Microbial metabolites in colorectal tumorigenesis and cancer therapy

ABSTRACTTrillions of microbes are indigenous to the human gastrointestinal tract, together forming an ecological community known as the gut microbiota. The gut microbiota is involved in dietary digestion to produce various metabolites. In healthy condition, microbial metabolites have unneglectable roles in regulating host physiology and intestinal homeostasis. However, increasing studies have reported the correlation between metabolites and the development of colorectal cancer (CRC), with the identification of oncometabolites. Meanwhile, metabolites can also influence the efficacy of cancer treatments. In this review, metabolites derived from microbes-mediated metabolism of dietary carbohydrates, proteins, and cholesterol, are introduced. The roles of pro-tumorigenic (secondary bile acids and polyamines) and anti-tumorigenic (short-chain fatty acids and indole derivatives) metabolites in CRC development are then discussed. The impacts of metabolites on chemotherapy and immunotherapy are further elucidated. Collectively, given the importance of microbial metabolites in CRC, therapeutic approaches that target metabolites may be promising to improve patient outcome

Gastric microbiota beyond h. Pylori: An emerging critical character in gastric carcinogenesis

Gastric cancer (GC) is one of the global leading causes of cancer death. The association between Helicobacter pylori, which is a predominant risk factor for GC, with GC development has been well-studied. Recently, accumulating evidence has demonstrated the presence of a large population of microorganisms other than H. pylori in the human stomach. Existing sequencing studies have revealed microbial compositional and functional alterations in patients with GC and highlighted a progressive shift in the gastric microbiota in gastric carcinogenesis with marked enrichments of oral or intestinal commensals. Moreover, using a combination of gastric bacterial signatures, GC patients could be significantly distinguished from patients with gastritis. These findings, therefore, emphasize the importance of a collective microbial community in gastric carcinogenesis. Here, we provide an overview of non-H. pylori gastric microbes in gastric carcinogenesis. The molecular mechanisms of gastric microbes-related carcinogenesis and potential clinical applications of gastric microbiota as biomarkers of GC are also explored

Mouse Models for Application in Colorectal Cancer: Understanding the Pathogenesis and Relevance to the Human Condition

Colorectal cancer (CRC) is a malignant disease that is the second most common cancer worldwide. CRC arises from the complex interactions among a variety of genetic and environmental factors. To understand the mechanism of colon tumorigenesis, preclinical studies have developed various mouse models including carcinogen-induced and transgenic mice to recapitulate CRC in humans. Using these mouse models, scientific breakthroughs have been made on the understanding of the pathogenesis of this complex disease. Moreover, the availability of transgenic knock-in or knock-out mice further increases the potential of CRC mouse models. In this review, the overall features of carcinogen-induced (focusing on azoxymethane and azoxymethane/dextran sulfate sodium) and transgenic (focusing on ApcMin/+) mouse models, as well as their mechanisms to induce colon tumorigenesis, are explored. We also discuss limitations of these mouse models and their applications in the evaluation and study of drugs and treatment regimens against CRC. Through these mouse models, a better understanding of colon tumorigenesis can be achieved, thereby facilitating the discovery of novel therapeutic strategies against CRC

Metagenomic Sequencing for Microbial DNA in Human Samples: Emerging Technological Advances

Whole genome metagenomic sequencing is a powerful platform enabling the simultaneous identification of all genes from entirely different kingdoms of organisms in a complex sample. This technology has revolutionised multiple areas from microbiome research to clinical diagnoses. However, one of the major challenges of a metagenomic study is the overwhelming non-microbial DNA present in most of the host-derived specimens, which can inundate the microbial signals and reduce the sensitivity of microorganism detection. Various host DNA depletion methods to facilitate metagenomic sequencing have been developed and have received considerable attention in this context. In this review, we present an overview of current host DNA depletion approaches along with explanations of their underlying principles, advantages and disadvantages. We also discuss their applications in laboratory microbiome research and clinical diagnoses and, finally, we envisage the direction of the further perfection of metagenomic sequencing in samples with overabundant host DNA

Gut Microbiome in Colorectal Cancer: Clinical Diagnosis and Treatment

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and the leading cause of cancer-associated deaths. Epidemiological studies have shown that both genetic and environmental risk factors contribute to the development of CRC. Several metagenomic studies of CRC have identified gut dysbiosis as a fundamental risk factor in the evolution of colorectal malignancy. Although enormous efforts and substantial progresses have been made in understanding the relationship between human gut microbiome and CRC, the precise mechanisms involved remain elusive. Recent data have shown a direct causative role of the gut microbiome in DNA damage, inflammation, and drug resistance in CRC, suggesting that modulation of gut microbiome could act as a powerful tool in CRC prevention and therapy. Here, we provide an overview of the relationship between gut microbiome and CRC, and explore relevant mechanisms of colorectal tumorigenesis. We next highlight the potential of bacterial species as clinical biomarkers, as well as their roles in therapeutic response. Factors limiting the clinical translation of gut microbiome and strategies for resolving current challenges are further discussed

N6-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic cell mRNA, and this modification plays a key role in regulating mRNA translation, splicing, and stability. Emerging evidence implicates aberrant m6A as a crucial player in the occurrence and development of diseases, especially GI cancers. Among m6A regulators, YTHDF1 is the most abundant m6A reader that functionally connects m6A-modified mRNA to its eventual fate, mostly notably protein translation. Here, we summarized the function, molecular mechanisms, and clinical implications of YTHDF1 in GI cancers. YTHDF1 is largely upregulated in multiple GI cancer and its high expression predicts poor patient survival. In vitro and in vivo experimental evidence largely supports the role of YTDHF1 in promoting cancer initiation, progression, and metastasis, which suggests the oncogenic function of YTHDF1 in GI cancers. Besides, YTHDF1 overexpression is associated with changes in the tumor microenvironment that are favorable to tumorigenesis. Mechanistically, YTHDF1 regulates the expression of target genes by promoting translation, thereby participating in cancer-related signaling pathways. Targeting YTHDF1 holds therapeutic potential, as the overexpression of YTHDF1 is associated with tumor resistance to chemotherapy and immunotherapy. In summary, YTHDF1-mediated regulation of m6A modified mRNA is an actionable target and a prognostic factor for GI cancers

Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8⁺ T cells

Objective: Roseburia intestinalis is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of R. intestinalis in colorectal tumourigenesis and immunotherapy. Design: R. intestinalis abundance was evaluated in stools of patients with colorectal cancer (CRC) (n=444) and healthy controls (n=575). The effects of R. intestinalis were studied in Apc(Min/+) or azoxymethane (AOM)-induced CRC mouse models, and in syngeneic mouse xenograft models of CT26 (microsatellite instability (MSI)-low) or MC38 (MSI-high). The change of immune landscape was evaluated by multicolour flow cytometry and immunohistochemistry staining. Metabolites were profiled by metabolomic profiling. Results: R. intestinalis was significantly depleted in stools of patients with CRC compared with healthy controls. R. intestinalis administration significantly inhibited tumour formation in Apc(Min/+) mice, which was confirmed in mice with AOM-induced CRC. R. intestinalis restored gut barrier function as indicated by improved intestinal permeability and enhanced expression of tight junction proteins. Butyrate was identified as the functional metabolite generated by R. intestinalis. R. intestinalis or butyrate suppressed tumour growth by inducing cytotoxic granzyme B+, interferon (IFN)-& gamma;(+) and tumour necrosis factor (TNF)-& alpha;(+) CD8(+) T cells in orthotopic mouse models of MC38 or CT26. R. intestinalis or butyrate also significantly improved antiprogrammed cell death protein 1 (anti-PD-1) efficacy in mice bearing MSI-low CT26 tumours. Mechanistically, butyrate directly bound to toll-like receptor 5 (TLR5) receptor on CD8(+) T cells to induce its activity through activating nuclear factor kappa B (NF-& kappa;B) signalling. Conclusion: R. intestinalis protects against colorectal tumourigenesis by producing butyrate, which could also improve anti-PD-1 efficacy by inducing functional CD8(+) T cells. R. intestinalis is a potential adjuvant to augment anti-PD-1 efficacy against CRC.Nanyang Technological UniversityNational Medical Research Council (NMRC)Published versionThis project was supported by Research Talent Hub-Innovation and Technology Fund Hong Kong (ITS/177/21FP); RGC Research Impact Fund Hong Kong (R4032-21F); Shenzhen-Hong Kong-Macao Science and Technology Programme (Category C) Shenzhen (SGDX20210823103535016); Vice-Chancellor’s Discretionary Fund Chinese University of Hong Kong (4930775); Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist Individual Research Grant (CS-IRG) (MOH-CIRG23jan-0001), NTU Start Up Grant (021337-00001, 021281-00001), Centre for Microbiome Medicine, and Wang Lee Wah Memorial Fund

Uncovering 1058 novel human enteric DNA viruses through deep long-read third-generation sequencing and their clinical impact

Lack of viral reference genomes poses a challenge to virome study. We investigated human gut virome and its clinical implication by ultra-deep metagenomic sequencing.Published versionThis study was supported by National Key R&D Program of China (2020YFA0509200/2020YFA0509203), Research Grants Council Research Impact Fund Hong Kong (R4632-21F), Research Grants Council Theme-Based Research Scheme Hong Kong (T21-705/20-N), Research Grants Council Collaborative Research Fund (C4039-19GF, C7065-18GF), Research Grants Council General Research Fund Hong Kong (14163817), Vice-Chancellor’s Discretionary Fund Chinese University of Hong Kong