Significance: We demonstrate, to our knowledge for the first time, that bacterial biofilms are associated with colorectal cancers, one of the leading malignancies in the United States and abroad. Colon biofilms, dense communities of bacteria encased in a likely complex matrix that contact the colon epithelial cells, are nearly universal on right colon tumors. Most remarkably, biofilm presence correlates with bacterial tissue invasion and changes in tissue biology with enhanced cellular proliferation, a basic feature of oncogenic transformation occurring even in colons without evidence of cancer. Microbiome profiling revealed that biofilm communities on paired normal mucosa cluster with tumor microbiomes but lack distinct taxa differences. This work introduces a previously unidentified concept whereby microbial community structural organization exhibits the potential to contribute to disease progression.

Colorectal cancer (CRC) remains the third most common cancer worldwide, with a growing incidence among young adults. Multiple studies have presented associations between the gut microbiome and CRC, suggesting a link with cancer risk. Although CRC microbiome studies continue to profile larger patient cohorts with increasingly economical and rapid DNA sequencing platforms, few common associations with CRC have been identified, in part due to limitations in taxonomic resolution and differences in analysis methodologies. Complementing these taxonomic studies is the newly recognized phenomenon that bacterial organization into biofilm structures in the mucus layer of the gut is a consistent feature of right-sided (proximal), but not left-sided (distal) colorectal cancer. In the present study, we performed 16S rRNA gene amplicon sequencing and biofilm quantification in a new cohort of patients from Malaysia, followed by a meta-analysis of eleven additional publicly available data sets on stool and tissue-based CRC microbiota using Resphera Insight, a high-resolution analytical tool for species-level characterization. Results from the Malaysian cohort and the expanded meta-analysis confirm that CRC tissues are enriched for invasive biofilms (particularly on right-sided tumors), a symbiont with capacity for tumorigenesis (Bacteroides fragilis), and oral pathogens includingFusobacterium nucleatum,Parvimonas micra, andPeptostreptococcus stomatis. Considered in aggregate, species from the Human Oral Microbiome Database are highly enriched in CRC. Although no detected microbial feature was universally present, their substantial overlap and combined prevalence supports a role for the gut microbiota in a significant percentage (>80%) of CRC cases.

IL17-producing Th17 cells, generated through a STAT3-dependent mechanism, have been shown to promote carcinogenesis in many systems, including microbe-driven colon cancer. Additional sources of IL17, such as γδ T cells, become available under inflammatory conditions, but their contributions to cancer development are unclear. In this study, we modeled Th17-driven colon tumorigenesis by colonizing MinApc+/− mice with the human gut bacterium, enterotoxigenic Bacteroides fragilis (ETBF), to investigate the link between inflammation and colorectal cancer. We found that ablating Th17 cells by knocking out Stat3 in CD4+ T cells delayed tumorigenesis, but failed to suppress the eventual formation of colonic tumors. However, IL17 blockade significantly attenuated tumor formation, indicating a critical requirement for IL17 in tumorigenesis, but from a source other than Th17 cells. Notably, genetic ablation of γδ T cells in ETBF-colonized Th17-deficient Min mice prevented the late emergence of colonic tumors. Taken together, these findings support a redundant role for adaptive Th17 cell- and innate γδT17 cell-derived IL17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources. Cancer Res; 76(8); 2115–24. ©2016 AACR.

Escherichia coli (E. coli) from the B2 phylogenetic group is implicated in colorectal cancer (CRC) as it possesses a genomic island, termed polyketide synthetase (pks), which codes for the synthesis of colibactin, a genotoxin that induces DNA damage, cell cycle arrest, mutations and chromosomal instability in eukaryotic cells. The aim of this study was to detect and compare the prevalence of E. coli expressing pks (pks⁺ E. coli) in CRC patients and healthy controls followed by investigating the virulence triggered by pks⁺ E. coli using an in-vitro model. Mucosal colon tissues were collected and processed to determine the presence of pks⁺ E. coli. Thereafter, primary colon epithelial (PCE) and colorectal carcinoma (HCT116) cell lines were used to detect cytopathic response to the isolated pks⁺ E. coli strains. Our results showed 16.7% and 4.3% of CRC and healthy controls, respectively were pks⁺ E. coli. Further, PCE displayed syncytia and cell swelling and HCT116 cells, megalocytosis, in response to treatment with the isolated pks⁺ E. coli strains. In conclusion, pks⁺ E. coli was more often isolated from tissue of CRC patients compared to healthy individuals, and our in-vitro assays suggest these isolated strains may be involved in the initiation and development of CRC.

Colorectal cancer (CRC) is ranked the third most common cancer in human worldwide. However, the exact mechanisms of CRC are not well established. Furthermore, there may be differences between mechanisms of CRC in the Asian and in the Western populations. In the present study, we utilized a liquid chromatography-mass spectrometry (LC-MS) metabolomic approach supported by the 16S rRNA next-generation sequencing to investigate the functional and taxonomical differences between paired tumor and unaffected (normal) surgical biopsy tissues from 17 Malaysian patients. Metabolomic differences associated with steroid biosynthesis, terpenoid biosynthesis and bile metabolism could be attributed to microbiome differences between normal and tumor sites. The relative abundances of Anaerotruncus, Intestinimonas and Oscillibacter displayed significant relationships with both steroid biosynthesis and terpenoid and triterpenoid biosynthesis pathways. Metabolites involved in serotonergic synapse/ tryptophan metabolism (Serotonin and 5-Hydroxy-3-indoleacetic acid [5-HIAA]) were only detected in normal tissue samples. On the other hand, S-Adenosyl-L-homocysteine (SAH), a metabolite involves in methionine metabolism and methylation, was frequently increased in tumor relative to normal tissues. In conclusion, this study suggests that local microbiome dysbiosis may contribute to functional changes at the cancer sites. Results from the current study also contributed to the list of metabolites that are found to differ between normal and tumor sites in CRC and supported our quest for understanding the mechanisms of carcinogenesis.

Background: Common cold coronaviruses (ccCoVs) and influenza virus are common infectious agents causing upper respiratory tract infections (RTIs). However, clinical symptoms, comorbidities, and health effects of ccCoV infection remain understudied. Methods: A retrospective study evaluated 3,935 outpatients with acute upper RTI at a tertiary teaching hospital. The presence of ccCoV and influenza virus was determined by multiplex molecular assay. The demographic, clinical symptoms, and health outcomes were compared between patients with ccCoV (n = 205) and influenza (n = 417) infections. Multivariable logistic regression was employed to evaluate predictors and health outcomes over a one-year follow-up. Results: Sore throat, nasal discharge, headache, and myalgia were more predominant in ccCoV infection; fever was common in influenza. Most patients reported moderate symptoms severity (49.8% ccCoV, 56.1% influenza). Subsequent primary care visits with symptoms of RTI within a year were comparable for both infections (27.3% ccCoV vs. 27.6% influenza). However, patients with influenza reported increased primary care visits for non-RTI episodes and all-cause hospital admission. Baseline comorbidities were associated with increased primary care visits with symptoms of RTI in either ccCoV (adjusted odds ratio [aOR] 2.5; 95% confidence interval [CI] 1.1–5.9; P = 0.034) or influenza (OR 1.9; 95% CI 1.1–3.1; P = 0.017) infections, due probably to the dysregulation of the host immune response following acute infections. In patients infected with influenza infection, dyslipidemia was a predictor for subsequent primary care visits with symptoms of RTI (unadjusted OR 1.8; 95% CI 1.0–3.0; P = 0.040). Conclusions: Both influenza and ccCoV infection pose significant disease burden, especially in patients with comorbidities. The management of comorbidities should be prioritized to mitigate poor health outcomes in infected individuals.