TY - JOUR
T1 - Altered gut metabolites and microbiota interactions are implicated in colorectal carcinogenesis and can be non-invasive diagnostic biomarkers
AU - Coker, Olabisi Oluwabukola
AU - Liu, Changan
AU - Wu, William Ka Kei
AU - Wong, Sunny Hei
AU - Jia, Wei
AU - Sung, Joseph J. Y.
AU - Yu, Jun
N1 - Funding Information:
This study was supported by National Key R&D Program of China (2020YFA0509200/2020YFA0509203), RGC Theme-based Res Scheme Hong Kong (T21–705/20-N), RGC Collaborative Research Fund (C4039-19GF, C7065-18GF), RGC-GRF Hong Kong (14163817), Vice-Chancellor’s Discretionary Fund Chinese University of Hong Kong.
Publisher Copyright:
© The Author(s) 2022.
PY - 2022/2/21
Y1 - 2022/2/21
N2 - Background: Gut microbiota contributes to colorectal cancer (CRC) pathogenesis through microbes and their metabolites. The importance of microbiota-associated metabolites in colorectal carcinogenesis highlights the need to investigate the gut metabolome along the adenoma-carcinoma sequence to determine their mechanistic implications in the pathogenesis of CRC. To date, how and which microbes and metabolites interactively promote early events of CRC development are still largely unclear. We aim to determine gut microbiota-associated metabolites and their linkage to colorectal carcinogenesis. Results: We performed metabolomics and metagenomics profiling on fecal samples from 386 subjects including 118 CRC patients, 140 colorectal adenomas (CRA) patients and 128 healthy subjects as normal controls (NC). We identified differences in the gut metabolite profiles among NC, CRA and CRC groups by partial least squares-discriminant and principal component analyses. Among the altered metabolites, norvaline and myristic acid showed increasing trends from NC, through CRA, to CRC. CRC-associated metabolites were enriched in branched-chain amino acids, aromatic amino acids and aminoacyl-tRNA biosynthesis pathways. Moreover, metabolites marker signature (twenty metabolites) classified CRC from NC subjects with an area under the curve (AUC) of 0.80, and CRC from CRA with an AUC of 0.79. Integrative analyses of metabolomics and metagenomics profiles demonstrated that the relationships among CRC-associated metabolites and bacteria were altered across CRC stages; certain associations exhibited increasing or decreasing strengths while some were reversed from negative to positive or vice versa. Combinations of gut bacteria with the metabolite markers improved their diagnostic performances; CRC vs NC, AUC: 0.94; CRC vs CRA, AUC 0.92; and CRA vs NC, AUC: 0.86, indicating a potential for early diagnosis of colorectal neoplasia. Conclusions: This study underscores potential early-driver metabolites in stages of colorectal tumorigenesis. The Integrated metabolite and microbiome analysis demonstrates that gut metabolites and their association with gut microbiota are perturbed along colorectal carcinogenesis. Fecal metabolites can be utilized, in addition to bacteria, for non-invasive diagnosis of colorectal neoplasia.
AB - Background: Gut microbiota contributes to colorectal cancer (CRC) pathogenesis through microbes and their metabolites. The importance of microbiota-associated metabolites in colorectal carcinogenesis highlights the need to investigate the gut metabolome along the adenoma-carcinoma sequence to determine their mechanistic implications in the pathogenesis of CRC. To date, how and which microbes and metabolites interactively promote early events of CRC development are still largely unclear. We aim to determine gut microbiota-associated metabolites and their linkage to colorectal carcinogenesis. Results: We performed metabolomics and metagenomics profiling on fecal samples from 386 subjects including 118 CRC patients, 140 colorectal adenomas (CRA) patients and 128 healthy subjects as normal controls (NC). We identified differences in the gut metabolite profiles among NC, CRA and CRC groups by partial least squares-discriminant and principal component analyses. Among the altered metabolites, norvaline and myristic acid showed increasing trends from NC, through CRA, to CRC. CRC-associated metabolites were enriched in branched-chain amino acids, aromatic amino acids and aminoacyl-tRNA biosynthesis pathways. Moreover, metabolites marker signature (twenty metabolites) classified CRC from NC subjects with an area under the curve (AUC) of 0.80, and CRC from CRA with an AUC of 0.79. Integrative analyses of metabolomics and metagenomics profiles demonstrated that the relationships among CRC-associated metabolites and bacteria were altered across CRC stages; certain associations exhibited increasing or decreasing strengths while some were reversed from negative to positive or vice versa. Combinations of gut bacteria with the metabolite markers improved their diagnostic performances; CRC vs NC, AUC: 0.94; CRC vs CRA, AUC 0.92; and CRA vs NC, AUC: 0.86, indicating a potential for early diagnosis of colorectal neoplasia. Conclusions: This study underscores potential early-driver metabolites in stages of colorectal tumorigenesis. The Integrated metabolite and microbiome analysis demonstrates that gut metabolites and their association with gut microbiota are perturbed along colorectal carcinogenesis. Fecal metabolites can be utilized, in addition to bacteria, for non-invasive diagnosis of colorectal neoplasia.
KW - Biomarker
KW - Colorectal adenoma
KW - Gut microbiota
KW - Stool metabolites
UR - http://www.scopus.com/inward/record.url?scp=85125157483&partnerID=8YFLogxK
U2 - 10.1186/s40168-021-01208-5
DO - 10.1186/s40168-021-01208-5
M3 - Journal article
C2 - 35189961
AN - SCOPUS:85125157483
SN - 2049-2618
VL - 10
JO - Microbiome
JF - Microbiome
IS - 1
M1 - 35
ER -
