# Mediating Effects of Immunophenotypes on the Causal Relationship of Gut Microbiota and Their Metabolic Pathways With Osteonecrosis: A Mendelian Randomization Analysis

## TL;DR

This study explores how gut microbiota and their metabolic pathways may cause or protect against osteonecrosis, with immune cells playing a mediating role.

## Contribution

The study identifies specific gut microbial species, metabolic pathways, and immune cell types with causal and mediating roles in osteonecrosis.

## Key findings

- 16 gut microbial species and 23 immunophenotypes were identified as causal factors in osteonecrosis susceptibility.
- The sulfate assimilation and cysteine biosynthesis superpathway of gut microbiota showed a protective effect against osteonecrosis.
- CD33− HLA DR + Myeloid cell and T cell % lymphocyte mediated 4.15% and 12.16% of the protective effect, respectively.

## Abstract

This study examined the potential causal relationship between gut microbiota and osteonecrosis and analyzed the mediating effects of immunophenotypes to establish evidence-based causal associations.

Bayesian weighted Mendelian randomization and the inverse-variance weighted method were used to evaluate the causal relationships between osteonecrosis and 412 gut microbial species and their metabolic pathways, as well as between osteonecrosis and 731 immune cell signatures. Mediation analysis was conducted to assess the role of immune cells in mediating the relationship between gut microbiota and osteonecrosis.

A total of 16 gut microbial species and their metabolic pathways and 23 immunophenotypes were identified as causal factors in susceptibility to osteonecrosis (p < 0.05). The superpathway of sulfate assimilation and cysteine biosynthesis of the gut microbiota demonstrated a protective effect against osteonecrosis. The absolute count of CD33− HLA DR + Myeloid cell exhibited a mediation effect of 4.15%, while T cell %lymphocyte demonstrated a mediation effect of 12.16% in this protective mechanism.

The study findings highlighted the role of the superpathway of sulfate assimilation and cysteine biosynthesis of the gut microbiota in exerting a protective effect against osteonecrosis. This protective effect is substantially mediated by a decrease in the absolute count of CD33− HLA DR + Myeloid cell and an increase in T cell % lymphocyte.