Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity

Robert H. Mills; Parambir S. Dulai; Yoshiki Vázquez-Baeza; Consuelo Sauceda; Noëmie Daniel; Romana R. Gerner; Lakshmi E. Batachari; Mario Malfavon; Qiyun Zhu; Kelly Weldon; Greg Humphrey; Marvic Carrillo-Terrazas; Lindsay De Right Goldasich; MacKenzie K. Bryant; Manuela Raffatellu; Robert A. Quinn; Andrew T. Gewirtz; Benoit Chassaing; Hiutung Chu; William J. Sandborn; Pieter C. Dorrestein; Rob Knight; David J. Gonzalez

doi:10.1038/s41564-021-01050-3

Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity

Robert H. Mills, Parambir S. Dulai, Yoshiki Vázquez-Baeza, Consuelo Sauceda, Noëmie Daniel, Romana R. Gerner, Lakshmi E. Batachari, Mario Malfavon, Qiyun Zhu, Kelly Weldon, Greg Humphrey, Marvic Carrillo-Terrazas, Lindsay De Right Goldasich, MacKenzie K. Bryant, Manuela Raffatellu, Robert A. Quinn, Andrew T. Gewirtz, Benoit Chassaing, Hiutung Chu, William J. SandbornPieter C. Dorrestein, Rob Knight^*, David J. Gonzalez^*

^*Corresponding author for this work

Medicine, Gastroenterology Division

Research output: Contribution to journal › Article › peer-review

202 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	262-276
Number of pages	15
Journal	Nature Microbiology
Volume	7
Issue number	2
DOIs	https://doi.org/10.1038/s41564-021-01050-3
State	Published - Feb 2022

Funding

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. 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.

ASJC Scopus subject areas

Microbiology
Immunology
Applied Microbiology and Biotechnology
Genetics
Microbiology (medical)
Cell Biology

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10.1038/s41564-021-01050-3

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Mills, R. H., Dulai, P. S., Vázquez-Baeza, Y., Sauceda, C., Daniel, N., Gerner, R. R., Batachari, L. E., Malfavon, M., Zhu, Q., Weldon, K., Humphrey, G., Carrillo-Terrazas, M., Goldasich, L. D. R., Bryant, M. K., Raffatellu, M., Quinn, R. A., Gewirtz, A. T., Chassaing, B., Chu, H., ... Gonzalez, D. J. (2022). Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity. Nature Microbiology, 7(2), 262-276. https://doi.org/10.1038/s41564-021-01050-3

@article{b40b68a5034d4191914df8559687bf42,

title = "Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity",

abstract = "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{\textquoteright}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.",

author = "Mills, {Robert H.} and Dulai, {Parambir S.} and Yoshiki V{\'a}zquez-Baeza and Consuelo Sauceda and No{\"e}mie Daniel and Gerner, {Romana R.} and Batachari, {Lakshmi E.} and Mario Malfavon and Qiyun Zhu and Kelly Weldon and Greg Humphrey and Marvic Carrillo-Terrazas and Goldasich, {Lindsay De Right} and Bryant, {MacKenzie K.} and Manuela Raffatellu and Quinn, {Robert A.} and Gewirtz, {Andrew T.} and Benoit Chassaing and Hiutung Chu and Sandborn, {William J.} and Dorrestein, {Pieter C.} and Rob Knight and Gonzalez, {David J.}",

note = "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: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = feb,

doi = "10.1038/s41564-021-01050-3",

language = "English (US)",

volume = "7",

pages = "262--276",

journal = "Nature Microbiology",

issn = "2058-5276",

publisher = "Nature Research",

number = "2",

}

Mills, RH, Dulai, PS, Vázquez-Baeza, Y, Sauceda, C, Daniel, N, Gerner, RR, Batachari, LE, Malfavon, M, Zhu, Q, Weldon, K, Humphrey, G, Carrillo-Terrazas, M, Goldasich, LDR, Bryant, MK, Raffatellu, M, Quinn, RA, Gewirtz, AT, Chassaing, B, Chu, H, Sandborn, WJ, Dorrestein, PC, Knight, R & Gonzalez, DJ 2022, 'Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity', Nature Microbiology, vol. 7, no. 2, pp. 262-276. https://doi.org/10.1038/s41564-021-01050-3

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.

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DO - 10.1038/s41564-021-01050-3

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VL - 7

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EP - 276

JO - Nature Microbiology

JF - Nature Microbiology

IS - 2

ER -

Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity

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