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Lymphotoxin regulates commensal responses to enable diet-induced obesity.

ABSTRACT: Microbiota are essential for weight gain in mouse models of diet-induced obesity (DIO), but the pathways that cause the microbiota to induce weight gain are unknown. We report that mice deficient in lymphotoxin, a key molecule in gut immunity, were resistant to DIO. Ltbr(-/-) mice had different microbial community composition compared to their heterozygous littermates, including an overgrowth of segmented filamentous bacteria (SFB). Furthermore, cecal transplantation conferred leanness to germ-free recipients. Housing Ltbr(-/-) mice with their obese siblings rescued weight gain in Ltbr(-/-) mice, demonstrating the communicability of the obese phenotype. Ltbr(-/-) mice lacked interleukin 23 (IL-23) and IL-22, which can regulate SFB. Mice deficient in these pathways also resisted DIO, demonstrating that intact mucosal immunity guides diet-induced changes to the microbiota to enable obesity.

SUBMITTER: Upadhyay V

PROVIDER: S-EPMC3718316 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Lymphotoxin regulates commensal responses to enable diet-induced obesity.

Upadhyay Vaibhav V Poroyko Valeriy V Kim Tae-jin TJ Devkota Suzanne S Fu Sherry S Liu Donald D Tumanov Alexei V AV Koroleva Ekaterina P EP Deng Liufu L Nagler Cathryn C Chang Eugene B EB Tang Hong H Fu Yang-Xin YX

Nature immunology 20120826 10

Microbiota are essential for weight gain in mouse models of diet-induced obesity (DIO), but the pathways that cause the microbiota to induce weight gain are unknown. We report that mice deficient in lymphotoxin, a key molecule in gut immunity, were resistant to DIO. Ltbr(-/-) mice had different microbial community composition compared to their heterozygous littermates, including an overgrowth of segmented filamentous bacteria (SFB). Furthermore, cecal transplantation conferred leanness to germ-f ...[more]

PMID: 22922363

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Project description:Changes in the gut microbiota have been linked to metabolic endotoxemia as a contributing mechanism in the development of obesity and type 2 diabetes. Although identifying specific microbial taxa associated with obesity and type 2 diabetes remains difficult, certain bacteria may play an important role in initiating metabolic inflammation during disease development. The enrichment of the family Enterobacteriaceae, largely represented by Escherichia coli, induced by a high-fat diet (HFD) has been correlated with impaired glucose homeostasis; however, whether the enrichment of Enterobacteriaceae in a complex gut microbial community in response to an HFD contributes to metabolic disease has not been established. To investigate whether the expansion of Enterobacteriaceae amplifies HFD-induced metabolic disease, a tractable mouse model with the presence or absence of a commensal E. coli strain was established. With an HFD treatment, but not a standard-chow diet, the presence of E. coli significantly increased body weight and adiposity and induced impaired glucose tolerance. In addition, E. coli colonization led to increased inflammation in liver and adipose and intestinal tissue under an HFD regimen. With a modest effect on gut microbial composition, E. coli colonization resulted in significant changes in the predicted functional potential of microbial communities. The results demonstrated the role of commensal E. coli in glucose homeostasis and energy metabolism in response to an HFD, indicating contributions of commensal bacteria to the pathogenesis of obesity and type 2 diabetes. The findings of this research identified a targetable subset of the microbiota in the treatment of people with metabolic inflammation. IMPORTANCE Although identifying specific microbial taxa associated with obesity and type 2 diabetes remains difficult, certain bacteria may play an important role in initiating metabolic inflammation during disease development. Here, we used a mouse model distinguishable by the presence or absence of a commensal Escherichia coli strain in combination with a high-fat diet challenge to investigate the impact of E. coli on host metabolic outcomes. This is the first study to show that the addition of a single bacterial species to an animal already colonized with a complex microbial community can increase severity of metabolic outcomes. This study is of interest to a wide group of researchers because it provides compelling evidence to target the gut microbiota for therapeutic purposes by which personalized medicines can be made for treating metabolic inflammation. The study also provides an explanation for variability in studies investigating host metabolic outcomes and immune response to diet interventions.

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Lymphotoxin regulates commensal responses to enable diet-induced obesity.

Publications

Lymphotoxin regulates commensal responses to enable diet-induced obesity.

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