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Research Paper|Volume 17, Issue 5|pp 1298—1312

The aspartate superpathway in gut microbiota-related metabolic pathways mediates immune cell protection against COPD and IPF: a Mendelian randomization analysis

Lei Chen1, Haoyan Chen1, Qin Li2, Jun Ma3, Yanzhi Feng2, Shenghua Zhang4, Yu Han1, Jie Pan5, Mingjiong Zhang1, Kai Sun1, Shuangshuang Wu1
  • 1Department of Geriatrics, Jiangsu Key Laboratory of Geriatrics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
  • 2Center of Molecular and Cellular Oncology, Yale School of Medicine, New Haven, CT 06510, USA
  • 3Department of Respiratory Medicine, Affiliated Nantong Hospital of Shanghai University (The Sixth People’s Hospital of Nantong), Nantong, China
  • 4The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
  • 5Department of Rheumatology and Immunology, Liyang Branch of Jiangsu Province Hospital, Liyang, China
* Equal contribution
Received: January 20, 2025Accepted: March 20, 2025Published: May 15, 2025
https://doi.org/10.18632/aging.206250

Copyright: © 2025 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: Both genetic and environmental factors can influence idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) development. The gut microbiota plays crucial roles in maintaining tissue homeostasis. Dysregulation of the gut microbiota can result in disease. However, whether the alteration of the gut microbiota influences IPF and COPD remains unknown.

Research Question: What is the causal relationship between IPF, COPD and the gut microbiota-related metabolic pathways? What are the potential intermediate mediators in this relationship?

Study Design and Methods: Intersect the gut microbiota and its metabolic pathways associated with IPF and COPD. Utilizing summary data from GWAS in public databases, a two-sample Mendelian randomization (MR) analysis was conducted on the gut microbiota-related metabolic pathway, the aspartate superpathway, in relation to IPF and COPD. Furthermore, we employed a two-step MR to quantify the proportion of influence mediated by monocytes and cDCs on the aspartate superpathway in relation to IPF and COPD.

Results: The MR analysis found that the aspartate superpathway decreased the risk of developing IPF and COPD. Monocytes and cDCs acted as intermediary substances, participating in this with influence proportions of 7.88% and 6.27%, respectively.

Interpretation: There is a causal link between the gut microbiota-related metabolic pathway, the aspartate superpathway, and IPF and COPD, where the influence is partially mediated by monocytes and cDCs. In clinical practice, we increase the focus on gut microbiota-mediated immune cells in relation to IPF and COPD.