Colonic aberrant crypt formation accompanies an increase of opportunistic pathogenic bacteria in C57BL/6 mice fed a high-fat diet

Authors: Zeng, Huawei; ISHAQ, SUZANNE - MONTANA STATE UNIVERSITY; LIU, ZHENHUA - UNIVERSITY OF MASSACHUSETTS; Bukowski, Michael

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/7/2017
Publication Date: 11/10/2017
Citation: Zeng, H., Ishaq, S.L., Liu, Z., Bukowski, M.R. 2017. Colonic aberrant crypt formation accompanies an increase of opportunistic pathogenic bacteria in C57BL/6 mice fed a high-fat diet. Journal of Nutritional Biochemistry. https://doi.org/10.1016/j.jnutbio.2017.11.001.

Interpretive Summary: Colon cancer is a major public health issue in the US, with approximately 137,000 new cases and 50,000 deaths per year. Obesity has emerged as one of the leading environmental risk factors for colon cancer development as supported by epidemiological studies as well as controlled experimental animal studies. Recent studies have shown that accumulation of excess body fat is associated with chronic inflammation and changes in the gut bacteria. However, little is known about the interplay between obesity related colonic inflammation, cancer and hindgut bacterial composition. In this study, we demonstrate that obesity enhances development of colonic tumors in mice, inflammation, and an increase in opportunistic pathogenic bacteria in the hind-gut. These data provide novel insights into obesity-related cancer risk and will be useful for scientists who are interested in the prevention of obesity-related colon cancer.

Technical Abstract: Background: The increasing worldwide incidence of colon cancer has been linked to obesity and consumption of a high-fat western diet, but the mechanism underlying this relationship remains to be determined. Objective: We tested the hypothesis that a high-fat diet promotes aberrant crypt (AC) formation. Moreover, we examined the extent to which obesity and AC formation were associated with a dysbiosis in the hindgut. Methods: Four-week-old male C57/BL6 mice were fed a modified AIN93G diet containing 16% or 45% of energy from fat (n=25/group) for 14 weeks. We used biochemical, histological and multi-omics approaches to characterize the interplay between azoxymethane (AOM)-induced colonic ACF, inflammatory status and microbiome composition. Results: Mice receiving the high-fat diet (HFD, 45% fat, energy) exhibited increased plasma leptin, body weight, body fat composition and inflammatory cell infiltration in the ileum compared with those on a modified AIN93G control (AIN, 16% fat, energy) diet. Consistent with the gut inflammatory phenotype, we observed an increase in colonic ACF, plasma interleukin 6 (IL6), tumor necrosis factor alpha (TNF alpha), monocyte chemoattractant protein 1 (MCP1), and inducible nitric oxide synthase (iNOS) in the ileum of the HFD-AOM group compared with those in the AIN-AOM group. Although the HFD and AIN groups did not differ in bacterial species number, the HFD and AIN diets resulted in different bacterial community structures in the hindgut. With AOM treatment, the abundance of certain short chain fatty acid (SCFA) producing bacteria (e.g., Barnesiella) and fecal SCFA (e.g., acetic acid) content were lower in the HFD-AOM group compared with those in the AIN and AIN-AOM groups. Furthermore, we identified a high abundance of Anaeroplasma bacteria; an opportunistic pathogen, concurrent with ACF formation in the HFD-AOM group. Conclusions: We demonstrate that a high-fat diet promotes AC formation concurrent with an increase of opportunistic pathogenic bacteria in the inflammatory hindgut of C57BL/6 mice.