Obesogenic diet leads to luminal overproduction of the complex IV inhibitor H2S and mitochondrial dysfunction in mouse colonocytes

Obesity is characterized by systemic low-grade inflammation associated with disturbances of intestinal homeostasis and microbiota dysbiosis. Mitochondrial metabolism sustains epithelial homeostasis by providing energy to colonic epithelial cells (CEC) but can be altered by dietary modulations of the luminal environment. Our study aimed at evaluating whether the consumption of an obesogenic diet alters the mitochondrial function of CEC in mice. Mice were fed for 22 weeks with a 58% kcal fat diet (diet-induced obesity [DIO] group) or a 10% kcal fat diet (control diet, CTRL). Colonic crypts were isolated to assess mitochondrial function while colonic content was collected to characterize microbiota and metabolites. DIO mice developed obesity, intestinal hyperpermeability, and increased endotoxemia. Analysis of isolated colonic crypt bioenergetics revealed a mitochondrial dysfunction marked by decreased basal and maximal respirations and lower respiration linked to ATP production in DIO mice. Yet, CEC gene expression of mitochondrial respiration chain complexes and mitochondrial dynamics were not altered in DIO mice. In parallel, DIO mice displayed increased colonic bile acid concentrations, associated with higher abundance of Desulfovibrionaceae. Sulfide concentration was markedly increased in the colon content of DIO mice. Hence, chronic treatment of CTRL mouse colon organoids with sodium sulfide provoked mitochondrial dysfunction similar to that observed in vivo in DIO mice while acute exposure of isolated mitochondria from CEC of CTRL mice to sodium sulfide diminished complex IV activity. Our study provides new insights into colon mitochondrial dysfunction in obesity by revealing that increased sulfide production by DIO-induced dysbiosis impairs complex IV activity in mouse CEC.

Automated summary

Obesity is associated with inflammation, intestinal imbalance, and dysbiosis of the microbiota. This study aimed to investigate the effect of an obesogenic diet on mitochondrial function in colonic epithelial cells (CEC) of mice. The results showed that mice on the obesogenic diet developed obesity, intestinal hyperpermeability, and increased endotoxemia. Mitochondrial dysfunction, characterized by decreased respiration and lower ATP production, was observed in CEC of these mice. Additionally, increased sulfide production and altered bile acid concentrations were found in the colonic content of obese mice. Chronic treatment of control mouse colon organoids with sodium sulfide induced similar mitochondrial dysfunction, while acute exposure of isolated mitochondria from control mice to sodium sulfide decreased complex IV activity. These findings suggest that dysbiosis-induced sulfide production impairs mitochondrial function in CEC of obese mice.