Deletion of mucin 2 induces colitis with concomitant metabolic abnormalities in mice.

Patients with inflammatory bowel disease (IBD) are at increased risk of under-recognized metabolic comorbidities. Chronic intestinal inflammation in IBD along with changes to the gut microbiome leads to broader systemic effects. Despite the existence of multiple animal models to study colitis, limited studies have examined the metabolic abnormalities associated with these models. In this study, a spontaneous model of colitis (mucin 2 knock-out mouse, Muc2-/-) was used to investigate the impact of intestinal disease on metabolic dysfunction. Before the onset of severe colitis, such as rectal prolapse, Muc2-/- mice exhibited impaired glucose clearance. Defects were noted in the insulin signaling pathway corresponding with upregulated genes in lipid utilization pathways, increased mitochondrial number, and peroxisome proliferator-activated coactivator 1α (PGC-1α), a transcription factor central to energy metabolism regulation. Parallel to these metabolic alterations, Muc2-/- mice exhibited systemic inflammation and bacteremia. We further characterized the dysbiotic microbiome's predicted functional categories given its contributing role to the colitic phenotype in the Muc2-/- mice. In addition to less butyrate levels, we show an increased predisposition to lipid metabolism and lipid biosynthesis pathways in the microbiome associated with the host's altered metabolic state. This study establishes the Muc2-/- mouse model that develops spontaneous colitis, as an ideal model for studying early comorbid metabolic dysfunction. Clarification of the underlying etiology of two phenotypes in this model could unravel important clues regarding the treatment of metabolic comorbidities during colitis.NEW & NOTEWORTHY This study discloses the impaired systemic energy metabolism in a classic colitis murine model (Muc2-/- knock-out model). Investigating the interaction between colitis and metabolic disorders helps to extend our knowledge on deciphering inflammatory bowel disease-associated comorbidities and provides new insight into clinical treatment.

Citation

Jiayu Ye, Natasha Haskey, Hansika Dadlani, Hatem Zubaidi, Jacqueline A Barnett, Sanjoy Ghosh, Deanna L Gibson. Deletion of mucin 2 induces colitis with concomitant metabolic abnormalities in mice. American journal of physiology. Gastrointestinal and liver physiology. 2021 May 01;320(5):G791-G803

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PMID: 33728986

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