Stem Cell Impairment at the Host-Microbiota Interface in Colorectal Cancer

Abstract

Colorectal cancer (CRC) initiation is believed to result from the conversion of normal intestinal stem cells (ISCs) into cancer stem cells (CSCs), also known as tumor-initiating cells (TICs). Hence, CRC evolves through the multiple acquisition of well-established genetic and epigenetic alterations with an adenoma–carcinoma sequence progression. Unlike other stem cells elsewhere in the body, ISCs cohabit with the intestinal microbiota, which consists of a diverse community of microorganisms, including bacteria, fungi, and viruses. The gut microbiota communicates closely with ISCs and mounting evidence suggests that there is significant crosstalk between host and microbiota at the ISC niche level. Metagenomic analyses have demonstrated that the host–microbiota mutually beneficial symbiosis existing under physiologic conditions is lost during a state of pathological microbial imbalance due to the alteration of microbiota composition (dysbiosis) and/or the genetic susceptibility of the host. The complex interaction between CRC and microbiota is at the forefront of the current CRC research, and there is growing attention on a possible role of the gut microbiome in the pathogenesis of CRC through ISC niche impairment. Here we primarily review the most recent findings on the molecular mechanism underlying the complex interplay between gut microbiota and ISCs, revealing a possible key role of microbiota in the aberrant reprogramming of CSCs in the initiation of CRC. We also discuss recent advances in OMICS approaches and single-cell analyses to explore the relationship between gut microbiota and ISC/CSC niche biology leading to a desirable implementation of the current precision medicine approaches.

Natural and after colon washing fecal samples: the two sides of the coin for investigating the human gut microbiome

“…Bacteroides vulgatus and Bacteroides fragilis were isolated from patients suffering from Crohn’s disease, in addition Bacteroides fragilis was associated with intra-abdominal abscesses, appendicitis, and inflammatory bowel disease. As thoroughly reviewed by us in Marzano et al, 2021 (19) we highlighted the interaction between some species, including Bacteroides fragilis and the colorectal cancer, suggesting the identification of the gut microbiota biomarkers with diagnostic, prognostic or predictive significance, as well as the the possibility of intestinal microbiota modulation to prevent cancer or enhance the effect of specific therapies. In this study, we found Bacteroides vulgatus and Bacteroides uniformis were associated to F samples.…”

“…The alteration in the stable composition of the gut microbiota, a condition known as dysbiosis, leads to a disruption of homeostasis with the host. Different types of dysbiosis are associated with various harmful effects on human health and long-term consequences may induce a wide range of diseases including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), diabetes mellitus, obesity, and colorectal cancer (15)(16)(17)(18)(19)(20). Understanding the composition of the gut microbiota, throughout the GI tract, and the role that microbial populations can play in human intestinal health and disease can be critical for achieving a possible early diagnosis but also for the eventual development of appropriate therapeutic approaches based on the gut microbiota manipulation (i.e.…”

Mycobiome and Cancer: What Is the Evidence?

“…In the framework of cancer microbiota, a variety of metabolites may originate from bacterial, fungal and host metabolisms, or cometabolic networks between the host and microbial communities. In order to circumvent the compositional nature of metabarcoding data in the metagenomics strategy, a multi system-based approach (integrative multi-omics) could broaden our knowledge of the function of the interplay of microbial communities and cancer stem cells in carcinogenesis [71]. Llyod-Price et al used an innovative multi-omics network analysis of ten omics data (metagenomic, metabolomic, metatrascriptomic data, etc.)…”

“…Finally, a growing body of evidence has suggested that there is a significant interplay between gut microbiota and the host at the intestinal stem cell niche level, where microbiota may affect directly or indirectly the proliferation, differentiation and reprogramming of the intestinal stem cells and their transformation to cancer stem cells, resulting in CRC initiation and progression through a plethora of mechanisms reviewed elsewhere [71]. The totality of studies has focused on the role of gut bacteria on the abnormal reprogramming of intestinal and cancer stem cells without examining the role of fungi in this interplay.…”

Microbiota-Associated Metabolites and Related Immunoregulation in Colorectal Cancer

“…Indeed, African Americans with a higher risk of CRC have a higher concentration of secondary bile acids in their feces in comparison with rural Africans [11,126]. Emerging experimental evidence supports that a high level of secondary bile acids is carcinogenic to the colon, for example, by driving malignant transformations in cancer stem cells [127,128]. As an example, the HFD diet appreciably increased the levels of tauro-β-muricholic acid (T-βMCA) and DCA in Apc Min/+ mice, which markedly impaired intestinal integrity and promoted tumor growth.…”