Investigating the Role of Gut Microbiota in IPF

New evidence is elucidating the apparent link between gut microbiota and idiopathic pulmonary fibrosis (IPF), which may be mediated by circulating inflammatory proteins. The study, which was published in The Clinical Respiratory Journal, identifies 1 particular protein that appears to play a key mediating role.¹

IPF has been linked with a number of risk factors, including age, a history of smoking, and air pollution, the authors noted. Yet, the specific pathogenic factors behind the disease have not yet been clarified.

One novel theory highlights the role of the so-called “gut-lung axis,” arguing that “long-distance cross-talk” between the lungs and the gut, gut microbiota imbalance, lung homeostasis, and susceptibility to lung diseases may create the conditions for lung disease to develop.²

A 2024 study found that the cannabidiol could reverse intestinal microbiota imbalances in mice and that such a reversal had the effect of attenuating pulmonary fibrosis in the animal model.³

Given that a key role of the gut microbiota is to regulate immune and inflammatory levels, the authors investigated the genetic role of gut microbiota in IPF to determine whether it is mediated by circulating inflammatory proteins.

The investigators set up a two-step Mendelian randomization study to analyze the question, primarily using an inverse variance weighted approach. Mendelian randomization uses whole genome association analysis to infer causal relationships between exposures and outcomes. The data used in the study were gathered from public data sets, the authors said. Their analysis implicated 12 taxa of gut microbiota and 8 circulating inflammatory proteins as potentially playing a causal role in IPF.

Among those 12 taxa, they found that only the taxon Actinomyces and the circulating inflammatory protein C-C motif chemokine ligand 11 (CCL11) had a significant connection. They found that the proportion of indirect effects of CCL11 was 0.063 (95% CI, 1.016-1.126; P = .004), meaning that it accounted for 13.035% of the total effect.

“These data indicated that CCL11 was a critical moderator in the causal pathway from Actinomyces to IPF,” the authors wrote.

There is already a significant amount of evidence that Actinomyces plays a role in multiple diseases. For instance, a study from last year implicated Actinomyces and other opportunistic bacteria as playing a role in severe COVID-19.³ CCL11 has been associated with eosinophilic inflammatory diseases, the authors noted, and one study found that inhibiting CCL11 release from T helper 2 cells “could control the transition from an acute inflammatory response to chronic fibrosis.”⁴

The investigators said further research will be needed to better understand how these new findings about Actinomyces and CCL11 might translate into the clinic.

There were a number of limitations in the study. The datasets used were based primarily on European populations, which the authors noted may limit the generalizability of their findings. They also said that some of the single nucleotide polymorphisms that were weakly associated with exposure factors in the study may be influenced by other unknown factors. They noted that they only analyzed the role of 211 bacteria and 91 circulating inflammatory proteins on IPF, and only approximately 14,000 bacteria samples and cases were collected, which they said could lead to bias.

While Actinomyces-CCL11 was the only significant connection with IPF identified in the study, the authors said there may well be other mediators that have yet to be studied.

References

1. Zhu H, Chen C, Guo H, Zhang B, Hu Q. The role of gut microbiota on idiopathic pulmonary fibrosis mediated by circulating inflammatory proteins: A two-step, two-sample Mendelian randomization study. Clin Respir J. 2025;19(9):e70120. doi:10.1111/crj.70120
2. Ananya FN, Ahammed MR, Fahem MM, et al. Association of intestinal microbial dysbiosis with chronic obstructive pulmonary disease. Cureus. 2021;13(11):e19343. doi:10.7759/cureus.19343
3. Shimizu K, Hirata H, Tokuhira N, et al. Dysbiosis of gut microbiota in patients with severe COVID-19. Acute Med Surg. 2024;11(1):e923. doi:10.1002/ams2.923
4. Dong J, Ma Q. In vivo activation of a T helper 2-driven innate immune response in lung fibrosis induced by multi-walled carbon nanotubes. Arch Toxicol. 2016;90(9):2231-2248. doi:10.1007/s00204-016-1711-1