Mycobiota Signatures and Colorectal Cancer: A True Association or Not?

Abstract

See “Altered mycobiota signatures and enriched pathogenic Aspergillus rambellii are associated with colorectal cancer based on multicohort fecal metagenomic analyses” by Lin Y, Lau HC-H, Liu Y, et al, on page 908. See “Altered mycobiota signatures and enriched pathogenic Aspergillus rambellii are associated with colorectal cancer based on multicohort fecal metagenomic analyses” by Lin Y, Lau HC-H, Liu Y, et al, on page 908. The association between gut bacteria and colorectal cancer (CRC) has been intensively investigated in recent years with the identification of a list of putatively procarcinogenic bacteria (eg, Fusobacterium nucleatum, Escherichia coli, and more).1Song M. Chan A.T. Sun J. Influence of the gut microbiome, diet, and environment on risk of colorectal cancer.Gastroenterology. 2020; 158: 322-340Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 2Kostic A.D. Gevers D. Pedamallu C.S. et al.Genomic analysis identifies association of Fusobacterium with colorectal carcinoma.Genome Res. 2012; 22: 292-298Crossref PubMed Scopus (1216) Google Scholar, 3Castellarin M. Warren R.L. Freeman J.D. et al.Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma.Genome Res. 2012; 22: 299-306Crossref PubMed Scopus (1202) Google Scholar However, the role of gut fungal microbiota in etiology and progression of CRC is undiscovered due to the low abundance of fungi in the human gut (≤0.1%–1% of total microorganisms) as well as a lack of well-characterized reference genomes for aligning sequencing reads.4Lin Y. Lau H.C.-H. Liu Y. et al.Altered mycobiota signatures and enriched pathogenic Aspergillus rambellii are associated with colorectal cancer based on multicohort fecal metagenomic analyses.Gastroenterology. 2022; 163: 908-921Abstract Full Text Full Text PDF Scopus (5) Google Scholar The fungal community has gained much more attention most recently because of the additive value of fungi to the predictive model of the gut microbiome in colon carcinogenesis, which may provide an ideal approach for screening and early detection of CRC.4Lin Y. Lau H.C.-H. Liu Y. et al.Altered mycobiota signatures and enriched pathogenic Aspergillus rambellii are associated with colorectal cancer based on multicohort fecal metagenomic analyses.Gastroenterology. 2022; 163: 908-921Abstract Full Text Full Text PDF Scopus (5) Google Scholar Characterizing the human mycobiota (group of all fungi) or mycobiome (the entirety of fungi and their genome) in healthy individuals has showed that the gastrointestinal tract contains hundreds of fungal species. As the smaller proportion of the commensal microbial community, fungi were considered passive colonizers that could become pathogenic when the environment changes (eg, use of antibiotics or immunosuppressive drugs that reduce or suppress the microbe community). Several studies have reported the association of gut mycobiota and colon carcinogenesis.5Luan C. Xie L. Yang X. et al.Dysbiosis of fungal microbiota in the intestinal mucosa of patients with colorectal adenomas.Sci Rep. 2015; 5: 7980Crossref PubMed Scopus (103) Google Scholar, 6Gao R. Kong C. Li H. et al.Dysbiosis signature of mycobiota in colon polyp and colorectal cancer.Eur J Clin Microbiol Infect Dis. 2017; 36: 2457-2468Crossref PubMed Scopus (57) Google Scholar, 7Richard M.L. Liguori G. Lamas B. et al.Mucosa-associated microbiota dysbiosis in colitis associated cancer.Gut Microbes. 2018; 9: 131-142Crossref PubMed Scopus (97) Google Scholar, 8Malik A. Sharma D. Malireddi R.K.S. et al.SYK-CARD9 signaling axis promotes gut fungi-mediated inflammasome activation to restrict colitis and colon cancer.Immunity. 2018; 49: 515-530.e5Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 9Coker O.O. Nakatsu G. Dai R.Z. et al.Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer.Gut. 2019; 68: 654-662Crossref PubMed Scopus (177) Google Scholar For instance, decreased fungal richness and diversity and a dysregulated ratio of Ascomycota to Basidiomycota was commonly observed in CRC patients. Specific mycobiotic signatures in CRC have been reported, but the results were inconsistent, which might be due to fluctuations across different populations, discrepant standards for metagenomic data generation and processing, and small sample size with insufficient statistical power. Lin and colleagues4Lin Y. Lau H.C.-H. Liu Y. et al.Altered mycobiota signatures and enriched pathogenic Aspergillus rambellii are associated with colorectal cancer based on multicohort fecal metagenomic analyses.Gastroenterology. 2022; 163: 908-921Abstract Full Text Full Text PDF Scopus (5) Google Scholar initiated a meta-analysis to pool studies with shotgun metagenomic sequencing data, totaling 1329 metagenomes (454 CRC, 350 adenoma, and 525 healthy subjects) from 8 cohorts and intended to a provide less biased evaluation of the gut mycobiome on CRC.4Lin Y. Lau H.C.-H. Liu Y. et al.Altered mycobiota signatures and enriched pathogenic Aspergillus rambellii are associated with colorectal cancer based on multicohort fecal metagenomic analyses.Gastroenterology. 2022; 163: 908-921Abstract Full Text Full Text PDF Scopus (5) Google Scholar The results of mycobiota composition analysis revealed a number of enriched (eg, Aspergillus rambellii, Cordyceps sp. RAO-2017, Erysiphe pulchra, Moniliophthora perniciosa, Sphaerulina musiva, and Phytophthora capsica) and depleted fungal species (eg, A kawachii) that are associated with CRC. Among them, A rambellii was identified as the top one enriched fungal species in the pooled analysis and was consistently associated with CRC in 7 of 8 cohorts. The further function studies demonstrated that A rambellii promoted CRC cell growth in vitro and tumor growth in xenograft mice. Previous studies have showed that A rambellii promoted secretion of aflatoxin, which is a confirmative carcinogen and mutagen for liver cancer.10Khan R. Ghazali F.M. Mahyudin N.A. et al.Aflatoxin biosynthesis, genetic regulation, toxicity, and control strategies: a review.J Fungi (Basel). 2021; 7: 606Crossref PubMed Scopus (13) Google Scholar,11Llovet J.M. Zucman-Rossi J. Pikarsky E. et al.Hepatocellular carcinoma.Nat Rev Dis Primers. 2016; 216018Crossref PubMed Scopus (1484) Google Scholar Whether A rambellii produces aflatoxins that contribute to colorectal carcinogenesis is unknown and is yet to be examined. In the analysis of microbiome interactions, intrakingdom (fungi-fungi) interactions and transkingdom (fungi-bacteria) interactions enhanced along CRC progression. The central role of A rambellii in the enteric mycobiota across colon carcinogenesis was further identified. This result may indicate the status of microbial dysbiosis was characterized by growth of pathogenic bacteria and decreased diversity of fungi. Such transkingdom or intrakingdom interactions could be mediated by multiple mechanisms, including secretory products and competition for nutrients,12Mukherjee P.K. Sendid B. Hoarau G. et al.Mycobiota in gastrointestinal diseases.Nat Rev Gastroenterol Hepatol. 2015; 12: 77-87Crossref PubMed Scopus (119) Google Scholar which reveal the underlying link between diet and microbiota. Accumulating studies have showed the different associations between diet and different microbes. For example, bacteria Bacteroides were strongly correlated with the diet rich in animal protein, whereas fungal abundance correlated with consumption of a diet rich in carbohydrates.12Mukherjee P.K. Sendid B. Hoarau G. et al.Mycobiota in gastrointestinal diseases.Nat Rev Gastroenterol Hepatol. 2015; 12: 77-87Crossref PubMed Scopus (119) Google Scholar Further studies on fungal-bacterial interaction to unravel the underlying mechanism between diet and microbes may provide evidence for dietary intervention on colorectal cancer prevention. Moreover, the current study has demonstrated that combined fungal and bacterial signatures have better prediction of CRC than pure bacterial species. The results of the current study are slightly dissimilar to another meta-analysis13Liu N.N. Jiao N. Tan J.C. et al.Multi-kingdom microbiota analyses identify bacterial-fungal interactions and biomarkers of colorectal cancer across cohorts.Nat Microbiol. 2022; 7: 238-250Crossref PubMed Scopus (20) Google Scholar that included fewer studies (4 cohorts) compared with the current study. They found discrepant fungal species that may further indicate the dissimilarities among different populations. Even in the current meta-analysis with 8 studies, an apparent discrepancy of fungal species was observed when different groups of patients were analyzed and compared. Other studies have also explored multikingdom predictive models (eg, including virus and archaea besides just bacteria and fungi). These studies have achieved a similarly high level of diagnostic power. Nevertheless, the studies with the highest predictive power were provided by bacterial and fungal markers, whereas the multikingdom models, including virus and archaea, did not further enhance the performance of the diagnostic models.13Liu N.N. Jiao N. Tan J.C. et al.Multi-kingdom microbiota analyses identify bacterial-fungal interactions and biomarkers of colorectal cancer across cohorts.Nat Microbiol. 2022; 7: 238-250Crossref PubMed Scopus (20) Google Scholar The current study did a comprehensive analysis of metagenomic data across 8 cohorts and identified a list of promising fungi, especially A rambellii, that might play a role in the development of CRC. Unfortunately, a single fungus is unlikely to provide a strong causal relation to CRC. The network of intrakingdom and interkingdom interactions generated from this study was still descriptive but was informative for causal pathway analyses in depth. On the other hand, due to the nature-borne drawbacks of the cross-sectional study design for all studies included in this meta-analysis, fungal dysbiosis might not be the cause of CRC but the outcome of cancer progression. Further large longitudinal studies are warranted to verify the temporality of the mycobiota on CRC pathogenesis. The studies of the gut microbiome and CRC have opened opportunities for using stool-based microbial species as noninvasive diagnostic biomarkers for CRC. These opportunities become more promising when multikingdom species, especially the added fungal species, improved the predictive performance of models to a significantly high level with areas under the receiver operating characteristic curves reaching ≥80%. Translational application of fungal species on CRC, for instance, dietary intervention that will influence microbiome abundance, including the fungal community, may further terminate or delay the progression of CRC. Of note, we cannot ignore the clear variability between different studies that is due to heterogeneity among populations, including diet, geography, and race/ethnicity. The discrepant sample qualities, different metagenomic sequencing platforms, and bioinformatic pipeline for analysis may further enlarge the discrepancies between studies. Ultimately, the relatively low sensitivity but high costs of the metagenomics sequencing technique may further hinder the application of findings from the current study in the general population. Development of standardized and low-cost sequencing technique and analytical approach of the pipeline, increasing quality of data collection, and launching longitudinal studies with large samples size across different populations are critical for future studies in this field. Altered Mycobiota Signatures and Enriched Pathogenic Aspergillus rambellii Are Associated With Colorectal Cancer Based on Multicohort Fecal Metagenomic AnalysesGastroenterologyVol. 163Issue 4PreviewMultipopulation analyses were conducted to identify signature colorectal cancer-associated fungal species, including Aspergillus rambellii, and these fungi can be used for the noninvasive diagnosis of patients with colorectal cancer. Full-Text PDF Open Access