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Khaloian, S.

Publications and source records attributed to Khaloian, S..

2 recordsLinked to original sources
bioRxiv2023

Mitochondrial perturbation of the epithelium causes microbial dysbiosis and unresolved tissue injury in intestinal inflammation

Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBD). To understand how microbial-metabolic circuits contribute to intestinal tissue injury, we disrupt mitochondrial function in the epithelium by deleting heat shock protein 60 (Hsp60{Delta}/{Delta}IEC). While metabolic perturbation causes self-resolving tissue injury, regeneration is disrupted in the absence of aryl hydrocarbon receptor (Hsp60{Delta}/{Delta}IEC;AhR-/-) or IL-10 (Hsp60{Delta}/{Delta}IEC;Il10-/-) leading to IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60{Delta}/{Delta}IEC mice, highlighting bacterial control of metabolic injury. Selective colonization of GF Hsp60{Delta}/{Delta}IEC mice with the synthetic community OMM12 confirms consistent expansion of metabolically-flexible Bacteroides spp. across all models and mono-colonization with B. caecimuris recapitulates injury. Transcriptional profiling of metabolically-impaired epithelium identifies gene signatures, including Ido1, Nos2, and Duox2, distinguishing active from inactive tissue inflammation in 343 resected samples from Crohns disease patients. In conclusion, mitochondrial perturbation of the epithelium causes microbiota-dependent tissue injury and discriminative inflammatory gene profiles relevant for IBD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/549844v6_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@240c5forg.highwire.dtl.DTLVardef@a84382org.highwire.dtl.DTLVardef@e829e3org.highwire.dtl.DTLVardef@163625_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Control of metabolic injury by microbial signals. C_FIG O_LIMitochondrial perturbation of the intestinal epithelium induces tissue injury C_LIO_LILoss of IL-10 and AhR-related host mechanisms accelerate injury and inflammation C_LIO_LIMitochondrial dysfunction induces dysbiosis and expansion of Bacteroides spp. C_LIO_LIMetabolic injury gene signature discriminates inflamed vs. non-inflamed IBD samples C_LI

microbiology↗
bioRxiv2022

Diet prevents the expansion of segmented filamentous bacteria and ileo-colonic inflammation in a model of Crohn's disease

Crohns disease (CD) is associated with changes in the microbiota, and murine models of CD-like ileo-colonic inflammation depend on the presence of microbial triggers. Increased abundance of unknown Clostridiales and the microscopic detection of filamentous structures close to the epithelium of Tnf {Delta}ARE mice pointed towards segmented filamentous bacteria (SFB), a commensal well-known to induce the maturation of Th17 cell-derived immune responses that is highly implicated in the pathogenesis of IBD. We show that the abundance of SFB strongly correlates with the severity of CD-like ileal inflammation in Tnf {Delta}ARE and SAMP/Yit mice. SFB mono-colonization of germ-free Tnf {Delta}ARE mice confirmed the causal link and resulted in severe ileo-colonic inflammation, characterized by elevated tissue levels of Tnf and Il-17, neutrophil infiltration and loss of Paneth and goblet cell function. Co-colonization of SFB in human-microbiota associated Tnf {Delta}ARE mice confirmed that SFB presence is indispensable for disease development. Screening of 412 ileal and colonic mucosal biopsies from IBD patients using previously published and newly designed human SFB-specific primer sets showed no presence of SFB in human tissue samples. Simulating the protective effect of exclusive enteral nutrition (EEN) by feeding SFB mono-colonized Tnf {Delta}ARE mice EEN-like purified diet antagonized SFB colonization and prevented disease development in Tnf {Delta}ARE mice, clearly demonstrating the important role of diet in modulating this IBD-related but murine pathobiont.

microbiology↗