High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity

Abstract

Summary Several aspects common to a Western lifestyle, including obesity and decreased physical activity, are known risks for gastrointestinal cancers1. There is substantial evidence suggesting that diet profoundly affects the composition of the intestinal microbiota2. Moreover, there is now unequivocal evidence linking dysbiosis to cancer development3. Yet the mechanisms through which high-fat diet (HFD)-mediated changes in the microbial community impact the severity of tumorigenesis in the gut remain to be determined. Here we demonstrate that HFD promotes tumor progression in the small intestine of genetically susceptible K-rasG12Dint mice independently of obesity. HFD consumption in conjunction with K-Ras mutation mediates a shift in the composition of gut microbiota, which is associated with a decrease in Paneth cell antimicrobial host defense that compromises dendritic cell (DC) recruitment and MHC-II presentation in the gut-associated lymphoid tissues (GALTs). DC recruitment in GALTs can be normalized, and tumor progression attenuated, when K-rasG12Dint mice are supplemented with butyrate. Importantly, Myd88-deficiency blocks tumor progression. Transfer of fecal samples from diseased donors into healthy adult K-rasG12Dint mice is sufficient to transmit disease in the absence of HFD. Furthermore, treatment with antibiotics completely blocks HFD-induced tumor progression suggesting a pivotal role for distinct microbial shifts in aggravating disease. Collectively, these data underscore the importance of the reciprocal interaction between host and environmental factors in selecting microbiota that favor carcinogenesis, and suggest tumorigenesis may be transmissible among genetically predisposed individuals.

Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer

“…In contrast to the paradigm that links cancer risk to obesity through endocrine, adipokine, or inflammatory changes reflecting adiposity, dietary manipulation revealed that loss of guanylin expression in obesity is independent of body mass , consistent with another recent report of a calorie-modulated, obesity-independent colorectal cancer mechanism (Schulz et al, 2014). Indeed, whereas a high-fat diet is associated with both hypercaloric intake and weight gain, mice on a high-carbohydrate diet maintain lean body weights despite consuming ∼40% excess calories (Dogan et al, 2007).…”

Dietary Influence of the Gut Microbiome Potential Hazards and Benefits

“…Of particular interest, a HFD decreased the amount of SCFAs in the colon, while the administration of butyrate, a SCFA, markedly decreased the incidence of duodenal carcinoma in HFD-mice [8]. There was also a sharp increase in Bifidobacteriaceae and Porphyromonadaceae, decrease in Helicobacteraceae, and partial reversal of the HFD-induced deficits on mucin production and immune function.…”

“…HFD has been shown to influence the inflammatory environment through a balanced effect on the gut microbiome, which has also been shown to affect the immune system [8]. In addition, specific bacterial species promoted by a high fiber diet produce SCFAs that have demonstrated a protective effect against cancer progression through anti-inflammatory as well as mucinous barrier functions [9].…”

“…Mice expressing the oncogene K-ras develop spontaneous serrated hyperplasia in the duodenum and downregulate the Paneth-cell mediated secretion of antimicrobial defensins [8]. The addition of a HFD alters the microbiome in mice and significantly decreased the amount of mucin on the intestinal lining, which serves as a barrier to microbial damage and maintains gut homeostasis [9].…”

“…This results in altered immunological and mucinous barriers of the intestinal lumen, which allows increased exposure to potential pathogenic effects of the individual's gut microbiome. When Schulz, Atay, Heringer et al performed fecal transplants from HFD K-ras mice into healthy K-ras mice, they conferred an elevated risk for small bowel carcinoma, while treatment with antibiotics eliminated HFD-induced carcinomas [8].…”