Abstract
The clinical spectra of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) intersect to form a scantily defined overlap syndrome, termed pre-IBD. We show that increased Enterobacteriaceae and reduced Clostridia abundance distinguish the fecal microbiota of pre-IBD patients from IBS patients. A history of antibiotics in individuals consuming a high-fat diet was associated with the greatest risk for pre-IBD. Exposing mice to these risk factors resulted in conditions resembling pre-IBD and impaired mitochondrial bioenergetics in the colonic epithelium, which triggered dysbiosis. Restoring mitochondrial bioenergetics in the colonic epithelium with 5-amino salicylic acid, a PPAR-γ (peroxisome proliferator–activated receptor gamma) agonist that stimulates mitochondrial activity, ameliorated pre-IBD symptoms. As with patients, mice with pre-IBD exhibited notable expansions of Enterobacteriaceae that exacerbated low-grade mucosal inflammation, suggesting that remediating dysbiosis can alleviate inflammation. Thus, environmental risk factors cooperate to impair epithelial mitochondrial bioenergetics, thereby triggering microbiota disruptions that exacerbate inflammation and distinguish pre-IBD from IBS.
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•A combination of antibiotics and high-fat diet increases the risk for pre-IBD•Antibiotics and high-fat diet jointly impair epithelial mitochondrial function•Impaired mitochondrial bioenergetics drive an Enterobacteriaceae expansion•An Enterobacteriaceae expansion exacerbates mucosal inflammation in pre-IBD
Lee et al. find that antibiotics and high-fat diet cooperate to increase the risk for pre-IBD, characterized by low-grade mucosal inflammation and changes in the microbiota composition (dysbiosis). In a mouse model of pre-IBD, antibiotics and high-fat diet jointly impair epithelial mitochondrial function to drive dysbiosis that exacerbates mucosal inflammation.