Dietary Fructose Alters the Composition, Localization, and Metabolism of Gut Microbiota in Association With Worsening Colitis

Abstract

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

Diet Rich in Simple Sugars Promotes Pro-Inflammatory Response via Gut Microbiota Alteration and TLR4 Signaling

“…This experiment revealed that HSD microbiota induced immune cell redistribution, but did not aggravate DSS-induced colitis. This is an interesting finding because we transferred high-sucrose-associated microbiota, while two other studies using microbiota from high-fructose-or high-glucose-fed mice showed increased severity of colitis in exGF mice [33,34].…”

“…Colitis in HSD-fed mice was associated with pronounced weight reduction and infiltration of neutrophils into colon, together with increased levels of pro-inflammatory cytokines. Increased susceptibility to colitis has been also observed in other studies in mice fed with high-fructose [18,[32][33][34], high-glucose [18,34], or high-sucrose diets [17,34]. Unfortunately, none of these studies followed the effect of HSD in the model of chronic colitis, which allows to study repeated remissions and relapses typical for ulcerative colitis [54].…”

“…Muc2 −/− mice, which have increased gut permeability and high levels of Gram-negative bacteria in spleen and lymph nodes, are more prone to sepsis when challenged with a low dose of LPS [53]. Recent studies have shown that consumption of a high-fructose diet causes a reduction of mucus thickness, which results in close proximity of microbiota to intestinal epithelial cells [33,34]. Upon stimulation with microbes, epithelial cells produce greater amount of antimicrobial peptides Reg3β and Reg3γ [56].…”

“…There are clinical studies evaluating the effect of high intake of simple sugars in inflammatory bowel disease (IBD) patients, but the results are inconclusive [30,31]. Unfortunately, the discrepancies are also found in animal studies; nevertheless, most of them agree that high intake of simple sugars is detrimental in mice with colitis [17,[32][33][34]. Moreover, the effect of a high-sugar diet alone on immune system reactivity has been studied only marginally.…”

The Role of Diet in the Pathogenesis and Management of Inflammatory Bowel Disease: A Review

“…Desai and colleagues demonstrated that fed a low-fibre diet, the gut microbiota in mice resorted to mucus layer glycoproteins as a nutrient source, leading to erosion of the colonic mucus barrier, which serves as a primary defence against enteric pathogens [56]. When [34,35] Reduces risk of flares [59] Improves disease activity [60] FODMAPs Fermented by commensal bacteria in distal gut to produce gas and distension [62] Exclusion improves symptoms [63,65] Exclusion improves symptoms [63,65] Wheat/Gluten ATI proteins stimulate release of inflammatory cytokines, activate Toll-Like Receptors and induce a T-Cell response [69,70] Improved symptoms, especially in stricturing CD [71][72][73] Improved symptoms [71][72][73] Sugar Increased gut permeability Decreased microbial diversity Increased pro-inflammatory cytokines [66,67] Restriction improved clinical indices and mucosal healing in a small paediatric study [101] Reported by patients but no trials to support [21] Fat Saturated fat>increased taurine conjugation of hepatic bile acids>increases sulphate reducing microorganisms>promote pro-inflammatory T-cell response [102][103][104] n-3 PUFA anti-inflammatory vs. n-6 PUFA pro-inflammatory [105][106][107] Higher n-3 PUFA: n-6 PUFA ratio improves remission rates [108] High dietary fat intake [78], in particular myristic acid (found in palm oil, coconut oil and dairy fat) associated with flares [109] Emulsifiers Erode mucus barrier [110] Increase translocation of invasive E. Coli [111] Increase pro-inflammatory cytokines [110] No studies in humans No studies in humans Nanop...…”