Obesity-Induced Dysbiosis Exacerbates IFN-γ Production and Pulmonary Inflammation in the Mycobacterium tuberculosis Infection

Abstract

The microbiota of the gut–lung axis affects local and far-reaching immune responses and might also trigger chronic and inflammatory diseases. We hypothesized that gut dysbiosis induced by obesity, which coexists in countries with a high tuberculosis burden, aggravates the host susceptibility and the pulmonary damage tolerance. To assess our hypothesis, we used a model of high-fat diet (HFD)-induced obesity, followed by infection of C57BL/6 mice with Mycobacterium tuberculosis. We showed that obesity increased the susceptibility, the pulmonary inflammation and IFN-γ levels in M. tuberculosis-infected mice. During the comorbidity obesity and tuberculosis, there is an increase of Bacteroidetes and Firmicutes in the lungs, and an increase of Firmicutes and butyrate in the feces. Depletion of gut microbiota by antibiotic treatment in the obese infected mice reduced the frequencies of CD4+IFN-γ+IL-17− cells and IFN-γ levels in the lungs, associated with an increase of Lactobacillus. Our findings reinforce the role of the gut–lung axis in chronic infections and suggest that the gut microbiota modulation may be a potential host-directed therapy as an adjuvant to treat TB in the context of IFN-γ-mediated immunopathology.

Obesity-related indicators and tuberculosis: A Mendelian randomization study

“…Relevant studies have demonstrated a strong link between TB and impaired immune response [53]. One study elucidated another potential regulatory mechanism of the intestine-lung axis [54], suggesting that obesity can lead to dysbiosis of the intestinal flora and dysregulation of the intestinal microenvironment, thereby increasing susceptibility to TB and decreasing tolerance to lung injury. Although some studies have reported that TB is strongly associated with impaired immune response and that the risk for latent TB recurrence is extremely low in immunocompetent patients, the risk for recurrence is, in fact, significantly elevated in this patient population [55].…”

Tuberculosis in an Aging World

“…Although complement activation is considered a supportive component of our first line of defense against pathogens, its detrimental (bystander) activation might lead to increased tissue damage and susceptibility to TB. M.tb infected obese mice on a high-fat diet (HFD) demonstrate increased pulmonary inflammation, IFN-γ-mediated immunopathology, and susceptibility to M.tb infection [ 73 ]. Data that link aging, obesity, and TB are so far conflicting.…”

Mouse Models for Mycobacterium tuberculosis Pathogenesis: Show and Do Not Tell

“…The effect of overnutrition is not as marked as the effect of undernutrition, but while some studies in humans report that, apparently, obesity is related to enhanced resistance to the infection [ 240 , 241 ], studies with mice point to the opposite direction, finding that obesity models obtained by administration of high fat diets deal worse with M. tuberculosis infection and relate this susceptibility difference to the intestinal microbiome change caused by the diet [ 242 , 243 , 244 ]. So, it can be hypothesized that, in the case of overnutrition, as long as the intestinal microbiome, which depends on other factors than the nutritional income of the diet, remains diverse and functional, there might be no additional enhancement of susceptibility, but other parameters must be included to evaluate the status of the host.…”