Gut microbiota plays a key role in the development of colorectal cancer

Abstract

This letter addresses the recently published manuscript by Darnindro et al, which investigates the diversity and composition of colonic mucosal microbiota in Indonesian patients with and without colorectal cancer (CRC). Although the analysis revealed no statistically significant differences in alpha diversity between the CRC and non-CRC groups, the authors identified notable distinctions in the composition and diversity of colonic mucosal microbiota among patients with CRC compared to those without. At the genus level, a statistically significant difference in microbiota composition was documented between the two cohorts. Specifically, the genera Bacteroides, Campylobacter, Peptostreptococcus, and Parvimonas were found to be elevated in individuals with CRC, while Faecalibacterium, Haemophilus, and Phocaeicola were more prevalent in the non- CRC group.

Key Words: Colorectal cancer; Gut microbiota; Microbial dysbiosis; Intratumoral microbiota; Gut metabolites

Core Tip: Colorectal cancer (CRC) represents the most prevalent malignancy within the digestive system, characterized by elevated rates of mortality and morbidity. In this letter, we provide commentary on the research conducted by Darnindro et al, which identified the four most dominant phyla present in their study as Firmicutes, Proteobacteria, Bacteroidetes, and Fusobacteria. Importantly, the study revealed a significant disparity in beta diversity at both the genus and species levels when comparing groups with CRC to those without.

TO THE EDITOR

Colorectal cancer (CRC) represents the most prevalent malignancy within the digestive system, characterized by elevated rates of mortality and morbidity[1]. The gut microbiota, residing primarily in the intestines, particularly the colorectum, engages in complex interactions with the host that influence various physiological processes[2]. In this letter, we provide commentary on the research conducted by Darnindro et al[3], which identified the four most dominant phyla present in their study as Firmicutes, Proteobacteria, Bacteroidetes, and Fusobacteria. Importantly, the study revealed a remarkable disparity in microbe diversity when comparing groups with CRC to those without.

Microbial dysbiosis in CRC

Case-control study by Darnindro et al[3] indicated an altered gut bacterial composition in patients with CRC. Dysbiosis of gut bacteria, characterized by an imbalance in the most prevalent microorganisms within the gastrointestinal tract, is a well-documented phenomenon that plays a significant role in the development and progression of CRC[4]. Given the considerable geographical and ethnic variability in gut microbiota composition, numerous meta-analyses have been undertaken to elucidate universal correlations between specific bacterial populations and CRC[5]. A comprehensive meta-analysis of sequencing data derived from 768 and 969 fecal metagenomes of patients with CRC from diverse geographical backgrounds has identified several core pathogenic species that are notably enriched in these individuals[6,7]. Among these, oral pathogens such as Fusobacterium nucleatum (F. nucleatum), Parvimonas micra, Peptostreptococcus stomatis, Prevotella anaerobius, Porphyromonas asaccharolytica, Solobacterium moorei (S. moorei), and Prevotella intermedia are particularly prominent. Furthermore, elevated levels of oral pathogens, including F. nucleatum, S. moorei, and Lachnoclostridium species, have also been observed in the gut microbiota of patients with colorectal adenomas, indicating that gut dysbiosis may represent an early event in the process of colorectal tumorigenesis[8,9].

Interaction between gut microbiota and CRC

Recent research has indicated that the gut microbiota, which encompasses species such as Escherichia coli (E. coli), Enterococcus, Bacteroides, and Clostridium, may play a significant role in the development of CRC by exacerbating the formation of abnormal crypt foci induced by 1,2-dimethylhydrazine[10]. Notably, studies involving mice that received gut microbiota transplants from CRC patients demonstrated a higher incidence of intestinal polyps compared to those that were transplanted with microbiota from healthy individuals[11]. Comparative metagenomic and metataxonomic analyses have unequivocally established that individuals with CRC exhibit a dysregulated taxonomic composition relative to healthy counterparts, characterized by an increase in pro-oncogenic bacteria and a decrease in protective bacteria, such as Roseburia, etc.[12]. These findings underscore the critical influence of microbes on CRC, leading to unpredictable interactions between the host and its microbiota[13].

Microbes and CRC pathogenesis

Certain scholars suggest that gut microbiota, which does not engage directly with the intestinal mucosa, may not possess the ability to induce CRC. However, these microbial communities could play a role in cancer development indirectly through metabolic changes, particularly in relation to obesity and Western dietary habits. The gut metabolic products generated by microbiota are associated with the onset and progression of CRC, potentially through mechanism involving inflammation and DNA damage. Short-chain fatty acids produced by specific microbial groups, including Firmicutes and Bacteroidetes, are closely associated with the incidence and progression of CRC[14]. Furthermore, the activation of Gpr109a, a receptor for niacin and the commensal metabolite butyrate, has been demonstrated to inhibit colonic inflammation and the onset of carcinogenesis[15].

Intratumoral microbiota in CRC

The emergence of metagenomic sequencing has underscored the significance of the tumor microbiota as a crucial component of the tumor microenvironment that influences tumor progression. Notably, the prevalence of Fusobacterium has been observed to increase in liver metastatic CRC as opposed to primary liver cancers[16]. Additionally, the presence of intratumoral E. coli has been shown to compromise the integrity of the gut vascular barrier[17], further emphasizing the role of the intratumoral microbiota. The composition of the CRC microbiota is characterized by heterogeneity and undergoes progressive alterations as CRC transitions from adenoma to carcinoma[18]. However, the mechanisms driving these changes remain poorly understood. One investigation analyzing samples from CRC and adenomas identified some increased microbes, including Fusobacterium, Bacteroides, etc.[18]. However, a previous study indicated an decrease in the abundance of Firmicutes[19].

Gut microbiota metabolites and their effects on CRC

Metabolites play a crucial role in the interaction between the gut microbe and host[20]. These metabolites are intricately linked to the pathogenesis of cancer, including CRC[21,22]. The array of metabolites produced by gut microbiota encompasses volatile small molecules, lipids, proteins and peptides, carbohydrates, secondary bile acids, terpenes, biogenic amines, oligosaccharides, glycolipids, organic acids, and amino acids[23]. The properties of these metabolites vary significantly based on the regulatory pathways involved. Some exhibit health-promoting and antineoplastic properties, while others may possess pro-inflammatory and carcinogenic effects[24]. Furthermore, these metabolites hold potential utility from bench to bedside, especially for the early identification of cancers like CRC and in predicting therapeutic outcomes[25]. Additionally, metabolites may offer advantages over microbial taxa in terms of application, as they influence microbial functions and the metabolic interactions between the host and microbiota[21]. Meanwhile, Mima et al[26] found that the prevalence of F. nucleatum-high CRCs exhibits a progressive increase from the rectum to the cecum. The authors provide evidence for the colorectal continuum model, which illustrates the pathogenic effects of gut microbiota on neoplastic and immune cells, thereby contesting the established dichotomy of the colon into proximal and distal regions.

CONCLUSION

Overall, this study has documented variations in the composition and abundance of gut microbiota among patients with CRC, as well as the interactions between gut microbiota and CRC. The gut microbiota, along with its metabolites, engages in significant interactions with host epithelial cells and plays a vital role in the development of CRC. As investigations clarify the contributions of intestinal flora to carcinogenesis, they present unprecedented opportunities for advancing applications in the diagnosis, treatment, and prognosis of CRC. The utilization of microbiota for the early diagnosis of CRC, the development of novel therapeutic approaches, and the implementation of biomarkers present significant potential for advancement in this field.