterium avium resemble symptoms observed in Crohn’s disease

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