An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice

Abstract

Lipopolysaccharide endotoxin is the only known bacterial product which, when subcutaneously infused into mice in its purified form, can induce obesity and insulin resistance via an inflammation-mediated pathway. Here we show that one endotoxin-producing bacterium isolated from a morbidly obese human's gut induced obesity and insulin resistance in germfree mice. The endotoxin-producing Enterobacter decreased in relative abundance from 35% of the volunteer's gut bacteria to non-detectable, during which time the volunteer lost 51.4 kg of 174.8 kg initial weight and recovered from hyperglycemia and hypertension after 23 weeks on a diet of whole grains, traditional Chinese medicinal foods and prebiotics. A decreased abundance of endotoxin biosynthetic genes in the gut of the volunteer was correlated with a decreased circulating endotoxin load and alleviated inflammation. Mono-association of germfree C57BL/6J mice with strain Enterobacter cloacae B29 isolated from the volunteer's gut induced fully developed obesity and insulin resistance on a high-fat diet but not on normal chow diet, whereas the germfree control mice on a high-fat diet did not exhibit the same disease phenotypes. The Enterobacter-induced obese mice showed increased serum endotoxin load and aggravated inflammatory conditions. The obesity-inducing capacity of this human-derived endotoxin producer in gnotobiotic mice suggests that it may causatively contribute to the development of obesity in its human host.

Figure 1

Gnotobiotic mice mono-associated with E. cloacae B29 become obese and insulin resistant with increased endotoxin load and provoked systemic inflammation under HFD feeding (data collected at the end of 16 weeks after inoculation). (a) Body weight; (b) mass of epididymal, mesenteric, subcutaneous inguinal and retroperitoneal fat pad; (c) abdominal photographs; (d) oral glucose tolerance test (OGTT) and the areas under the curve (AUC) for the plasma glucose; (e) serum 2 h post load insulin; (f) enzyme-linked immunosorbent assay (ELISA) analysis of serum LPS-binding protein (LBP); (g) serum amyloid A (SAA); and (h) adiponectin corrected for bodyweight. The two-way analysis of variance (ANOVA) revealed a significant effect of the diet (P<0.01), a significant effect of B29 (P<0.01) and a significant diet × B29 interaction effect (P<0.01) on body weight, mass of epididymal, mesenteric, subcutaneous inguinal and retroperitoneal fat pad, serum LBP; a significant effect of the diet (P<0.01) and a significant effect of B29 (P<0.01) on OGTT; a significant effect of B29 (P<0.05) on serum 2 h post load insulin. Data are shown as means±s.e.m. (n=6). NS, no significant difference; *P<0.05; **P<0.01. Color code for animal groups: NCD+LB, blue slash; NCD+B29, blue; HFD+LB, red slash; HFD+B29, red. LB, Luria–Bertani medium.