Diet-Induced Alterations in Gut Microflora Contribute to Lethal Pulmonary Damage in TLR2/TLR4-Deficient Mice

• TLR2/TLR4-null mice on chronic high-fat diet have lethal pulmonary damage
• Mortality is transmissible to WT mice upon cohousing and fecal transplantation
• HFD and innate immune deficiency synergistically influence gut microbiota composition
• Hyperendotoxemia and increased pulmonary cell death were observed in DKO mice on HFD

SummaryChronic intake of Western diet has driven an epidemic of obesity and metabolic syndrome, but how it induces mortality remains unclear. Here, we show that chronic intake of a high-fat diet (HFD), not a low-fat diet, leads to severe pulmonary damage and mortality in mice deficient in Toll-like receptors 2 and 4 (DKO). Diet-induced pulmonary lesions are blocked by antibiotic treatment and are transmissible to wild-type mice upon either cohousing or fecal transplantation, pointing to the existence of bacterial pathogens. Indeed, diet and innate deficiency exert significant impact on gut microbiota composition. Thus, chronic intake of HFD promotes severe pulmonary damage and mortality in DKO mice in part via gut dysbiosis, a finding that may be important for immunodeficient patients, particularly those on chemotherapy or radiotherapy, where gut-microbiota-caused conditions are often life threatening.

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