# Project 4: Impact of the Gut Microbiome on Liver Innate Immunity and Skeletal Function

> **NIH NIH P20** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $224,250

## Abstract

Project 4 – Project Summary
The innate immune response helps maintain a balanced homeostatic relationship with the commensal gut
microbiota, but importantly has potent indirect effects on host physiology. Gut microbiota immunomodulatory
actions impact bone remodeling, but the mechanisms are unclear. Bone remodeling is the continuous process
in which the skeleton is dynamically renewed by the actions of bone resorbing osteoclasts and bone forming
osteoblasts. Skeletal deterioration occurs when the action of the osteoclasts exceeds those of the osteoblasts.
Young-adult germfree (GF) mice have increased bone mass, which is reversed upon colonization with gut
microbiota from specific pathogen free (SPF) mice. Commensal microbiota in SPF mice enhance
osteoclastogenesis and suppress osteoblastogenesis, which drives bone loss. Intriguingly, gut microbiota effects
on bone remodeling do not appear to be mediated by immune responses within the gut, but rather reflect
communication between the gut and liver. When compared to GF mice, SPF mice have increased inflammatory
cytokines in the liver, but not in the ileum. SPF mice also have enhanced inflammatory monocytes in liver draining
lymph nodes, but not the mesenteric lymph nodes. These findings support a novel signaling axis between the
gut and liver that regulates bone remodeling. The scientific premise is supported by preliminary data showing
that Myd88-dependent signaling components were increased and hepatocyte-associated innate immune factors
were upregulated in the livers of SPF compared to GF mice. Commensal gut microbiota increased liver and
serum levels of lipocalin-2 (LCN2), which is a candidate innate immune factor that controls bone remodeling.
This research will test the overall hypothesis that circulating gut microbiota-derived ligands stimulate liver cell
MyD88-dependent synthesis of innate immune serum factors that regulate bone remodeling. Hepatocyte-specific
null and myeloid-specific null mice will be housed under GF and SPF conditions, and proteomics, microbiome
sequencing, and osteoimmunology research techniques will be applied. Aim 1 will test the hypothesis that the
gut microbiota stimulates liver innate immunity and the synthesis of related serum factors through MyD88-
dependent signaling in hepatocytes and liver macrophages. Aim 2 will test the hypothesis that gut microbiota
stimulation of hepatocyte-derived LCN2 enhances osteoclastogenesis and suppresses osteoblastogenesis.!The
proposed studies will determine the relationship between the commensal gut microbiota, liver innate immune
response, and bone remodeling. This research is clinically relevant because the mechanisms driving continuous
bone loss in the young adult skeleton are unknown. Individuals with gut and liver disorders have an increased
prevalence of osteoporosis, which further underscores the relationship between the gut, liver and bone.

## Key facts

- **NIH application ID:** 9853392
- **Project number:** 1P20GM130457-01A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Chad Michael Novince
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $224,250
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853392

## Citation

> US National Institutes of Health, RePORTER application 9853392, Project 4: Impact of the Gut Microbiome on Liver Innate Immunity and Skeletal Function (1P20GM130457-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9853392. Licensed CC0.

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