TY - JOUR
T1 - Novel Fecal Biomarkers That Precede Clinical Diagnosis of Ulcerative Colitis
AU - The CCC Genetics, Environmental, Microbial Project Research Consortium
AU - Galipeau, Heather J.
AU - Caminero, Alberto
AU - Turpin, Williams
AU - Bermudez-Brito, Miriam
AU - Santiago, Alba
AU - Libertucci, Josie
AU - Constante, Marco
AU - Raygoza Garay, Juan Antonio
AU - Rueda, Gaston
AU - Armstrong, Sarah
AU - Clarizio, Alex
AU - Smith, Michelle I.
AU - Surette, Michael G.
AU - Bercik, Premysl
AU - Beck, Paul
AU - Bernstein, Charles
AU - Croitoru, Kenneth
AU - Dieleman, Leo
AU - Feagan, Brian
AU - Griffiths, Anne
AU - Guttman, David
AU - Jacobson, Kevan
AU - Kaplan, Gilaad
AU - Krause, Denis O.
AU - Madsen, Karen
AU - Marshall, John
AU - Moayyedi, Paul
AU - Ropeleski, Mark
AU - Seidman, Ernest
AU - Silverberg, Mark
AU - Snapper, Scott
AU - Stadnyk, Andy
AU - Steinhart, Hillary
AU - Surette, Michael
AU - Turner, Dan
AU - Walters, Thomas
AU - Vallance, Bruce
AU - Aumais, Guy
AU - Bitton, Alain
AU - Cino, Maria
AU - Critch, Jeff
AU - Denson, Lee
AU - Deslandres, Colette
AU - El-Matary, Wael
AU - Herfarth, Hans
AU - Higgins, Peter
AU - Huynh, Hien
AU - Hyams, Jeff
AU - Mack, David
AU - McGrath, Jerry
N1 - Publisher Copyright:
© 2021 AGA Institute
PY - 2021/4
Y1 - 2021/4
N2 - Background & Aims: Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown. Methods: We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs). Results: Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC–colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice. Conclusions: We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.
AB - Background & Aims: Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown. Methods: We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs). Results: Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC–colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice. Conclusions: We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.
KW - Microbiome
KW - Proteolytic Activity
KW - Ulcerative Colitis
UR - http://www.scopus.com/inward/record.url?scp=85103712116&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2020.12.004
DO - 10.1053/j.gastro.2020.12.004
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C2 - 33310084
AN - SCOPUS:85103712116
SN - 0016-5085
VL - 160
SP - 1532
EP - 1545
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -