# Role of Peritoneal Macrophage in Spontaneous Bacterial Peritonitis

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $536,389

## Abstract

Abstract
 Spontaneous bacterial peritonitis (SBP) is a major complication of cirrhosis and associated with high
mortality rate. Moreover, the effectiveness of antimicrobial therapy, the current standard of care, is deteriorating
due to the global emergence of multidrug-resistant pathogens. Hence, it is essential to develop novel
management strategies, for which furthering our understanding of the pathophysiology is imperative.
 Gut dysbiosis and impaired intestinal immunity in cirrhosis cooperatively predispose to the translocation of
gut flora into the mesenteric lymphatics and, subsequently, to the peritoneum. Although this mechanism has
been regarded as the primary pathophysiology, SBP develops only when the balance between peritoneal
antibacterial immunity and bacterial virulence shifts in favor of the invading pathogen.
 Peritoneal macrophage (PM) is the major cell type in the peritoneum and is considered as the first line of
antibacterial defense owing to the robust capacity in the engulfment and phagolysosomal digestion of pathogens.
Moreover, PM sensing of microbe results in the production of cytokines/chemokines required for neutrophil
recruitment and activation. Accordingly, PM is also essential for triggering the second wave of antibacterial
response. Despite its perceived importance, the role of PM in SBP has been poorly understood. Furthermore, it
remains largely elusive whether the development of cirrhosis alters the antibacterial properties of PM, and how
it impacts the overall potency of peritoneal antibacterial immunity.
 Our single cell RNA sequencing analyses of peritoneal immune cells of rat with cirrhosis demonstrate a
profound alteration of PM characteristics, including a substantial downregulation of the master regulator of PM,
GATA6, a vitamin A (VA)-inducible transcription factor. In addition, PM of cirrhotic rats exhibit a markedly reduced
capacity to produce inflammatory mediators in response to bacterial peritonitis, resulting in impaired neutrophil
recruitment and activation as well as the insufficient bacterial clearance. Our studies also reveal that two common
features of cirrhosis, VA deficiency and ascites accumulation, both independently contribute to the dysregulation
of PM antibacterial function, with both processes involving GATA6 downregulation. Moreover, PM isolated from
cirrhosis patients demonstrate a decreased number of GATA6-expressing PM, which correlates with the degree
of antibacterial function impairment. These findings led to our hypothesis: “cirrhosis impairs the antibacterial
properties of PM through the downregulation of GATA6 expression, which contributes to SBP development”.
 Accordingly, this proposal aims to close the knowledge gap regarding the role of PM in SBP through
defining: (Aim 1) the impact of cirrhosis on PM antibacterial functions, (Aim 2) the influence of VA insufficiency
on PM antibacterial properties, and (Aim 3) the effect of cirrhotic ascites on the antimicrobial activity of P...

## Key facts

- **NIH application ID:** 10877921
- **Project number:** 5R01AI179019-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Takeshi Saito
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,389
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877921

## Citation

> US National Institutes of Health, RePORTER application 10877921, Role of Peritoneal Macrophage in Spontaneous Bacterial Peritonitis (5R01AI179019-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10877921. Licensed CC0.

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