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The gut microbiome has coevolved with humans to aid in physiologic functions and prevent disease. An increasing prevalence of gut dysbiosis in modern society exists and has strong linkages to multiple disease processes common in the developed world. Mechanisms for microbiome-human interactions that impact host homeostasis include bacterial metabolite/toxin production, biofilm formation with mucous layer infiltration, and host immune system modulation. Most of this crosstalk occurs at the epithelial layer of the gut, and as such the role of these interactions in the induction of colorectal cancer—a highly prevalent disease globally and one undergoing significant epidemiologic shifts—is under increasing scrutiny. Although multiple individual gut bacteria have been hypothesized as possible driver organisms in the oncogenic process, no bacterium has been definitively identified as a causal agent of colorectal cancer, suggesting that host lifestyle factors, microbiome community interactions, and the mucosal and/or systemic immune response may play a critical role in the process. Recent evidence has emerged implicating the ubiquitous human pathogen Clostridioides difficile as a possible promoter of colorectal cancer through chronic toxin-mediated cellular changes. Although much remains to be defined regarding the natural history of infections caused by this pathogen and its potential for oncogenesis, it provides a strong model for the role of both individual bacteria and of the gut microbial community as a whole in the development of colorectal cancer. The gut microbiome can play a crucial role in the development and prevention of human cancers through a variety of individual bacterial and broader community mechanisms. Emerging evidence suggests that Clostridioides difficile could be an important contributor to this balance. [ABSTRACT FROM AUTHOR]

Obesity is a complex metabolic disease caused, in part, by the interaction between an individual's genetics, metabolism, and environment. Emerging evidence supports the role of gut microbiota in mediating the interaction between the host and environment by extracting energy from food otherwise indigestible by the host and producing metabolites and cytokines that affect host metabolism. Furthermore, gut microbial imbalance or dysbiosis has been shown in metabolic diseases including obesity, and recent studies are beginning to unravel the mechanisms involved. The gut microbiota affects host metabolism and obesity through several pathways involving gut barrier integrity, production of metabolites affecting satiety and insulin resistance, epigenetic factors, and metabolism of bile acids and subsequent changes in metabolic signaling. While the field of gut microbiome and its role in obesity is early in its stage of development, it holds a promising future in providing us with novel therapeutic targets that may restore the gut microbiome to a healthy state and help in the prevention and treatment of obesity. [ABSTRACT FROM AUTHOR]

The human body comprises fewer host cells than bacterial cells, most of which are obligate anaerobes residing in the gut. The symbiont Bacteroides fragilis constitutes a relatively small proportion (up to 1%-2%) of cultured fecal bacteria, but colonizes most humans. There are 2 classes of B. fragilis distinguished by their ability to secrete a zinc-dependent metalloprotease toxin, B. fragilis toxin (BFT). Strains that do not secrete BFT are nontoxigenic B. fragilis (NTBF), and those that do are called enterotoxigenic B. fragilis (ETBF). ETBF can induce clinical pathology, including inflammatory diarrhea, although asymptomatic colonization may be common. Intestinal inflammation is mediated by BFT, as yet the only known virulence factor of ETBF. Recent experimental evidence demonstrating that ETBF-driven colitis promotes colon tumorigenesis has generated interest in the potential contribution of ETBF to human colon carcinogenesis. Critical questions about the epidemiology of chronic, subclinical human colonization with ETBF and its impact on the biology of the colon need to be addressed. [ABSTRACT FROM AUTHOR]

The article discusses gut microbiota and how it acts as a critical determinant for immunotherapy responses. It cites a research by L. F. Mager published in this issue, which reveals how inosine produced by specific gut bacteria improves immune checkpoint inhibitor (ICI) efficacy in numerous mouse models. It mentions the need to understand the biosynthetic metabolite redundancy among bacterial species.

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]

The human microbiota is a complex ecosystem of diverse microorganisms consisting of bacteria, viruses, and fungi residing predominantly in epidermal and mucosal habitats across the body, such as skin, oral cavity, lung, intestine and vagina. These symbiotic communities in health, or dysbiotic communities in disease, display tremendous interaction with the local environment and systemic responses, playing a critical role in the host’s nutrition, immunity, metabolism and diseases including cancers. While the profiling of normal microbiota in healthy populations is useful and necessary, more recent studies have focused on the microbiota associated with disease, particularly cancers. In this paper, we review current evidence on the role of the human microbiota in four cancer types (colorectal cancer, head and neck cancer, pancreatic cancer, and lung cancer) proposed as affected by both the oral and gut microbiota, and provide a perspective on current gaps in the knowledge of the microbiota and 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]

Background Whether human immunodeficiency virus (HIV) infection impacts gut microbial α-diversity is controversial. We reanalyzed raw 16S ribosomal RNA (rRNA) gene sequences and metadata from published studies to examine α-diversity measures between HIV-uninfected (HIV–) and HIV-infected (HIV+) individuals. Methods We conducted a systematic review and individual level meta-analysis by searching Embase, Medline, and Scopus for original research studies (inception to 31 December 2017). Included studies reported 16S rRNA gene sequences of fecal samples from HIV+ patients. Raw sequence reads and metadata were obtained from public databases or from study authors. Raw reads were processed through standardized pipelines with use of a high-resolution taxonomic classifier. The χ2 test, paired t tests, and generalized linear mixed models were used to relate α-diversity measures and clinical metadata. Results Twenty-two studies were identified with 17 datasets available for analysis, yielding 1032 samples (311 HIV–, 721 HIV+). HIV status was associated with a decrease in measures of α-diversity (P <.001). However, in stratified analysis, HIV status was associated with decreased α-diversity only in women and in men who have sex with women (MSW) but not in men who have sex with men (MSM). In analyses limited to women and MSW, controlling for HIV status, women displayed increased α-diversity compared with MSW. Conclusions Our study suggests that HIV status, sexual risk category, and gender impact gut microbial community α-diversity. Future studies should consider MSM status in gut microbiome analyses. [ABSTRACT FROM AUTHOR]

Background The microbiome influences malaria parasite fitness and transmission efficiency in mosquitoes and appears to affect malaria dynamics in mammalian hosts as well. Nascent research examining the interrelationship of malaria and the mammalian microbiome has yielded interesting insights inviting further study. Methods We conducted a systematic review of the literature examining associations between the microbiome and malaria in mammalian hosts. An electronic search algorithm was adapted to PubMed, MEDLINE, Scopus, Embase, and Web of Science, and reference lists of relevant sources were manually searched. Identified studies were screened and assessed independently by 2 authors, and results were compiled in a qualitative synthesis of the evidence. Results Ten relevant studies were identified. They demonstrate associations between certain intestinal communities and protection against Plasmodium infection and modulation of disease severity. Plasmodium infection acutely and reversibly reshapes gut microbial composition in mice. The makeup of human skin microbial communities may influence mosquito attraction and thus disease transmission. Conclusions Early research supports a relationship between malaria and the microbiome. The evidence is incomplete, but the observed associations are evocative and signal a promising avenue of inquiry. Microbiome-based studies of malaria can be readily integrated into field-based research. [ABSTRACT FROM AUTHOR]

Background Individuals born in 1990 have twice the risk of developing colon cancer and four times the risk of developing rectal cancer as those born in 1950. The gut microbiome is being proposed as a potential contributor to this difference because of the surge in obesity in the United States, the link between obesity and gut dysbiosis, and the growing number of studies which have associated a dysbiotic gut microbiome with CRC. Enterotoxigenic Bacteroides fragilis (ETBF) is one of the bacteria most studied in relation to CRC development; it is found at a higher frequency in both the stool and mucosa of CRC patients, and it rapidly induces tumor formation in an Apc min/+ mouse model of CRC. In this model, tumor formation typically occurs via loss of heterozygosity (LOH) of the Apc gene, the genetic mutation found in approximately 80% of sporadic CRC cases. ETBF produces a potent exotoxin (BFT) which induces E-cadherin cleavage, β-catenin nuclear localization and colonic epithelial cell proliferation. But we still do not understand how these downstream effects cause lasting changes in the genome of colon epithelial cells that then initiate tumor formation and growth. As cancer is ultimately a disease that arises and progresses via changes in the genome, understanding these interactions is essential. Methods We hypothesize that ETBF induces DNA mutations via BFT that encourage tumor formation, and enhance tumor growth. To test this hypothesis, we performed whole-exome sequencing on tumors and normal tissue isolated from Apc min/+ mice after ETBF or sham inoculation. Additionally, we isolated colon organoids from Apc min/+ mouse normal tissue (colonoids) and Apc min/+ mouse tumors (tumoroids) after ETBF or sham inoculation. We performed in vitro DNA damage assays and qPCR for Apc LOH on these colon organoids. Results Our preliminary data indicate that ETBF-induced tumors have lower rates of Apc LOH and that double-stranded DNA breaks are observed as soon as 3-hours after BFT treatment of colonoids and as soon as 72-hours after ETBF inoculation. Conclusion These data suggest that in vivo, ETBF may induce mutations in cancer-driver genes which cause tumor formation via pathways other than somatic recombination at the Apc locus, a result we are now testing with additional (N = 19) whole-exome tumor sequencing in-progress. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]