# Gut regulation of bariatric surgery-induced bone loss

> **NIH NIH P20** · MAINEHEALTH · 2024 · $265,587

## Abstract

Gut regulation of bariatric surgery-induced bone loss (Z. Li, Project Lead)
Bariatric surgery-associated skeletal complications include a two-fold risk in bone fracture, a side effect that
has been observed since the early 1990s. The most common bariatric surgery is vertical sleeve gastrectomy
(VSG), which leads to ~3-7% bone loss at the axial skeleton after 6-24 months. Current clinical management
includes bone mineral density assessments, consumption of adequate dietary calcium, vitamin D and protein,
and weight-bearing exercise. These countermeasures minimize, but do not fully prevent bone loss secondary
to bariatric surgery. A better mechanistic understanding of bone loss associated with bariatric surgery is
necessary to properly design and evaluate preventive and therapeutic strategies. Changes in gut hormones
and microbiota are potential mechanisms driving bone loss, but the contribution of the major surgical site (the
stomach) has been largely neglected. We propose that gastric hormones contribute to bariatric surgery-
induced skeletal complications. In key preliminary data, we found gastric X/A-like cells (P/D1 cells in humans),
a unique endocrine cell population, contribute to the regulation of global lipid metabolism, marrow adiposity
and bone formation, suggesting a stomach-bone axis. The aims of this proposal are: 1) to determine the
effects of gastric X/A-like cell-derived secretory factors on VSG-induced bone loss; and 2) to identify and
characterize gastric hormones (in additional to ghrelin) derived from X/A-like cells that regulate bone marrow
cells and skeletal homeostasis. For the first aim, we will utilize a diphtheria toxin model to deplete X/A-like cells
in the adult mouse stomach, and analyze bone parameters to determine the importance of X/A-like cells in
bone homeostasis. In addition, X/A-like cell derived ghrelin concentrations are decreased following VSG;
therefore, we will test the protective effects of ghrelin on VSG-induced bone complications. For the second
aim, we will determine the effects of X/A-like cell-derived secretome on adipogenesis, bone remodeling and
hematopoiesis. Furthermore, unbiased transcriptomic and proteomic screens will be performed to define the
secretome of X/A-like cells. This project will be supported by the Physiology Core for analyses of mouse body
composition, activity, and energy expenditure. The Histopathology and Microscopy Core will provide services
to characterize the tissue (gut and bone) phenotypes via histological and immunostaining analyses. The
Proteomics and Lipidomics Core will perform protein profiling of the gastric X/A-like cell secretome. The
proposed strategy will rigorously test the hypothesis that gastric X/A-like cell-derived secretory factors
contribute to VSG-associated skeletal complications. Determination of the importance of this cell population in
bone metabolism will provide new therapeutic targets for managing bariatric surgery-induced bone loss. This
project is...

## Key facts

- **NIH application ID:** 10888339
- **Project number:** 5P20GM121301-07
- **Recipient organization:** MAINEHEALTH
- **Principal Investigator:** Ziru Li
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $265,587
- **Award type:** 5
- **Project period:** 2017-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888339

## Citation

> US National Institutes of Health, RePORTER application 10888339, Gut regulation of bariatric surgery-induced bone loss (5P20GM121301-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10888339. Licensed CC0.

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