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Science (New York, N.Y.) Apr 2024A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater...
A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of , which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.
Topics: Animals; Female; Humans; Male; Mice; Bacteroides fragilis; Gastrointestinal Microbiome; Immune Checkpoint Inhibitors; Immunotherapy; Intestinal Mucosa; Mice, Inbred C57BL; Neoplasms; Vitamin D; Diet; Cell Line, Tumor; Calcifediol; Vitamin D-Binding Protein
PubMed: 38662827
DOI: 10.1126/science.adh7954 -
World Journal of Gastroenterology Aug 2022The gut microbiota is a complex community of microorganisms that inhabit the digestive tracts of humans, living in symbiosis with the host. Dysbiosis, characterized by... (Review)
Review
The gut microbiota is a complex community of microorganisms that inhabit the digestive tracts of humans, living in symbiosis with the host. Dysbiosis, characterized by an imbalance between the beneficial and opportunistic gut microbiota, is associated with several gastrointestinal disorders, such as irritable bowel syndrome (IBS); inflammatory bowel disease (IBD), represented by ulcerative colitis and Crohn's disease; and colorectal cancer (CRC). Dysbiosis can disrupt the mucosal barrier, resulting in perpetuation of inflammation and carcinogenesis. The increase in some specific groups of harmful bacteria, such as () and enterotoxigenic (ETBF), has been associated with chronic tissue inflammation and the release of pro-inflammatory and carcinogenic mediators, increasing the chance of developing CRC, following the inflammation-dysplasia-cancer sequence in IBD patients. Therefore, the aim of the present review was to analyze the correlation between changes in the gut microbiota and the development and maintenance of IBD, CRC, and IBD-associated CRC. Patients with IBD and CRC have shown reduced bacterial diversity and abundance compared to healthy individuals, with enrichment of and . Specific bacteria are also associated with the onset and progression of CRC, such as , , , , and ETBF. Future research can evaluate the advantages of modulating the gut microbiota as preventive measures in CRC high-risk patients, directly affecting the prognosis of the disease and the quality of life of patients.
Topics: Bacteria; Bacteroides fragilis; Colorectal Neoplasms; Dysbiosis; Escherichia coli; Gastrointestinal Microbiome; Humans; Inflammation; Inflammatory Bowel Diseases; Quality of Life; Sand
PubMed: 36157114
DOI: 10.3748/wjg.v28.i30.4053 -
Nature Communications Oct 2022Renal fibrosis is an inevitable outcome of various manifestations of progressive chronic kidney diseases (CKD). The need for efficacious treatment regimen against renal...
Renal fibrosis is an inevitable outcome of various manifestations of progressive chronic kidney diseases (CKD). The need for efficacious treatment regimen against renal fibrosis can therefore not be overemphasized. Here we show a novel protective role of Bacteroides fragilis (B. fragilis) in renal fibrosis in mice. We demonstrate decreased abundance of B. fragilis in the feces of CKD patients and unilateral ureteral obstruction (UUO) mice. Oral administration of live B. fragilis attenuates renal fibrosis in UUO and adenine mice models. Increased lipopolysaccharide (LPS) levels are decreased after B. fragilis administration. Results of metabolomics and proteomics studies show decreased level of 1,5-anhydroglucitol (1,5-AG), a substrate of SGLT2, which increases after B. fragilis administration via enhancement of renal SGLT2 expression. 1,5-AG is an agonist of TGR5 that attenuates renal fibrosis by inhibiting oxidative stress and inflammation. Madecassoside, a natural product found via in vitro screening promotes B. fragilis growth and remarkably ameliorates renal fibrosis. Our findings reveal the ameliorative role of B. fragilis in renal fibrosis via decreasing LPS and increasing 1,5-AG levels.
Topics: Adenine; Animals; Bacteroides fragilis; Biological Products; Disease Models, Animal; Fibrosis; Gastrointestinal Microbiome; Kidney; Kidney Diseases; Lipopolysaccharides; Mice; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2; Ureteral Obstruction
PubMed: 36241632
DOI: 10.1038/s41467-022-33824-6 -
Gut Microbes 2022Gut microbiota and its association with cancer development/treatment has been intensively studied during the past several years. Currently, there is a growing interest... (Review)
Review
Gut microbiota and its association with cancer development/treatment has been intensively studied during the past several years. Currently, there is a growing interest toward next-generation probiotics (NGPs) as therapeutic agents that alter gut microbiota and impact on cancer development. In the present review we focus on three emerging NGPs, namely , and as their presence in the digestive tract can have an impact on cancer incidence. These NGPs enhance gastrointestinal immunity, maintain intestinal barrier integrity, produce beneficial metabolites, act against pathogens, improve immunotherapy efficacy, and reduce complications associated with chemotherapy and radiotherapy. Notably, the use of NGPs in cancer patients does not have a long history and, although their safety remains relatively undefined, recently published data has shown that they are non-toxigenic. Notwithstanding, may promote colitis whereas enterotoxigenic stimulates chronic inflammation and participates in colorectal carcinogenesis. Nevertheless, the majority of strains provide a beneficial effect to the host, are non-toxigenic and considered as the best current NGP candidate. Overall, emerging studies indicate a beneficial role of these NGPs in the prevention of carcinogenesis and open new promising therapeutic options for cancer patients.
Topics: Animals; Antineoplastic Agents; Combined Modality Therapy; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Neoplasms; Probiotics
PubMed: 35167406
DOI: 10.1080/19490976.2022.2035659 -
Circulation Research Mar 2020High-salt diet is one of the most important risk factors for hypertension. Intestinal flora has been reported to be associated with high salt-induced hypertension...
RATIONALE
High-salt diet is one of the most important risk factors for hypertension. Intestinal flora has been reported to be associated with high salt-induced hypertension (hSIH). However, the detailed roles of intestinal flora in hSIH pathogenesis have not yet been fully elucidated.
OBJECTIVE
To reveal the roles and mechanisms of intestinal flora in hSIH development.
METHODS AND RESULTS
The abovementioned issues were investigated using various techniques including 16S rRNA gene sequencing, untargeted metabolomics, selective bacterial culture, and fecal microbiota transplantation. We found that high-salt diet induced hypertension in Wistar rats. The fecal microbiota of healthy rats could dramatically lower blood pressure (BP) of hypertensive rats, whereas the fecal microbiota of hSIH rats had opposite effects. The composition, metabolism, and interrelationship of intestinal flora in hSIH rats were considerably reshaped, including the increased corticosterone level and reduced and arachidonic acid levels, which tightly correlated with BP. The serum corticosterone level was also significantly increased in rats with hSIH. Furthermore, the above abnormalities were confirmed in patients with hypertension. The intestinal could inhibit the production of intestinal-derived corticosterone induced by high-salt diet through its metabolite arachidonic acid.
CONCLUSIONS
hSIH could be transferred by fecal microbiota transplantation, indicating the pivotal roles of intestinal flora in hSIH development. High-salt diet reduced the levels of and arachidonic acid in the intestine, which increased intestinal-derived corticosterone production and corticosterone levels in serum and intestine, thereby promoting BP elevation. This study revealed a novel mechanism different from inflammation/immunity by which intestinal flora regulated BP, namely intestinal flora could modulate BP by affecting steroid hormone levels. These findings enriched the understanding of the function of intestinal flora and its effects on hypertension.
Topics: Animals; Arachidonic Acid; Bacteroides fragilis; Blood Pressure; Corticosterone; Fecal Microbiota Transplantation; Feces; Gastrointestinal Microbiome; Humans; Hypertension; Intestines; Metabolomics; Rats, Wistar; Sodium Chloride, Dietary
PubMed: 32078445
DOI: 10.1161/CIRCRESAHA.119.316394 -
Science (New York, N.Y.) Feb 2018Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with...
Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of and Genes for colibactin () and toxin (), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with (expressing colibactin), and enterotoxigenic showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.
Topics: Adenomatous Polyposis Coli; Animals; Bacterial Toxins; Bacteroides fragilis; Biofilms; Carcinogenesis; Colon; Colonic Neoplasms; DNA Damage; Escherichia coli; Gastrointestinal Microbiome; Humans; Interleukin-17; Intestinal Mucosa; Metalloendopeptidases; Mice; Peptides; Polyketides; Precancerous Conditions
PubMed: 29420293
DOI: 10.1126/science.aah3648 -
Cell Host & Microbe Feb 2018Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc mice...
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.
Topics: Adenomatous Polyposis Coli Protein; Animals; Bacterial Toxins; Bacteroides fragilis; Carcinogenesis; Cell Line, Tumor; Colon; Colorectal Neoplasms; Enzyme Activation; Epithelial Cells; Female; Gene Deletion; HT29 Cells; Humans; Inflammation; Interleukin-17; Male; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells; Receptors, Interleukin-17; Receptors, Interleukin-8B; STAT3 Transcription Factor; Transcription Factor RelA
PubMed: 29398651
DOI: 10.1016/j.chom.2018.01.007 -
Cell Nov 2020Interferon (IFN)-Is are crucial mediators of antiviral immunity and homeostatic immune system regulation. However, the source of IFN-I signaling under homeostatic...
Interferon (IFN)-Is are crucial mediators of antiviral immunity and homeostatic immune system regulation. However, the source of IFN-I signaling under homeostatic conditions is unclear. We discovered that commensal microbes regulate the IFN-I response through induction of IFN-β by colonic DCs. Moreover, the mechanism by which a specific commensal microbe induces IFN-β was identified. Outer membrane (OM)-associated glycolipids of gut commensal microbes belonging to the Bacteroidetes phylum induce expression of IFN-β. Using Bacteroides fragilis and its OM-associated polysaccharide A, we determined that IFN-β expression was induced via TLR4-TRIF signaling. Antiviral activity of this purified microbial molecule against infection with either vesicular stomatitis virus (VSV) or influenza was demonstrated to be dependent on the induction of IFN-β. In a murine VSV infection model, commensal-induced IFN-β regulated natural resistance to virus infection. Due to the physiological importance of IFN-Is, discovery of an IFN-β-inducing microbial molecule represents a potential approach for the treatment of some human diseases.
Topics: Animals; Bacteroides fragilis; Bone Marrow Cells; Cell Membrane; Colon; Dendritic Cells; Female; Gene Expression Regulation; Glycolipids; Immunity, Innate; Interferon-beta; Male; Mice, Inbred C57BL; Microbiota; Polysaccharides, Bacterial; Toll-Like Receptor 4; Vesiculovirus; Virus Diseases
PubMed: 33212011
DOI: 10.1016/j.cell.2020.10.047 -
Nature Communications Sep 2023Gut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown...
Gut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors' fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPβ transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPβ transgenic mice.
Topics: Mice; Animals; Bacteroides fragilis; Mice, Transgenic; Gastrointestinal Microbiome; Alzheimer Disease; Dinoprostone; Microglia; RNA, Ribosomal, 16S; Bacteroides; Bacterial Infections; Hydroxy Acids
PubMed: 37673907
DOI: 10.1038/s41467-023-41283-w