# Humoral immunodeficiency disrupts bile-acid-induced immune tolerance in the small intestine

> **NIH NIH R56** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2022 · $246,504

## Abstract

Project Summary
Humoral immunodeficiency is the most frequently diagnosed form of primary immunodeficiency in humans.
Common variable immunodeficiency (CVID) is the most clinically severe form, and chronic gastrointestinal
complications are both common in CVID patients and refractory to treatment by intravenous Ig therapy. A severe
GI disorder is termed 'CVID enteropathy'; a small intestine (SI)-specific enteropathy that presents clinically as
chronic diarrhea and malabsorption. Bile acids (BAs) are emulsifiers produced by the liver and secreted into the
gut that promote the solubilization and absorption of dietary lipids and lipid-soluble vitamins. They may also serve
as signaling molecules capable of inducing tolerogenic responses in tissue-resident immune cells. Mucosal
antibody deficiency alters microbiota composition. Given that the microbiota profoundly influence luminal BA
biochemistry, the overarching hypothesis this R01 proposal will address is that mucosal antibody-
deficiency results in aberrant bacterial BA metabolism that abolishes BA-induced immunological
tolerance in the SI. In this proposal, we provide evidence supporting that mucosal antibody-deficiency results
in aberrant inflammatory immune responses that are associated with the development of SI enteropathy;
potentially driven by elevated bacterial bile salt hydrolase (bsh) activity that causes BA malabsorption (BAM).
We also identify that bsh ablation or oral BA supplementation alleviates BAM and suppresses inflammatory
disease. The objective of Specific Aim #1 is to define how humoral immunity influences BA homeostasis, and
how this coordinates establishment of a tolerogenic immune phenotype in the SI. Several complementary models
will be utilized to address this fundamental question and will incorporate the advanced techniques of ultra-purity
liquid chromatography mass spectrometry (UPLC-MS) to comprehensively characterize BA pool composition,
and paired high-parameter flow cytometry and single cell RNA sequencing to characterize SI-resident immune
cell phenotypes. The objective of Specific Aim #2 is to demonstrate how mucosal antibody deficiency influences
the composition and BA-metabolizing capacity of the SI-resident microbial community. Several novel and
complementary microbial colonization models, adoptive transfer models, and next-gen sequencing approaches
will be utilized to address this. The objective of Specific Aim #3 is to test the efficacy of two candidate approaches
to alleviate inflammatory SI enteropathies and involve oral BA supplementation or pharmacological knockdown
of bacterial bsh activity. Innovations from this research include the first analysis of the role of humoral immunity
plays in regulating BA metabolism, a comprehensive assessment of the role mucosal IgA and IgM antibody
responses play in SI homeostasis, characterization of a novel mechanism by which dysbiosis drives disease,
and characterization of the role bsh ablation and oral BA supplementa...

## Key facts

- **NIH application ID:** 10664252
- **Project number:** 1R56AI162986-01A1
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Jason L Kubinak
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $246,504
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10664252

## Citation

> US National Institutes of Health, RePORTER application 10664252, Humoral immunodeficiency disrupts bile-acid-induced immune tolerance in the small intestine (1R56AI162986-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10664252. Licensed CC0.

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