Cosmc is an X-linked inflammatory bowel disease risk gene that spatially regulates gut microbiota and contributes to sex-specific risk

Abstract

Inflammatory bowel disease (IBD) results from aberrant immune stimulation against a dysbiotic mucosal but relatively preserved luminal microbiota and preferentially affects males in early onset disease. However, factors contributing to sex-specific risk and the pattern of dysbiosis are largely unexplored. Core 1 β3GalT-specific molecular chaperone (Cosmc), which encodes an X-linked chaperone important for glycocalyx formation, was recently identified as an IBD risk factor by genome-wide association study. We deleted Cosmc in mouse intestinal epithelial cells (IECs) and found marked reduction of microbiota diversity in progression from the proximal to the distal gut mucosa, but not in the overlying lumen, as seen in IBD. This loss of diversity coincided with local emergence of a proinflammatory pathobiont and distal gut restricted pathology. Mechanistically, we found that Cosmc regulates host genes, bacterial ligands, and nutrient availability to control microbiota biogeography. Loss of one Cosmc allele in males (IEC-Cosmc -/y ) resulted in a compromised mucus layer, spontaneous microbe-dependent inflammation, and enhanced experimental colitis; however, females with loss of one allele and mosaic deletion of Cosmc in 50% of crypts (IEC-Cosmc +/− ) were protected from spontaneous inflammation and partially protected from experimental colitis, likely due to lateral migration of normal mucin glycocalyx from WT cells over KO crypts. These studies functionally validate Cosmc as an IBD risk factor and implicate it in regulating the spatial pattern of dysbiosis and sex bias in IBD.

The Gut Microbiome: Connecting Spatial Organization to Function

“…Host genetics may also play an important role in digestive tract diseases. Recently, a specific host molecular chaperone, Cosmc, was shown to be associated with IBD in humans, and deletion of Cosmc in mice led to loss of gut microbiota diversity (Kudelka et al, 2016). Furthermore, the structure of the fecal microbiota is affected in patients with chronic idiopathic diarrhea, suggesting that gut homeostasis is an important feature in establishing commensal organization (Swidsinski et al, 2008).…”

Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

“…The sections were blocked using 0.3% H 2 O 2 and 5% BSA. Then, sections were incubated overnight at 4°C with a specific anti-Tn IgM monoclonal antibody (5 μg/mL, CA3638, clone 12A8-C7-F5, kindly provided by Dr. Tongzhong Ju, Emory University, Atlanta, Georgia, USA) 13,20,26 followed by horseradish peroxidase-conjugated antimouse IgM antibody (Abcam, ab97230) for 1 hour at room temperature. Finally, the sections were developed with DAB reagent (ZSGB-BIO, China) and counterstained with haematoxylin.…”

“…Interestingly, the expression and activity of T‐synthase require an endoplasmic reticulum(ER)‐resident molecular chaperone named Cosmc 15, 16, 17. Knockout of either T‐synthase or Cosmc in mice causes Tn expression in vivo 18, 19, 20. Besides, in gastrointestinal tract, Tn antigen can also be elongated into core 3 O‐glycans by specific glycosyltransferase‐C3GnT 21.…”

Accounting for sex in the genome

“…The study also reported gut microbiome changes in the rodents resulting from loss of Cosmc 4 . A follow-up published earlier this year characterized functional domains of the COSMC chaperone protein 5 .…”