Colorectal cancer in inflammatory bowel disease: a review of the role of gut microbiota and bacterial biofilms in disease pathogenesis.

The risk of colorectal cancer (CRC) is increased in patients with inflammatory bowel disease (IBD), particularly in extensive ulcerative colitis (UC) and Crohn's colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and pro-inflammatory properties by organizing into biofilms, potentially making them more resistant to the host's immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumor-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histologic inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. 5-aminosalicylates, commonly used in the treatment of UC, have antimicrobial and anti-carcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC via mechanisms independent of inflammation is still unknown. Further research is warranted to identify potential new microbial targets of therapy for chemoprevention of dysplasia and CRC in IBD.

Defining a universal measurement unit and scale for gross motor development.

Introduction: The ability of children to accomplish progressively more difficult gross motor tasks follows a predictable sequence that has been well documented as part of development. Current existing instruments were developed independently using classical test theory methods which led to the lack of a universal measurement scale and unit. The purpose of this study was to test a specification equation, anchored to commonly accepted and reproducible tasks in gross motor development, to generate a universal measurement scale and unit of measurement, called the Gross Motor (GM) unit. Methods: We rated component measures for each of the gross motor development tasks on the Gross Motor Function Measure-66 (GMFM). The GMFM is a gross motor development measure created with Rasch measurement theory to quantify observed difficulty levels measured on an interval scale. Component measures for body position, movement, and support were based on hypothesized contributions to gross motor development based on theory. Forward stepwise linear regression was used to test a specification equation. The specification equation was anchored to reference points to fix a unit size. Results: Our specification equation explained 87% of the variance in observed gross motor task difficulty. Predicted difficulty for gross motor tasks was strongly associated with observed task difficulty (r = 0.94, p < 0.0001). Our specification equation was anchored to 1) lying supine (0 GM units) and 2) walking unsupported (100 GM units) setting the size of the GM unit to 1/100 of the distance between lying supine and unsupported walking. Discussion: Our specification equation allows for experimental testing of gross motor development theories. This approach provides a framework for refining our understanding and measurement of gross motor development and creates a universal scale and unit. We expect that this will facilitate placing many, if not all, current gross motor development instruments on the same measurement scale.

Enrichment of Bacteroides fragilis and enterotoxigenic Bacteroides fragilis in CpG island methylator phenotype-high colorectal carcinoma.

OBJECTIVES: Data support that enterotoxigenic Bacteroides fragilis (ETBF) harbouring the Bacteroides fragilis toxin (bft) gene may promote colorectal tumourigenesis through the serrated neoplasia pathway. We hypothesized that ETBF may be enriched in colorectal carcinoma subtypes with high-level CpG island methylator phenotype (CIMP-high), BRAF mutation, and high-level microsatellite instability (MSI-high). METHODS: Quantitative PCR assays were designed to quantify DNA amounts of Bacteroides fragilis, ETBF, and each bft gene isotype (bft-1, bft-2, or bft-3) in colorectal carcinomas in the Health Professionals Follow-up Study and Nurses' Health Study. We used multivariable-adjusted logistic regression models with the inverse probability weighting method. RESULTS: We documented 4476 colorectal cancer cases, including 1232 cases with available bacterial data. High DNA amounts of Bacteroides fragilis and ETBF were positively associated with BRAF mutation (p ≤ 0.0003), CIMP-high (p ≤ 0.0002), and MSI-high (p < 0.0001 and p = 0.01, respectively). Multivariable-adjusted odds ratios (with 95% confidence interval) for high Bacteroides fragilis were 1.40 (1.06-1.85) for CIMP-high and 2.14 (1.65-2.77) for MSI-high, but 1.02 (0.78-1.35) for BRAF mutation. Multivariable-adjusted odds ratios for high ETBF were 2.00 (1.16-3.45) for CIMP-high and 2.86 (1.64-5.00) for BRAF mutation, but 1.09 (0.67-1.76) for MSI-high. Neither Bacteroides fragilis nor ETBF was associated with colorectal cancer-specific or overall survival. DISCUSSION: The tissue abundance of Bacteroides fragilis is associated with CIMP-high and MSI-high, whereas ETBF abundance is associated with CIMP-high and BRAF mutation in colorectal carcinoma. Our findings support the aetiological relevance of Bacteroides fragilis and ETBF in the serrated neoplasia pathway.

The microbial landscape of colorectal cancer.

Colorectal cancer (CRC) is a substantial source of global morbidity and mortality in dire need of improved prevention and treatment strategies. As our understanding of CRC grows, it is becoming increasingly evident that the gut microbiota, consisting of trillions of microorganisms in direct interface with the colon, plays a substantial role in CRC development and progression. Understanding the roles that individual microorganisms and complex microbial communities play in CRC pathogenesis, along with their attendant mechanisms, will help yield novel preventive and therapeutic interventions for CRC. In this Review, we discuss recent evidence concerning global perturbations of the gut microbiota in CRC, associations of specific microorganisms with CRC, the underlying mechanisms by which microorganisms potentially drive CRC development and the roles of complex microbial communities in CRC pathogenesis. While our understanding of the relationship between the microbiota and CRC has improved in recent years, our findings highlight substantial gaps in current research that need to be filled before this knowledge can be used to the benefit of patients.

The Role of the Gut Microbiome in Cancer: A Review, With Special Focus on Colorectal Neoplasia and Clostridioides difficile.

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.

Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors.

Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.

Subtle, persistent shaping of the gut microbiome by host genes: A critical determinant of host biology.

Although environmental impacts on the host microbiome have been well studied, it is less certain whether and how host genetics impact the microbiome. This commentary discusses current literature supporting host genetic influences on resident species and pathogenic microbes. Mechanistic experimental studies are warranted to understand host gene-microbiome interplay.

Understanding the mechanisms and translational implications of the microbiome for cancer therapy innovation.

The intersection of the microbiota and cancer and the mechanisms that define these interactions are a fascinating, rapidly evolving area of cancer biology and therapeutics. Here we present recent insights into the mechanisms by which specific bacteria or their communities contribute to carcinogenesis and discuss the bidirectional interplay between microbiota and host gene or epigenome signaling. We conclude with comments on manipulation of the microbiota for the therapeutic benefit of patients with cancer.

Gut colonization with an obesity-associated enteropathogenic microbe modulates the premetastatic niches to promote breast cancer lung and liver metastasis.

Introduction: Obesity, an independent risk factor for breast cancer growth and metastatic progression, is also closely intertwined with gut dysbiosis; and both obese state and dysbiosis promote each other. Enteric abundance of Bacteroides fragilis is strongly linked with obesity, and we recently discovered the presence of B. fragilis in malignant breast cancer. Given that enterotoxigenic B. fragilis or ETBF, which secretes B. fragilis toxin (BFT), has been identified as a procarcinogenic microbe in breast cancer, it is necessary to examine its impact on distant metastasis and underlying systemic and localized alterations promoting metastatic progression of breast cancer. Methods: We used syngeneic mammary intraductal (MIND) model harboring gut colonization with ETBF to query distant metastasis of breast cancer cells. Alterations in the immune network and cytokines/chemokines in the tumor microenvironment and distant metastatic sites were examined using flow cytometry, immunohistochemistry, and multiplex arrays. Results: ETBF infection initiates a systemic inflammation aiding in the establishment of the premetastatic niche formation in vital organs via increased proinflammatory and protumorigenic cytokines like IL17A, IL17E, IL27p28, IL17A/F, IL6, and IL10 in addition to creating a prometastatic immunosuppressive environment in the liver and lungs rich in myeloid cells, macrophages, and T regulatory cells. It induces remodeling of the tumor microenvironment via immune cell and stroma infiltration, increased vasculogenesis, and an EMT-like response, thereby encouraging early metastatic dissemination ready to colonize the conducive environment in liver and lungs of the breast tumor-bearing mice. Discussion: In this study, we show that enteric ETBF infection concomitantly induces systemic inflammation, reshapes the tumor immune microenvironment, and creates conducive metastatic niches to potentiate early dissemination and seeding of metastases to liver and lung tissues in agreement with the "seed and soil hypothesis." Our results also support the ETBF-induced "parallel model" of metastasis that advocates for an early dissemination of tumor cells that form metastatic lesions independent of the primary tumor load.

Is neighborhood deprivation index a risk factor for Staphylococcus aureus infections?

BACKGROUND: We assessed the association between neighborhood area deprivation index (ADI) and community-onset (co) and hospital-onset (ho) Staphylococcus aureus infection. METHODS: Demographic and clinical characteristics of patients admitted to 5 adult hospitals in the mid-Atlantic between 2016 and 2018 were obtained. The association of ADI with methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) S aureus infections was assessed using logistic regression models adjusting for severity of illness and days of admission. RESULTS: Overall, increasing ADI was associated with higher odds of co- and ho-MRSA and MSSA infection. In univariate analysis, Black race was associated with 44% greater odds of ho-MRSA infection (odds ratio [OR] 1.44; 95% CI 1.18-1.76) and Asian race (co-MRSA OR 0.355; Confidence Interval (CI) 0.240-0.525; co-MSSA OR 0.718; CI 0.557-0.928) and unknown race (co-MRSA OR 0.470; CI 0.365-0.606; co-MSSA OR 0.699; CI 0.577-0.848) was associated with lower odds of co-MSSA and co-MRSA infections. When both race and ADI were included in the model, Black race was no longer associated with ho-MRSA infections whereas Asian and unknown race remained associated with lower odds of co-MRSA and co-MSSA infection. In the multivariable logistic regression, ADI was consistently associated with increased odds of S aureus infection (co-MRSA OR 1.132; CI 1.064-1.205; co-MSSA OR 1.089; CI 1.030-1.15; ho-MRSA OR 1.29; CI 1.16-1.43: ho-MSSA OR 1.215; CI 1.096-1.346). CONCLUSIONS: The area deprivation index is associated with community and hospital-onset MRSA and MSSA infections.

Longitudinal Bile Acid Composition Changes Following Faecal Microbiota Transplantation for Clostridioides difficile Infection in Children With and Without Underlying Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Faecal microbiota transplant [FMT] is effective in treating recurrent Clostridioides difficile infection [CDI] and restores gut microbiota composition. This is unlikely to account for its entire mechanism of efficacy, as studies have shown that factors such as bile acids influence the risk of infection by affecting Clostridioides difficile germination. We therefore aimed to investigate longitudinal changes in the gut bile acid composition after FMT performed for recurrent CDI, in children with and without inflammatory bowel disease [IBD]. METHODS: Eight children received FMT; five had underlying IBD. Primary and secondary faecal bile acids were measured by liquid chromatography-mass spectrometry in recipients [pre-FMT and longitudinally post-FMT for up to 6 months] and donors. RESULTS: Pre-FMT, recipients had higher primary and lower secondary bile acid proportions compared with donors. Post-FMT, there was a gradual increase of secondary and decrease of primary bile acids. Whereas gut bacterial diversity had been shown to be restored in all children shortly after FMT, normalisation of bile acids to donor levels occurred only by 6 months. In children with IBD, although microbiota diversity returned to pre-FMT levels within 6 months, secondary bile acids remained at donor levels. CONCLUSIONS: The differences in bile acid profiles compared with gut bacterial diversity post-FMT suggests that interactions between the two may be more complex than previously appreciated and may contribute to FMT efficacy in different ways. This initial finding demonstrates the need to further investigate gut metabolites in larger cohorts, with longitudinal sampling to understand the mechanisms of FMT effectiveness.

Diet-Related and Gut-Derived Metabolites and Health Outcomes: A Scoping Review.

We conducted a scoping review to map available evidence about the health impact of gut microbiota-derived metabolites. We searched PubMed and Embase for studies that assessed the health impact of ten metabolites on any health condition: deoxycholate or deoxycholic acid (DCA), lithocholate or lithocholic acid (LCA), glycolithocholate or glycolithocholic acid, glycodeoxycholate or glycodeoxycholic acid, tryptamine, putrescine, d-alanine, urolithins, N-acetylmannosamine, and phenylacetylglutamine. We identified 352 eligible studies with 168,072 participants. Most (326, 92.6%) were case-control studies, followed by cohort studies (14, 4.0%), clinical trials (8, 2.3%), and cross-sectional studies (6, 1.7%). Most studies assessed the following associations: DCA on hepatobiliary disorders (64 studies, 7976 participants), colorectal cancer (19 studies, 7461 participants), and other digestive disorders (27 studies, 2463 participants); LCA on hepatobiliary disorders (34 studies, 4297 participants), colorectal cancers (14 studies, 4955 participants), and other digestive disorders (26 studies, 2117 participants); putrescine on colorectal cancers (16 studies, 94,399 participants) and cancers excluding colorectal and hepatobiliary cancers (42 studies, 4250 participants). There is a need to conduct more prospective studies, including clinical trials. Moreover, we identified metabolites and conditions for which systemic reviews are warranted to characterize the direction and magnitude of metabolite-disease associations.

Microbial metabolites damage DNA.

Unexpected members of the gut microbiota produce diverse host cell genotoxins.