Consuming cholera toxin counteracts age-associated obesity

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.

Peri‐weaning cholera toxin consumption suppresses chemically‐induced carcinogenesis in mice

“…Along the same lines, neutrophils were found universally decreased in cancer prone tissues and all lymphoid organs, whereas the immune system axis from the GI tract to the various peripheral lymph nodes and the thymus gland showed an overall but variable tendency toward increased numbers of CD8+ and Tregs, which are both key cells of the tumor‐immune system interaction 4,15,26,28,44–46 . By large, the effects of CT on immune cells and cytokines observed here, are in line with its previously reported immunomodulatory properties 9,10,18–23,47 . The immunological analysis in the present study, however, does not fully characterize the immune‐mediated mechanism of CT in suppressing cancer throughout the body.…”

“…4,15,26,28,[44][45][46] By large, the effects of CT on immune cells and cytokines observed here, are in line with its previously reported immunomodulatory properties. 9,10,[18][19][20][21][22][23]47 The immunological analysis in the present study, however, does not fully characterize the immune-mediated mechanism of CT in suppressing cancer throughout the body. Nonetheless, it provides proof of concept that CT is able to reprogram host's immune system toward prevention of cancer and highlights important immune cells and factors for further research in this context.…”

“…Bacterial toxins are being explored as potential anticancer agents for quite some time. 17 However, preclinical animal model studies testing CT or CT-B have focused on autoimmune diseases and allergies, [18][19][20] mucosal healing and inflammation, 10,21,22 and obesity, 23 rather than cancer. The exception being a study from our group where BALB/cJ male mice and the AOM/DSS protocol for inflammation-promoted colonic neoplasia were used to show that oral administration of CT suppresses colonic polyp formation, through mechanisms involving significant modulations of local intestinal immunity.…”

GPCR in Adipose Tissue Function—Focus on Lipolysis

“…GPCR signaling is mediated primarily through G proteins [36]. Concerning the activity of G proteins in adipocyte function per se, pivotal experiments in mice showed that enhancing Gs signaling (via application of the cholera toxin, CTX) prevents age-associated obesity and inflammation [37]. Treatment of white adipocytes with CTX induces increased lipolysis [38].…”