Biology subjects

Khaloian, S.

Publications and source records attributed to Khaloian, S..

4 recordsLinked to original sources

bioRxiv2025

Reduced intestinal GLP-1+ cell numbers are associated with an inflammation-related epithelial metabolic signature

Background & AimsEnteroendocrine cells (EECs) are known for their role in digestion and metabolism, yet their role in intestinal inflammation remains unclear. In inflammatory bowel diseases (IBD), a contribution of EECs to pathogenesis is indicated by autoantibodies affecting EEC function and general disease symptoms like insulin resistance and altered intestinal motility. Particularly, the L cell-derived hormone glucagon-like peptide 1 (GLP-1), suggested to orchestrate metabolic-inflammatory responses may influence inflammatory pathways in the intestine. MethodsWe quantified numbers of GLP-1+ cells in 4 different mouse models of intestinal inflammation and performed transcriptional analyses of colonic epithelial cells from inflamed interleukin (IL)10-deficient mice. Using a publicly available single-cell RNA sequencing dataset including mucosal biopsies from Crohns disease (CD) patients, we confirmed findings from the murine models. A model of mitochondrial dysfunction (ClpP{Delta}IEC mice) as well as murine and human intestinal organoids were used to study molecular mechanisms. ResultsNumbers of GLP-1 expressing cells are consistently reduced at the site of active disease in mouse models and CD patients. Despite this reduction, L cells from inflamed IL-10-deficient mice remained functional regarding GLP-1 secretion. Transcriptional analyses of intestinal epithelial cells indicate altered differentiation correlating with an inflammatory metabolic fingerprint. Reduced GLP-1+ cells in ClpP{Delta}IEC mice and inhibition of respiration in organoid cultures supports a causative role for metabolism in steering differentiation. ConclusionReduction of GLP-1+ cells represents a general feature of ileal and colonic inflammation in mice and human. Given the numerous properties of GLP-1, this reduction likely affects inflammatory processes in the mucosa and disease-related symptoms on multiple levels, and therefore, should be considered a therapeutic target in IBD. Data TransparencyAll data generated or analyzed during this study are included in this published article. Additional datasets, including raw data, are available from the corresponding author upon reasonable request. SynopsisThis study examines GLP-1+ cells in intestinal inflammation, showing consistent reductions in inflamed areas. Findings from mouse models and human data reveal an inflammatory metabolic profile linked to altered epithelial differentiation. GLP-1, involved in endocrine-immune crosstalk, may impact mucosal inflammation and symptoms, making it a therapeutic target. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/641577v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@136158borg.highwire.dtl.DTLVardef@1c08461org.highwire.dtl.DTLVardef@332635org.highwire.dtl.DTLVardef@117d5f_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Susceptibility to inflammatory bowel diseases promotes invasive carcinomas in a murine model of ATF6-driven colon cancer

Chronic inflammation in inflammatory bowel disease (IBD) patients represents a risk factor for developing colitis-associated cancer (CAC). We previously linked the endoplasmic reticulum unfolded protein response (UPRER) signal transducer activating transcription factor 6 (ATF6) with spontaneous microbiota-dependent colonic adenoma development in mice expressing epithelial-specific activated ATF6 (nATF6IEC). To investigate IBD-related risk factors in ATF6-mediated tumorigenesis, we crossed tumor-free monoallelic (tg/wt) nATF6IEC mice with Interleukin-10 deficient mice (Il10-/-). IL10 deficiency initiated tumor susceptibility, with 77% of 12-week tg/wt;Il10-/- mice developing colonic adenomas and invasive carcinomas in this novel CAC mouse model. Tumor formation correlated with mucosal immune cell infiltration, characterized by CD11b+ granulocytes and monocytes, and mucosa-associated dysbiosis. Colonization of germ-free nATF6IEC;Il10-/- mice with minimal biosynthetic consortia and IBD stool re-established CAC, confirming microbiota-dependent ATF6-driven tumorigenesis. Increased ATF6 expression in IBD patients during active disease highlights its human relevance. Our findings show that IBD susceptibility heightens the risk for ATF6-driven tumorigenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/624835v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@17e280eorg.highwire.dtl.DTLVardef@177ceacorg.highwire.dtl.DTLVardef@a1916borg.highwire.dtl.DTLVardef@152374f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

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↗