# Role of Gut Microbial Translocation in Initiating Autoimmunity

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2022 · —

## Abstract

Genetic and environmental factors contribute to systemic lupus erythematosus (SLE). Previous studies showed
environmental factors such as bacterial products or their-induced inflammatory mediators (e.g., IFN-α) are
involved in SLE pathogenesis. Previous studies from others and we revealed that multiple autoAbs are more
commonly detected in first-degree relatives of lupus patients (FDRs), compared to unrelated healthy controls
(UHCs). In addition, FDRs have heightened levels of inflammation (e.g., B lymphocyte stimulator (BLyS), and
IFN-α) associated with TLR stimulation and B cell activation compared with UHCs. It is unclear the initial trigger
for autoantibody production. This lack of understanding of early events in development of autoimmunity is a
critical barrier for disease prevention. FDRs, rather than patients, provide a study population, genetically prone
and possibly environmentally exposed, who are not on immune modulatory drugs nor impacted by disease,
allowing conclusions less confounded by external factors.
In preliminary studies, we found: 1) increased presence and diversity of autoAbs in healthy FDRs of lupus
patients compared to unrelated healthy controls (UHCs); 2) increased microbial product translocation (plasma
LPS) associated with elevated plasma autoAb levels (anti-dsDNA, anti-ssDNA, and anti-nucleosome); and 3)
decreased plasma microbial diversity in FDRs with enrichment of the family Streptococcaceae and genus of
Streptococcus product translocation in UHCs and relative enrichment of Pseudomonas product translocation in
FDRs relative to UHCs. Recently SNPs in the coding region of two genes that mediate gut permeability were
identified as associated with lupus disease risk. We hypothesize that increased gut microbial product
translocation and its-associated inflammation in FDR individuals, a result of a “leaky” gut, serve as
initiators for autoAb production and later SLE development. In the current study, we will recruit matched
UHCs, FDRs, and lupus patients. A “leaky” gut leading to systemic bacterial products and autoAb induction in
the pathogenesis of lupus represents a novel mechanism to explain disease initiation in susceptible genetic high-
risk individuals.
Specific Aim 1: Determine intestinal barrier integrity, systemic bacterial product translocation, and its
mediated inflammation in the activation of B cells. We hypothesize that plasma autoAb levels are associated
with intestinal barrier integrity, inflammation and systemic bacterial products. In vivo gut permeability tests,
plasma LPS and total bacterial rDNA levels, plasma TLR-related inflammation (e.g., IL-6 and IFN-α), B cell
subset activation and a series of lupus-related autoAbs (e.g., anti-dsDNA and anti-nucleosome IgGs) will be
assessed in patients, FDRs and UHCs.
Specific Aim 2: Determine systemic and mucosal microbial components and the effect of certain
bacterial product translocation on autoantibody production. We have observed relative enrichment of
P...

## Key facts

- **NIH application ID:** 10426227
- **Project number:** 5I01CX001211-08
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Gary S Gilkeson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-10-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426227

## Citation

> US National Institutes of Health, RePORTER application 10426227, Role of Gut Microbial Translocation in Initiating Autoimmunity (5I01CX001211-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10426227. Licensed CC0.

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