An efficient urine peptidomics workflow identifies chemically defined dietary gluten peptides from patients with celiac disease

Brad A Palanski; Nielson Weng; Lichao Zhang; Andrew J Hilmer; Lalla A Fall; Kavya Swaminathan; Bana Jabri; Carolina Sousa; Nielsen Q Fernandez-Becker; Chaitan Khosla; Joshua E Elias

doi:10.1038/s41467-022-28353-1

An efficient urine peptidomics workflow identifies chemically defined dietary gluten peptides from patients with celiac disease

Nat Commun. 2022 Feb 16;13(1):888. doi: 10.1038/s41467-022-28353-1.

Authors

Brad A Palanski^#^{1

2}, Nielson Weng^#^{1

3

4}, Lichao Zhang⁵, Andrew J Hilmer¹, Lalla A Fall⁶, Kavya Swaminathan⁷, Bana Jabri^{8

9

10}, Carolina Sousa¹¹, Nielsen Q Fernandez-Becker¹², Chaitan Khosla^{13

14

15}, Joshua E Elias¹⁶

Affiliations

¹ Department of Chemistry, Stanford University, Stanford, CA, USA.
² Department of Medicine, Brigham and Women's Hospital, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
³ School of Medicine, Stanford University, Stanford, CA, USA.
⁴ Medical Scientist Training Program, Stanford University, Stanford, CA, USA.
⁵ Chan Zuckerberg Biohub, San Francisco, CA, USA.
⁶ Stanford ChEM-H, Stanford University, Stanford, CA, USA.
⁷ Division of Blood and Bone Marrow Transplantation, Stanford University, Stanford, CA, USA.
⁸ Department of Medicine, University of Chicago, Chicago, IL, USA.
⁹ Committee on Immunology, University of Chicago, Chicago, IL, USA.
¹⁰ Department of Pathology and Pediatrics, University of Chicago, Chicago, IL, USA.
¹¹ Facultad de Farmacia, Departamento de Microbiología y Parasitología, Universidad de Sevilla, Sevilla, Spain.
¹² Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Stanford, CA, USA.
¹³ Department of Chemistry, Stanford University, Stanford, CA, USA. khosla@stanford.edu.
¹⁴ Stanford ChEM-H, Stanford University, Stanford, CA, USA. khosla@stanford.edu.
¹⁵ Department of Chemical Engineering, Stanford University, Stanford, CA, USA. khosla@stanford.edu.
¹⁶ Chan Zuckerberg Biohub, San Francisco, CA, USA. josh.elias@czbiohub.org.

^# Contributed equally.

Abstract

Celiac disease (CeD) is an autoimmune disorder induced by consuming gluten proteins from wheat, barley, and rye. Glutens resist gastrointestinal proteolysis, resulting in peptides that elicit inflammation in patients with CeD. Despite well-established connections between glutens and CeD, chemically defined, bioavailable peptides produced from dietary proteins have never been identified from humans in an unbiased manner. This is largely attributable to technical challenges, impeding our knowledge of potentially diverse peptide species that encounter the immune system. Here, we develop a liquid chromatographic-mass spectrometric workflow for untargeted sequence analysis of the urinary peptidome. We detect over 600 distinct dietary peptides, of which ~35% have a CeD-relevant T cell epitope and ~5% are known to stimulate innate immune responses. Remarkably, gluten peptides from patients with CeD qualitatively and quantitatively differ from controls. Our results provide a new foundation for understanding gluten immunogenicity, improving CeD management, and characterizing the dietary and urinary peptidomes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acid Sequence
Celiac Disease / immunology*
Celiac Disease / pathology
Chromatography, Liquid
Epitopes, T-Lymphocyte / immunology
Glutens / analysis*
Glutens / immunology
Glutens / metabolism
Hordeum / chemistry
Humans
Mass Spectrometry
Proteome / analysis*
Secale / chemistry
T-Lymphocytes / immunology
Triticum / chemistry
Urine / chemistry*

Substances

Epitopes, T-Lymphocyte
Proteome
Glutens

Grants and funding

R01 DK063158/DK/NIDDK NIH HHS/United States