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Comprehensive Profiling of the Human Fecal Proteome from IBD Patients with DIA-MS Enables Evaluation of Disease-Relevant Proteins
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  • Brandon Harder,
  • Annemarie Lekkerkerker,
  • Ellen Casavant,
  • Jason Hackney,
  • Allen Nguyen,
  • Jacqeline McBride,
  • W. Rodney Mathews,
  • Veronica Anania
Brandon Harder
Genentech Inc
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Annemarie Lekkerkerker
Genentech Inc
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Ellen Casavant
Genentech Inc
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Jason Hackney
Genentech Inc
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Allen Nguyen
Genentech Inc
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Jacqeline McBride
Genentech Inc
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W. Rodney Mathews
Genentech Inc
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Veronica Anania
Genentech Inc

Corresponding Author:[email protected]

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Abstract

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by chronic gastrointestinal inflammation. A high unmet need exists for non-invasive biomarkers in IBD to detect mucosal inflammation to monitor changes in disease severity and guide treatment decisions. Fecal proteomics has the potential to allow frequent, non-invasive monitoring of biomarkers in stool of IBD patients, however the fecal proteome remains under explored. Here a data-independent acquisition LC-MS/MS approach was used to profile the human fecal proteome in two independent cohorts of IBD patients and healthy controls (HC) to identify non-invasive biomarkers reflective of disease activity. 688 human proteins were quantified, with 523 measured in both cohorts. In UC stool 96 proteins were differentially abundant and in CD stool 126 proteins were differentially abundant compared to HC stool (absolute log2 fold change >1, p-value <0.05). Many of these fecal proteins are associated with infiltrating immune cells and ulceration/rectal bleeding, which are hallmarks of IBD pathobiology. Mapping of the identified fecal proteins to a whole blood single-cell RNA sequencing data set revealed the involvement of various immune cell subsets to the IBD fecal proteome. Findings from this study not only confirmed the presence of established fecal biomarkers for IBD, such as calprotectin and lactoferrin, but also revealed new fecal proteins from multiple pathways known to be dysregulated in IBD. These novel proteins could serve as potential non-invasive biomarkers to monitor specific aspects of IBD disease activity which could expedite clinical development of novel therapeutic targets.
25 Jun 2023Submitted to Clinical Applications
14 Jul 2023Assigned to Editor
14 Jul 2023Submission Checks Completed
14 Jul 2023Review(s) Completed, Editorial Evaluation Pending
18 Jul 2023Reviewer(s) Assigned
15 Nov 2023Editorial Decision: Revise Minor