The incidence of inflammatory bowel diseases is increasing worldwide, suggesting a potential role for dietary factors. Here, we demonstrate that a high fructose diet worsens colitis in a microbiota-dependent manner. Overall, this study highlights the importance of diet-microbe interactions in intestinal inflammation. BACKGROUND & AIMS: The incidence of inflammatory bowel diseases has increased over the last half century, suggesting a role for dietary factors. Fructose consumption has increased in recent years. Recently, a high fructose diet (HFrD) was shown to enhance dextran sodium sulfate (DSS)-induced colitis in mice. The primary objectives of the current study were to elucidate the mechanism(s) underlying the pro-colitic effects of dietary fructose and to determine whether this effect occurs in both microbially driven and genetic models of colitis. METHODS: Antibiotics and germ-free mice were used to determine the relevance of microbes for HFrD-induced worsening of colitis. Mucus thickness and quality were determined by histologic analyses. 16S rRNA profiling, in situ hybridization, metatranscriptomic analyses, and fecal metabolomics were used to determine microbial composition, spatial distribution, and metabolism. The significance of HFrD on pathogen and genetic-driven models of colitis was determined by using Citrobacter rodentium infection and Il10-/mice, respectively. RESULTS: Reducing or eliminating bacteria attenuated HFrDmediated worsening of DSS-induced colitis. HFrD feeding enhanced access of gut luminal microbes to the colonic mucosa

Although urban areas can be sources of abundant food for wildlife, anthropogenic foods may be lower in quality than natural food sources, with possible consequences for birds. We examined how urbanization and anthropogenic food were linked to cholesterol levels, condition, and survival of American Crows (Corvus brachyrhynchos). We collected cholesterol and landscape data from 140 crow nestlings along an urban-to-rural gradient in Davis, California, USA. We also ran a supplementation experiment with high-cholesterol fast food (McDonald’s cheeseburgers) on 86 nestlings in a rural population in Clinton, New York, USA. Plasma cholesterol increased with percentage of impervious surface along the urban-to-rural gradient. Cholesterol levels were sensitive to anthropogenic foods: crows supplemented with fast food cheeseburgers had higher cholesterol levels than unsupplemented crows. Elevated cholesterol levels had no detectable effects on survival and were associated with higher indices of body condition, although urbanization itself was linked to lower survival. Elevated cholesterol levels could indicate access to high-calorie, high-fat anthropogenic foods, which might, in some contexts, improve body condition, potentially offsetting other negative effects of urbanization. Observations over a longer time scale, assessing additional indices of health and fitness, are needed to evaluate long-term costs or benefits of elevated cholesterol for urban crows.

Diet is believed to be an important factor in the pathogenesis of Inflammatory Bowel Disease. High consumption of dietary fructose has been shown to exacerbate experimental colitis, an effect mediated through the gut microbiota. This study evaluated whether dietary alterations could attenuate the detrimental effects of a high fructose diet (HFrD) in experimental colitis. First, we determined whether the pro-colitic effects of a HFrD could be reversed by switching mice from a HFrD to a control diet. This diet change completely prevented HFrD-induced worsening of acute colitis, in association with a rapid normalization of the microbiota. Second, we tested the effects of dietary fiber, which demonstrated that psyllium was the most effective type of fiber for protecting against HFrD-induced worsening of acute colitis, compared to pectin, inulin or cellulose. In fact, supplemental psyllium nearly completely prevented the detrimental effects of the HFrD, an effect associated with a shift in the gut microbiota. We next determined whether the protective effects of these interventions could be extended to chronic colitis and colitis-associated tumorigenesis. Using the azoxymethane/dextran sodium sulfate model, we first demonstrated that HFrD feeding exacerbated chronic colitis and increased colitis-associated tumorigenesis. Using the same dietary changes tested in the acute colitis setting, we also showed that mice were protected from HFrD-mediated enhanced chronic colitis and tumorigenesis, upon either diet switching or psyllium supplementation. Taken together, these findings suggest that high consumption of fructose may enhance colon tumorigenesis associated with long-standing colitis, an effect that could be reduced by dietary alterations.

Patients with longstanding Inflammatory Bowel Disease, including ulcerative colitis and Crohn's disease, are at an increased risk of developing colorectal cancer (CRC). Over the past three decades, there has been a significant increase in the consumption of fructose, a monosaccharide that has been linked to increased growth of experimental intestinal tumors. Additionally, recent evidence shows that feeding a diet high in fructose worsens acute experimental colitis. The aims of the current study were to 1) determine if a high fructose diet (HFrD) exacerbated chronic colitis in mice and led to enhanced colorectal tumorigenesis and 2) evaluate the potential chemopreventive properties of dietary fiber in this context. To carry this out, the azoxymethane (AOM)/DSS model of colitis-associated colorectal neoplasia was utilized in male C57BL/6J mice. In comparison to control AIN93G diet, an isocaloric diet supplemented with fructose led to worse chronic colitis including weight suppression, worse diarrhea, colon shortening and a higher histologic score. Tumor incidence, number and size were all increased (Ps<0.001) in the HFrD compared to control diet group. Because eliminating fructose from the diet is impractical, it is important to identify other potential dietary constituents that may minimize its harmful effects. Dietary fiber has been suggested to be beneficial for reducing the severity of colitis. Therefore, we next determined whether the severity of HFrD-associated acute colitis was altered by dietary psyllium, pectin, inulin or cellulose fibers. In comparison to the other three fibers, psyllium protected against acute DSS- induced colitis. It also led to a significant shift in the fecal microbiota. Finally, we tested whether psyllium would attenuate the worsening of chronic colitis and colitis-associated colorectal neoplasia mediated by HFrD. Using the AOM/DSS model, we found that psyllium fiber protected against the exacerbation of chronic colitis mediated by HFrD with improved diarrhea, bleeding and histologic score. Consistent with its ability to suppress HFrD-mediated exacerbation of chronic colitis, psyllium markedly suppressed the increase in colorectal tumor incidence, number and size in mice that received the HFrD. Taken together, these results indicate that feeding a HFrD exacerbated chronic colitis leading to increased colitis-associated colorectal tumorigenesis. Supplemental psyllium fiber attenuated these procarcinogenic effects of a HFrD. Citation Format: Srijani Basu, Ryohei Nishiguchi, David C. Montrose, Hannah Staab, Xi Kathy Zhou, Hanhan Wang, Melanie Johncilla, Rhonda K. Yantiss, Andrew Dannenberg. Psyllium protects against high fructose diet induced exacerbation of colitis and colitis associated colorectal carcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3461.