Gut Microbiota and Host Gene Mutations in Colorectal Cancer Patients and Controls of Iranian and Finnish Origin

Abstract

Background/Aim: Gut microbiota plays an important role in colorectal cancer (CRC) and its composition in CRC patients can be influenced by ethnicity and tumour genomics. Herein, the aim was to study the possible associations of ethnicity and gene mutations with the gut microbiota in CRC patients. Materials and Methods: Bacterial composition in stool samples of 83 CRC patients and 60 controls from Iran and Finland was studied by 16S rRNA gene sequencing. The association of gut microbiota composition with CRC, host mutations in KRAS, NRAS and TP53, and ethnicity analysed. Results: Beta diversity analysis indicated significant differences between the Iranian and Finnish gut microbiota composition, in both controls and patients' groups. The Iranian controls had higher abundance of Prevotella and lower abundance of Bacteroides compared to the Finnish controls, while the Finnish patients had higher abundance of Clostridium compared to Iranian patients. Abundance of Ruminococcus was higher in patients compared to the controls. Higher abundances of Herbaspirillum, Catenibacterium and lower abundances of Barnesiella were associated with mutations in NRAS, TP53, and RAS respectively. Conclusion: A possible link of host gene mutations with gut bacterial composition is suggested. The gut microbiota plays an integral role in the regulation of different gastrointestinal functions. There is increasing evidence that the gut microbiota not only contributes to the initiation and progression of colorectal cancer (CRC) but also influences the host response to cancer treatment, especially chemo-and immunotherapy (1). In addition to its regional effect in the gastrointestinal tract, the gut microbiota also affects distant organs via its role in shaping the immune system and host metabolism (2). Diet, lifestyle and ethnicity are among the main determinants of microbiota composition, and changes in diet associated with a modern lifestyle have been linked to microbiota-mediated cancer risk (3). The host genetic variation is also known to effect bacterial composition (4), although this area has not been investigated extensively. The host genetics is reported to strongly influence the abundance of gut Christensenellaceae (5), the bacteria associated with low body mass index. The Bifidobacterium abundance has been linked with a variation in the lactose tolerance gene LCT loci (6, 7). On the other hand, tumour genome is reported to be a factor modulating colonization of certain bacteria around colorectal tumour tissue (8, 9). A high abundance of Fusobacterium has been reported to be associated with CpG island methylator phenotype (CIMP), microsatellite instability (MSI) and mutations in CHD7/8 (10). However, the associations between tumour mutations and gut microbiota composition remain poorly understood. The association of the gut microbiota composition with different disease states makes them useful as potential diagnostic markers of health and disease (11). Recent largescale studies have however demonstrated that ethnicity (12) and geogra...

Gut Microbiota Dysbiosis Drives the Development of Colorectal Cancer

“…Additionally, pks -positive E. coli promotes DNA double-strand breaks, cell cycle arrest, and aneuploid cell division in vivo [21, 22, 82]. Recently, it was also found that the differential abundance of several gut bacteria is associated with NRAS , TP53 , and RAS mutations in the host, based on 16S rRNA gene sequencing of fecal bacteria in 83 CRC patients and 60 normal controls from Iran and Finland [94]. Microbes directly or indirectly cause DNA damage and influence genome stability, making the microbiome a potential risk factor and therapeutic target for CRC.…”

Sporamin Intervention Altered the Gut Microbiome and Tumor Tissue Transcriptome in Mice Intraperitoneally Xenografted With the Human Colorectal Carcinoma LoVo Cells

“…In line with this, improving the composition and function of the gut microbiota via prebiotics or probiotics or antibiotics etc. has also been proposed as a method to prevent cancer and is successful in several studies [5,7,11]. Moreover, the scope of the agents that can be used to modulate the gut microbiome is expanding.…”

“…Mice in the TTG group were i.p. xenografted with 2.5×10 7 LoVo cells in 0.2 mL of PBS and then intragastrically infused with 0.5 mL of sporamin at 0.5 g/kg BW per day in distilled water for four weeks. All animals had free access to feed and drinking water throughout the experiment.…”

“…They can in uence the onset and development of CRC through multiple mechanisms such as regulating the gut microbiota dysbiosis, in uencing the integrity and function of the intestinal mucosal barriers, modifying the intestinal immune responses that may lead to in ammatory bowel diseases and CRC [4,5]. In this process, the gut microbiome may be one of the key mediators that can modify the process both directly through contact with the intestinal mucosa and indirectly through fermenting the intestinal contents and changing the secondary metabolites produced [5][6][7]. In addition, dietary factors and gut microbiota also play an important role in modulating the host's response to chemotherapeutics and other oral treatments by in uencing their bioavailability, toxicity, and e cacy [8,9].…”

TP53 and NRAS are the Most Frequently Mutated Genes in Stool DNA of CRC Patients from Central Part of Iran

“…Therefore, need to study extensively and comparative studies regarding molecular drivers of CRC between Iranian patients and those with different genetics background, like Western Europeans would be bene cial. For this reason we compared mutation spectrum of Iranian CRC patients and controls with Finnish CRC patients as a standard European population performed in the same laboratory at Helsinki university 23 .…”