Bacteria pathogens drive host colonic epithelial cell promoter hypermethylation of tumor suppressor genes in colorectal cancer

Abstract

Background Altered microbiome composition and aberrant promoter hypermethylation of tumor suppressor genes (TSGs) are two important hallmarks of colorectal cancer (CRC). Here we performed concurrent 16S rRNA gene sequencing and methyl-CpG binding domain-based capture sequencing in 33 tissue biopsies (5 normal colonic mucosa tissues, 4 pairs of adenoma and adenoma-adjacent tissues, and 10 pairs of CRC and CRC-adjacent tissues) to identify significant associations between TSG promoter hypermethylation and CRC-associated bacteria, followed by functional validation of the methylation-associated bacteria. Results Fusobacterium nucleatum and Hungatella hathewayi were identified as the top two methylation-regulating bacteria. Targeted analysis on bona fide TSGs revealed that H. hathewayi and Streptococcus spp . significantly correlated with CDX2 and MLH1 promoter hypermethylation, respectively. Mechanistic validation with cell-line and animal models revealed that F. nucleatum and H. hathewayi upregulated DNA methyltransferase. H. hathewayi inoculation also promoted colonic epithelial cell proliferation in germ-free and conventional mice. Conclusion Our integrative analysis revealed previously unknown epigenetic regulation of TSGs in host cells through inducing DNA methyltransferase by F. nucleatum and H. hathewayi , and established the latter as CRC-promoting bacteria.

Patients With Common Variable Immunodeficiency (CVID) Show Higher Gut Bacterial Diversity and Levels of Low-Abundance Genes Than the Healthy Housemates

“…This is in accordance with Jørgensen et al (45), who observed the enrichment of genus Hungatella in 16S rRNA microbiome of CVID patients. H. hathewayi is a part of the normal human intestinal microflora (44,46,47), but it is also involved in various human infections (48)(49)(50), and its abundance was increased among patients suffering from cystic fibrosis (51), primary IgA nephropathy (52), chronic kidney disease (53), and colon cancer (54)(55)(56).…”

Pectin supplement significantly enhanced the anti-PD-1 efficacy in tumor-bearing mice humanized with gut microbiota from patients with colorectal cancer

“…Recently, several independent studies have showed the important role of gut microbiota in influencing immunotherapy response in patients with melanoma, non-small cell lung cancer, and renal cell carcinoma 7 - 11 , which provides us a new target to influence the anti-PD-1 mAb outcomes. Meanwhile, studies have suggested that altered gut microbiota are closely associated with occurrence and development of CRC 12 - 14 and CRC patients are characterized by decreased richness and diversity, and significantly disturbed gut microbiota 15 . However, it remains uncertain how to modulate these gut microbiota dysbiosis to improve the anti-PD-1 mAb efficacy in clinic.…”

MetaFunc: Taxonomic and Functional Analyses of High Throughput Sequencing for Microbiomes

“…Indeed we could be seeing these effects upon looking at the microbes correlating with significantly abundant host genes in CRC samples from PRJNA413956. While C. lusitaniae is an opportunistic pathogen causing candidemia (Desnos-Ollivier et al, 2011;Krcmery et al, 1999) possibly exploiting the lowered immune responses in cancer patients (Aslani et al, 2018), and some Streptococcus species have previously been implicated in CRC (Kumar et al, 2017;Xia et al, 2020) with S. pyogenes having been known to cause invasive infections in humans (Parks et al, 2015), Cupriavidus necator (formerly known as Ralstonia eutropha (Reinecke and Steinbüchel, 2009)) is a soil bacterium that may be a sequencing contaminant in this dataset. Cupriavidus and Ralstonia species have been previously identified as common contaminants in metaomics studies (Guo et al, 2019;Salter et al, 2014).…”