TY - JOUR
T1 - Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity
AU - Mills, Robert H.
AU - Dulai, Parambir S.
AU - Vázquez-Baeza, Yoshiki
AU - Sauceda, Consuelo
AU - Daniel, Noëmie
AU - Gerner, Romana R.
AU - Batachari, Lakshmi E.
AU - Malfavon, Mario
AU - Zhu, Qiyun
AU - Weldon, Kelly
AU - Humphrey, Greg
AU - Carrillo-Terrazas, Marvic
AU - Goldasich, Lindsay De Right
AU - Bryant, MacKenzie K.
AU - Raffatellu, Manuela
AU - Quinn, Robert A.
AU - Gewirtz, Andrew T.
AU - Chassaing, Benoit
AU - Chu, Hiutung
AU - Sandborn, William J.
AU - Dorrestein, Pieter C.
AU - Knight, Rob
AU - Gonzalez, David J.
N1 - Funding Information:
P.S.D., R.H.M. and C.S. were supported through a UCSD training grant from the NIH/ NIDDK Gastroenterology Training Program (T32 DK007202). P.S.D. was also supported by an American Gastroenterology Association Research Scholar Award. We thank E. Griffis, D. Bindels and the Nikon Imaging Center at UCSD for help with confocal microscopy, and the UCSD Neuroscience Microscopy Shared Facility (NS047101). This study was supported in part by NIDDK-funded San Diego Digestive Diseases Research Center (P30 DK120515, D.J.G., P.S.D.) and the UCSD Collaborative Center of Multiplexed Proteomics.
Funding Information:
P.S.D., R.H.M. and C.S. were supported through a UCSD training grant from the NIH/NIDDK Gastroenterology Training Program (T32 DK007202). P.S.D. was also supported by an American Gastroenterology Association Research Scholar Award. We thank E. Griffis, D. Bindels and the Nikon Imaging Center at UCSD for help with confocal microscopy, and the UCSD Neuroscience Microscopy Shared Facility (NS047101). This study was supported in part by NIDDK-funded San Diego Digestive Diseases Research Center (P30 DK120515, D.J.G., P.S.D.) and the UCSD Collaborative Center of Multiplexed Proteomics.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/2
Y1 - 2022/2
N2 - Ulcerative colitis (UC) is driven by disruptions in host–microbiota homoeostasis, but current treatments exclusively target host inflammatory pathways. To understand how host–microbiota interactions become disrupted in UC, we collected and analysed six faecal- or serum-based omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic and amplicon sequencing profiles of faecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic and histologic measures of disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn’s disease, 20 healthy controls) was collected and analysed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an overabundance of proteases that originated from the bacterium Bacteroides vulgatus. To test whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus-induced barrier dysfunction in vitro, and prevented colitis in B. vulgatus monocolonized, IL10-deficient mice. Furthermore, transplantation of faeces from UC patients with a high abundance of B. vulgatus proteases into germfree mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provide a resource for identifying other pathways that could be inhibited as a strategy to treat this disease.
AB - Ulcerative colitis (UC) is driven by disruptions in host–microbiota homoeostasis, but current treatments exclusively target host inflammatory pathways. To understand how host–microbiota interactions become disrupted in UC, we collected and analysed six faecal- or serum-based omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic and amplicon sequencing profiles of faecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic and histologic measures of disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn’s disease, 20 healthy controls) was collected and analysed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an overabundance of proteases that originated from the bacterium Bacteroides vulgatus. To test whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus-induced barrier dysfunction in vitro, and prevented colitis in B. vulgatus monocolonized, IL10-deficient mice. Furthermore, transplantation of faeces from UC patients with a high abundance of B. vulgatus proteases into germfree mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provide a resource for identifying other pathways that could be inhibited as a strategy to treat this disease.
UR - http://www.scopus.com/inward/record.url?scp=85123772508&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123772508&partnerID=8YFLogxK
U2 - 10.1038/s41564-021-01050-3
DO - 10.1038/s41564-021-01050-3
M3 - Article
C2 - 35087228
AN - SCOPUS:85123772508
SN - 2058-5276
VL - 7
SP - 262
EP - 276
JO - Nature Microbiology
JF - Nature Microbiology
IS - 2
ER -