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Understanding the factors that drive formation of particular types of cancer can aid efforts to develop better diagnostics or treatments. The identification of a bacterial subspecies with a connection to colon cancer has clinical relevance. Revised view of the bacterial subspecies associated with colon cancer. [ABSTRACT FROM AUTHOR]

Human gut microbial species found to associate with clinical responses to immune checkpoint inhibitors (ICIs) are often tested in mice using fecal microbiota transfer (FMT), wherein tumor responses in recipient mice may recapitulate human responses to ICI treatment. However, many FMT studies have reported only limited methodological description, details of murine cohorts, and statistical methods. To investigate the reproducibility and robustness of gut microbial species that impact ICI responses, we performed human to germ-free mouse FMT using fecal samples from patients with non-small cell lung cancer who had a pathological response or nonresponse after neoadjuvant ICI treatment. R-FMT mice yielded greater anti-tumor responses in combination with anti-PD-L1 treatment compared to NR-FMT, although the magnitude varied depending on mouse cell line, sex, and individual experiment. Detailed investigation of post-FMT mouse microbiota using 16S rRNA amplicon sequencing, with models to classify and correct for biological variables, revealed a shared presence of the most highly abundant taxa between the human inocula and mice, though low abundance human taxa colonized mice more variably after FMT. Multiple Clostridium species also correlated with tumor outcome in individual anti-PD-L1-treated R-FMT mice. RNAseq analysis revealed differential expression of T and NK cell-related pathways in responding tumors, irrespective of FMT source, with enrichment of these cell types confirmed by immunohistochemistry. This study identifies several human gut microbial species that may play a role in clinical responses to ICIs and suggests attention to biological variables is needed to improve reproducibility and limit variability across experimental murine cohorts. [ABSTRACT FROM AUTHOR]

G protein-coupled receptor (GPR)35 is highly expressed in the gastro-intestinal tract, predominantly in colon epithelial cells (CEC), and has been associated with inflammatory bowel diseases (IBD), suggesting a role in gastrointestinal inflammation. The enterotoxigenic Bacteroides fragilis (ETBF) toxin (BFT) is an important virulence factor causing gut inflammation in humans and animal models. We identified that BFT signals through GPR35. Blocking GPR35 function in CECs using the GPR35 antagonist ML145, in conjunction with shRNA knock-down and CRISPRcas-mediated knock-out, resulted in reduced CEC-response to BFT as measured by E-cadherin cleavage, beta-arrestin recruitment and IL-8 secretion. Importantly, GPR35 is required for the rapid onset of ETBF-induced colitis in mouse models. GPR35-deficient mice showed reduced death and disease severity compared to wild-type C57Bl6 mice. Our data support a role for GPR35 in the CEC and mucosal response to BFT and underscore the importance of this molecule for sensing ETBF in the colon. Boleij et al. show that G protein-coupled receptor 35 (GPR35) regulates the responses to enterotoxigenic Bacteroides fragilis (ETBF) in colonic epithelial cells. They find that GPR35-deficiency nearly protected mice from ETBF-induced death, suggesting the importance of GPR35 in sensing ETBF in the colon. [ABSTRACT FROM AUTHOR]

Recent studies have raised interest in the possibility that dysbiosis of the gut microbiome (i.e., the communities of bacteria residing in the intestine) in HIV-infected patients could contribute to chronic immune activation, and, thus, to elevated mortality and increased risk of inflammation-related clinical diseases (e.g., stroke, cardiovascular disease, cancer, long-bone fractures, and renal dysfunction) found even in those on effective antiretroviral therapy. Yet, to date, a consistent pattern of HIV-associated dysbiosis has not been identified. What is becoming clear, however, is that status as a man who has sex with men (MSM) may profoundly impact the structure of the gut microbiota, and that this factor likely confounded many HIV-related intestinal microbiome studies. However, what factor associated with MSM status drives these gut microbiota-related changes is unclear, and what impact, if any, these changes may have on the health of MSM is unknown. In this review, we outline available data on changes in the structure of the gut microbiome in HIV, based on studies that controlled for MSM status. We then examine what is known regarding the gut microbiota in MSM, and consider possible implications for research and the health of this population. Lastly, we discuss knowledge gaps and needed future studies. [ABSTRACT FROM AUTHOR]

Background: Gut microbiota likely impact obesity and metabolic diseases. We evaluated the changes in gut microbiota after surgical versus medical weight loss in adults with diabetes and obesity. Methods: We performed 16S rRNA amplicon sequencing to identify the gut microbial composition at baseline and at 10% weight loss in adults with diabetes who were randomized to medical weight loss (MWL, n = 4), adjustable gastric banding (AGB, n = 4), or Roux-en-Y gastric bypass (RYGB, n = 4). Results: All participants were female, 75% reported black race with mean age of 51 years. At similar weight loss amount and glycemic improvement, the RYGB group had the most number of bacterial species (10 increased, 1 decreased) that significantly changed (p < 0.05) in relative abundance. Alpha-diversity at follow-up was significantly lower in AGB group compared to MWL and RYGB (observed species for AGB vs. MWL, p = 0.0093; AGB vs. RYGB, p = 0.0093). The relative abundance of Faecalibacterium prausnitzii increased in 3 participants after RYGB, 1 after AGB, and 1 after MWL. Conclusions: At similar weight loss and glycemic improvement, the greatest alteration in gut microbiota occurred after RYGB with an increase in the potentially beneficial bacterium, F. prausnitzii. Gut microbial diversity tended to decrease after AGB and increase after RYGB and MWL. Future studies are needed to determine the impact and durability of gut microbial changes over time and their role in long-term metabolic improvement after bariatric surgery in adults with type 2 diabetes. Clinical Trial Registration: NCTDK089557—ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

These steps will hasten our ability to bring new, reliable microbiome-derived tools and therapies to yield our desired outcomes, cancer prevention, and life-extending, life-improving therapies that complement traditional cancer therapy approaches. A key first is expanding the investment in longitudinal studies in high-risk children and adults with hereditary cancer syndromes and/or those with pre-neoplasia or early-stage cancers where microbiome impacts from prior therapies should be lessened. The unexpected observation of a pancreatic microbiome with potential oral and/or fecal microbiome contributors presents the opportunity to provide a new entry point for understanding and manipulating this deadly cancer. [Extracted from the article]

The gut microbiota has been hailed as an accessory organ, with functions critical to the host including dietary metabolic activities and assistance in the development of a proper functioning immune system. However, an aberrant microbiota (dysbiosis) may influence disease processes such as colorectal cancer. In this review, we discuss recent advances in our understanding of the contributions of the microbiota to prevention, initiation/progression, and treatment of colorectal cancer, with a major focus on biofilms and the antimicrobial and antitumoural immune response. [ABSTRACT FROM AUTHOR]

The intestinal flora may promote colon tumor formation. Here we explore immunologic mechanisms of colonic carcinogenesis by a human colonic bacterium, enterotoxigenic Bacteroides fragilis (ETBF). ETBF that secretes B. fragilis toxin (BFT) causes human inflammatory diarrhea but also asymptomatically colonizes a proportion of the human population. Our results indicate that whereas both ETBF and nontoxigenic B. fragilis (NTBF) chronically colonize mice, only ETBF triggers colitis and strongly induces colonic tumors in multiple intestinal neoplasia (Min) mice. ETBF induces robust, selective colonic signal transducer and activator of transcription-3 (Stat3) activation with colitis characterized by a selective T helper type 17 (TH17) response distributed between CD4+ T cell receptor-αβ (TCRαβ)+ and CD4–8–TCRγδ+ T cells. Antibody-mediated blockade of interleukin-17 (IL-17) as well as the receptor for IL-23, a key cytokine amplifying TH17 responses, inhibits ETBF-induced colitis, colonic hyperplasia and tumor formation. These results show a Stat3- and TH17-dependent pathway for inflammation-induced cancer by a common human commensal bacterium, providing new mechanistic insight into human colon carcinogenesis. [ABSTRACT FROM AUTHOR]

The human intestine provides an expansive interface for interactions with the microflora. Increasing data support the hypothesis that host-microflora relationships are markedly dynamic, contributing to host health and disease pathogenesis. Despite outnumbering human cells 10-fold, the microflora most often assist the host through symbiotic relationships. The microflora are involved in maximizing host utilization of nutrients, induction of host immune responses, and promotion of intestinal cell and mucosal development. However, evolving data suggest that disturbances in this symbiotic relationship can lead the microflora to be pathogenic in diverse conditions such as inflammatory bowel disease, irritable bowel disease, obesity, graft-versus-host disease, HIV immunopathogenesis, and possibly cancer. Defining those microflora attributes that result in health and those that trigger disease is key to harnessing the microflora to promote human health. [ABSTRACT FROM AUTHOR]