Abstract
During the past forty years there has been an inexplicable increase in chronic inflammatory disorders, including obesity. One theory, the ‘hygiene hypothesis’, involves dysregulated immunity arising after too few beneficial early life microbe exposures. Indeed, earlier studies have shown that gut microbe-immune interactions contribute to smoldering inflammation, adiposity, and weight gain. Here we tested a safe and well-established microbe-based immune adjuvant to restore immune homeostasis and counteract inflammation-associated obesity in animal models. We found that consuming Vibrio cholerae exotoxin subunit B (ctB) was sufficient to inhibit age-associated obesogenic outcomes in wild type mice, including reduced crown-like structures (CLS) and granulomatous necrosis histopathology in fat depots. Administration of cholera toxin reduced weight gain irrespective of age during administration; however, exposure during youth imparted greater slenderizing effects when compared with animals receiving ctB for the first time during adulthood. Beneficial effects were transplantable to other obesity-prone animals using immune cells alone, demonstrating an immune-mediated mechanism. Taken together, we concluded that oral vaccination with cholera toxin B helps stimulate health-protective immune responses that counteract age-associated obesity.
Highlights
The global burden of chronic inflammatory diseases is increasing at alarming rates [1, 2]
We found that consuming Vibrio cholerae exotoxin subunit B was sufficient to inhibit age-associated obesogenic outcomes in wild type mice, including reduced crown-like structures (CLS) and granulomatous necrosis histopathology in fat depots
Using C57BL/6 wild type mice, we discovered that three doses of cholerae exotoxin subunit B (ctB) every-other-week at 10 ug per mouse starting at four-weeks-of-age prevented ageassociated body weight gain when examined upon necropsy at nine months of age
Summary
The global burden of chronic inflammatory diseases is increasing at alarming rates [1, 2]. Underlying systemic immune imbalances linked with bacteria residing in the gut have been proposed as a probable cause of obesity [8,9]. In this context, obesity is one of many chronic inflammatory diseases associated with modernized living. Important effects of gut microbiota in mammalian physiology, including metabolism and CNS functions, place gut microbe-immune cell interactions in the hypothetical center of chronic inflammatory disorders such as obesity [7, 8] [10,11,12,13,14,15,16,17,18]. An intriguing microbecentric theory builds upon the so-called “hygiene hypothesis” and proposes that modernized domestication practices including sterile births, refined diets, and antibiotics, result in too few microbe exposures that reduce microbial diversity and favor gut bacterial dysbiosis, leading to a wide array of systemic health disorders
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