Gut microbiota composition in colorectal cancer patients is genetically regulated

Abstract

The risk of colorectal cancer (CRC) depends on environmental and genetic factors. Among environmental factors, an imbalance in the gut microbiota can increase CRC risk. Also, microbiota is influenced by host genetics. However, it is not known if germline variants influence CRC development by modulating microbiota composition. We investigated germline variants associated with the abundance of bacterial populations in the normal (non-involved) colorectal mucosa of 93 CRC patients and evaluated their possible role in disease. Using a multivariable linear regression, we assessed the association between germline variants identified by genome wide genotyping and bacteria abundances determined by 16S rRNA gene sequencing. We identified 37 germline variants associated with the abundance of the genera Bacteroides, Ruminococcus, Akkermansia, Faecalibacterium and Gemmiger and with alpha diversity. These variants are correlated with the expression of 58 genes involved in inflammatory responses, cell adhesion, apoptosis and barrier integrity. Genes and bacteria appear to be involved in the same processes. In fact, expression of the pro-inflammatory genes GAL, GSDMD and LY6H was correlated with the abundance of Bacteroides, which has pro-inflammatory properties; abundance of the anti-inflammatory genus Faecalibacterium correlated with expression of KAZN, with barrier-enhancing functions. Both the microbiota composition and local inflammation are regulated, at least partially, by the same germline variants. These variants may regulate the microenvironment in which bacteria grow and predispose to the development of cancer. Identification of these variants is the first step to identifying higher-risk individuals and proposing tailored preventive treatments that increase beneficial bacterial populations.

Aflatoxin B1 Induces Inflammatory Liver Injury via Gut Microbiota in Mice

“…Pearson’s correlation analysis showed that the relative abundance of microbiota relating to liver pyroptosis, e.g., Parabacteroides , Bacteroides , Lactobacillus , and Alistipes , were increased significantly in AFB 1 -treated mice, as well as in the transplanted group. Several lines of evidence indicated that Parabacteroides , Bacteroides , and Alistipes could activate NLRP3 signaling. The variation of these gut bacteria is consistent with the activation of liver pyroptosis, indicating that they could be the key factors to promote liver pyroptosis.…”

Tigecycline reduces tumorigenesis in colorectal cancer via inhibition of cell proliferation and modulation of immune response.

“…The relationship between A. muciniphila and CRC remains controversial. Different studies have shown an enrichment ofAkkermansia in CRC patients (Colombo et al , 2022), while others have reported that it can mitigate tumorigenesis in CRC with capacity to boost the effect of existing antitumor treatments (Houet al , 2021). In this study we observed an increase inAkkermansia genus in CAC mice compared to healthy mice, as well as increased levels in mice treated with tigecycline, which may contribute to its beneficial effect.…”

The Rise of Gastrointestinal Cancers as a Global Phenomenon: Unhealthy Behavior or Progress?

“…In addition, several studies have provided consistent data regarding the abundance of Parvimonas , Porphyromonas, and Peptostreptococcus in fecal and biopsy samples from patients with CRC [ 167 ]. The abundance of other intestinal bacteria, including Bacteroides , Akkermansia , and Ruminococcus, has also been implicated in the development or progression of CRC by inducing a proinflammatory milieu [ 168 ]. Similarly, the enrichment of Proteobacteria , including the genus Campylobacter [ 169 ] and the species E. coli [ 170 ], in the intestinal microbiome has also been associated with the development of CRC by modifying the tumor microenvironment.…”