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. Authors summaryGenetic variants describe the variation in the DNA sequence in our genomes and are unique for each person. These variants modify the risk of developing colorectal cancer (CRC) by regulating genes that participate in CRC-associated mechanisms. CRC risk is also affected by microbiota (the microorganisms residing in ourselves). A balanced microbiota helps perform our normal body functions, but can induce cancer, if this balance is lost. Microbiota is affected by factors such as pollution and diet, but is also regulated by genetic variants. However, can genetic variants predispose to cancer risk by regulating microbiota? To answer this question, we sequenced the genetic variants of 93 CRC patients and examined the composition of their intestinal microbiota. We identified variants that regulate the presence of benefic or pathogenic bacteria. The same variants also affect the expression of genes that participate in inflammation, immunity and integrity of intestinal tissue. We found that genetic variants regulate gene expression and microbiota at the same time, predisposing to a higher or lower CRC risk. People with variants predisposing to a higher risk may be benefitted by tailored preventive treatments that increase beneficial bacteria.