# The mechanisms underlying maternal obesity-induced microbial DNA accumulation in fetus and offspring metabolic abnormalities

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $237,000

## Abstract

Project Summary/Abstract
The increase in childhood obesity/Type 2 diabetes is paralleling a worldwide increase in obesity-associated
metabolic syndrome. Maternal obesity is one of the key drivers tightly associated with the incidence of
offspring obesity and metabolic disorders. However, the mechanisms underlying the impacts of maternal
obesity on offspring metabolic disorders are not fully understood. Our recent work has led to the discovery
that CRIg+ macrophages protect host cells from the gut microbial DNA-containing extracellular vesicle
(mEV)-induced cellular abnormalities, whereas CRIg+ macrophages are absent in the context of obesity in
both humans and mice, accompanied with enrichment of bacterial DNAs in host cells and worsen insulin
sensitivity or insulin secretion. Intestinal mEVs can readily pass through the gut barrier of obese mice and
further deliver microbial DNAs into key metabolic tissues. We further demonstrated the critical role of CRIg+
macrophages in clearing gut mEVs from bloodstream, as evidenced by a robust accumulation of microbial
DNAs within key metabolic tissues in NCD CRIg-/- mice after intravenously injected with gut mEVs. By contrast,
CRIg+ cells in NCD WT mice blocked the infiltration of gut mEVs through a C3-mediated mechanism, thus
preventing the enrichment of bacterial DNAs in host cells. Recovery of CRIg+ cells efficiently attenuated
tissue inflammation and metabolic disorders in obese mice. Depletion of microbial DNAs blunted the
pathogenic effects of gut mEVs, while accumulation of microbial DNAs triggered the activation of
cGAS/STING pathway for host cell abnormalities. By contrast, knockout of cGAS prevented microbial DNA-
induced cellular disorders. These results lead to the conclusion that CRIg+ macrophages protect host cells
from the pathogenesis of gut mEVs. We also found a significant reduction in CRIg+ macrophage population
in maternal liver and placenta in obese pregnancy, concomitant with bacterial DNA enrichment in embryos.
By contrast, lean pregnant mice harbored high abundance of CRIg+ macrophages in placenta, and no 16s
rRNAs were detected in their embryos. Maternal gut mEVs can reach and deliver microbial DNAs into
embryos in obese pregnant mice or lean CRIg-/- mice, but not in lean WT mice. Thus, this proposal seeks to
reveal the important roles of CRIg+ macrophages in pregnancy and the impacts of maternal obesity-induced
embryonic microbial DNA enrichment on offspring metabolic responses. We will further determine: 1) critical
roles of maternal CRIg+ macrophages in blocking the infiltration of gut mEVs into embryos; 2) effects of
maternal obesity on the development of embryonic CRIg+ macrophages; 3) effects of maternal obesity-
induced embryonic microbial DNA accumulation on offspring tissue inflammation and metabolic phenotypes.

## Key facts

- **NIH application ID:** 10350153
- **Project number:** 1R21HD107516-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Wei Ying
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $237,000
- **Award type:** 1
- **Project period:** 2022-06-20 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10350153

## Citation

> US National Institutes of Health, RePORTER application 10350153, The mechanisms underlying maternal obesity-induced microbial DNA accumulation in fetus and offspring metabolic abnormalities (1R21HD107516-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10350153. Licensed CC0.

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