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

The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.

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.

Summary Studies with gene‐deficient and gnotobiotic mice have identified many host and microbial factors that contribute to induced colitis, but information on whether specific factors determine susceptibility under more physiological conditions is lacking. Using wild‐type strains that differ in their IgA response but harbor a diverse gut microbiome, we found that the IgA‐high strain CBA/CaJ (CBA) is resistant to acute colitis induced with dextran sodium sulfate (DSS), unlike the IgA‐low strain C57BL/6 (B6). Resistance was associated with extensive IgA‐coating of fecal bacteria, lower fecal bacterial loads and greater abundance of barrier‐protective transcripts in colonic tissues under homeostatic conditions. Fecal microbial transplant (FT) experiments revealed that disease induction in B6 mice was associated with a cohort of bacteria that are not targeted by IgA. However, CBA mice continued to be resistant to colitis induction following FTs from B6 mice, indicating that they are able to contain such colitogenic members. In support of a role for bacterial exclusion in resistance, oral administration of immunoglobulins decreased DSS‐induced disease in B6 mice. In F1 mice derived separately with CBA and B6 dams and in F1 mice backcrossed to the two parental strains, resistance segregated with the IgA response of the pups and not with barrier‐associated transcripts or bacterial loads. Interestingly, B6 pups foster‐nursed on CBA dams continued to be susceptible in later life, whereas CBA pups foster‐nursed on B6 dams continued to be resistant. Together, the data indicate that a high‐IgA response in adult life can protect against colitis and compensate for IgA deficiency in early life.

The immune system interacts with cancer cells in multiple intricate ways that can shield the host against hyper-proliferation but can also contribute to malignancy. Understanding the protective roles of the immune system in its interaction with cancer cells can help device new and alternate therapeutic strategies. Many immunotherapeutic methodologies, including adaptive cancer therapy, cancer peptide vaccines, monoclonal antibodies, and immune checkpoint treatment, have transformed the traditional cancer treatment landscape. However, many questions remain unaddressed. The development of personalized combination therapy and neoantigen-based cancer vaccines would be the avant-garde approach to cancer treatment. Desirable chemotherapy should be durable, safe, and target-specific. Managing both tumor (intrinsic factors) and its microenvironment (extrinsic factors) are critical for successful immunotherapy. This review describes current approaches and their advancement related to monoclonal antibody-related clinical trials, new cytokine therapy, a checkpoint inhibitor, adoptive T cell therapy, cancer vaccine, and oncolytic virus. Supplementary Information The online version contains supplementary material available at 10.1007/s11033-022-07525-8.