The Interactions Between Gut Microbiota And Hereditary Nonpolyposis Colorectal Cancer(HNPCC)

Background:Colorectal cancer(CRC)is the 3rd most common cancer,which is a multi-gene and multi-step process caused by environmental factors and their own genome.With advance in metagenomic technology,growing evidence now suggests that dysbiosis of nomarl intestinal mictobiota is associated with CRC.Hereditary Nonpolyposis Colorectal Cancer(HNPCC)is the most common hereditary Colorectal cancer(HCRC).It is an autosomal dominant inheritance with mismatch repair(MMR)gene mutation.In clinical,we observed that the phenotypes of the age of onset were frequently different.Some patients were diagnosed with CRC at the age of 30-35 years old,while some patients were delayed to 55-60,and even in some families,several MMR gene mutation carrier has not occurred any HNPCC related tumor.The difference in the phenotype of the colorectal cancer can be observed in patients with the same genetic background.Reason may be partly related to the specific MMR genes(hMLH1,hMSH2,hMSH6,hPMS1)the different type of mutation and genetic backgrounds.And environmental factors may also contribute to the difference,including gut microbiota The analysis of gut microbiota among these patients with similar genetic background may promote us to understand the role of gut micirobiota in colon cancer.This study aims to compare gut microbiota with different phenotypes HNPCC family,between HNPCC and healthy control,as well as HNPCC(referred to as HCRC)and sporadic colorectal cancer(SCRC),and to explore the interaction between gut microbiota and HNPCCMethods:To screen suitable families(eg.Stool samples of CRC patients had been collected before operation)from 205 established HNPCC families.50 family members(including 10 HNPCC patients,11 adenoma patients with MMR gene mutations,7 cases with no lesion in colon and rectal but with MMR gene mutations and 8 spouses of HNPCC patients)and 14 SCRC patients was enrolled in the study,those tool sample were collected and DNA were extracted for sequencing 16s-rDNA V4 region by Illumina Miseq.We analysed difference of gut microbiota by bioinformatics analysis,including different families,CRC&adenoma&no colorectal lesion,no colorectal lesion with MMR gene mutation&no colorectal lesion without MMR gene mutation(healthy control),and HNPCC patients&SCRC.Results:There were significant difference of gut microbiota between HNPCC and adenoma patients(p<0.001),between HNPCC and no colorectal lesion with MMR gene mutation(p=0.014),between HNPCC and no colorectal lesion without MMR gene mutation(p=0.004),as well as between HNPCC and SCRC(p=0.001).But there weren’t significant difference of gut microbiota between adenoma and no colorectal lesion with MMR gene mutation(p=0.645),as well as between no colorectal lesion with MMR gene mutation and without MMR gene mutation.PCA analysis showed that the distance between HCRC and healthy controls was closer than SCRC with healthy.Among the top 20 different genera with higher abundance,Pan,imonas was particularly prominent in SCRC fecal Consistent with these findings,there was higher abundance of Parvimonas in SCRC relative to healthy controls,suggesting Parvimonas may play a role in the progression of CRC.Exploiting Spearman’s correlation coefficient analysis,we further evaluated the correlations of top 30 different genera with higher abundance between SCRC and HCRC.Parvimonas had significant positive correlations with Brevibacillus,Methylobacterium,A rmatimonas/A rmatimonadetes_gpl,Granulicella and Phenylobacterium,and those five genera were all be found to be enriched in SCRC than in HCRC.In addition,Parvimonas had a strong co-currence with Fusobacterium.Conclusion:1.HNPCC is associated with gut microbiota.There were significantly differences between different phenotype patient(p<0.001).The changes in gut microbiota occur in the process from adenoma tocancer and after CRC formation.2.MMR gene don’t affect gut microbita.3.Gut microbiota is significantly different between HCRC and SCRC.Compared with SCRC,microbiota of HCRC patients was closer to healthy controls.With similar phenotype of CRC,the marked variation of fecal microbiome can’t be explained as a consequence of CRC.Therefore,this finding cloud be as a strong evidence supporting gut microbiota is a causative factor for development of CRC.4.Significant over-representations of Parvimonas,CRC associated specific genus,in the fecal of SCRC patients compared with HCRC patients,suggesting Parvimonas may be a specific bacterial genus for CRC development.