THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



Link between the gut microbiome and lung disease gets researchers’ attention

Joyce Wu, PhD
Joyce Wu, PhD

The interaction between the gut microbiome and autoimmune arthritis-related lung disease will be examined in an ACR symposium, Microbes & Mucosal Immunity: Host Defense or Subversion on Sunday from 1:00 – 2:00 pm in Room W178b.

”A lot of rheumatoid arthritis patients have lung complications,” said Joyce Wu, PhD, Associate Professor of Immunology at the University of Arizona College of Medicine and Arthritis Center, Tucson, AZ. “It’s not joint disease that kills our patients; it is always something outside the joint. And lung complications are one of the worst kinds of development for RA patients. Once you have the fibrosis that you get with interstitial lung disease, your prognosis is about 2.6 years. It’s almost like having cancer.”

There are multiple effective therapies for joint disease in RA and more appearing every year, Dr. Wu noted, but no effective treatment for RA-related interstitial lung disease. The difference is basic research.

“It is clear that bacteria in the gut affect disease outside the gut, systemically. The bugs are not out there, so how exactly do they do it?”

Dr. Wu’s target is the interaction between the gut microbiome and autoimmune arthritis-related lung disease. Also on Sunday, William F.C. Rigby, MD, Professor of Microbiology and Immunology at the Geisel School of Medicine at Dartmouth University, Lebanon, NH, will explore interactions between the gut microbiome, adaptive immunity, and pseudomonas infections in the lung.

The pathogenesis and progression of RA joint disease is well understood; less so when the lung is involved. And without an understanding of mechanisms that lead to interstitial lung disease in RA, it is all but impossible to design effective therapies.

The good news, Dr. Wu said, is that her lab has a mouse model that develops lung disease involving the same lymphoid aggregate in the interstitial space that humans with RA can develop. In her mouse model, one of the key factors leading to the development of lymphoid aggregates in the lungs is a pathobiome in the gut.

“Lung and gut share similar homing receptors,” Dr. Wu said. “In the embryo, lung and intestine develop from the same cell type. So if you are an immune cell that is born in the gut, you are driven to the lung because of a particular chemokine and the shared homing receptors. There is a definite communication channel between the gut and the lung, a gut-lung axis.”

Commensal bacteria and the host have coevolved to maintain a relative balance that benefits both the bacterial communities and the host.

But if the gut microbiota is disrupted by antibiotics or some other event, the microbiome that regrows is not identical to the microbiome that was present before the insult. And the new microbiome may not be as well-behaved, particularly if it contains E.Coli or other proteobacteria.

Host defense molecules such as antimicrobial peptides in the gut mucosal layer keep most microbes about 50 micrometers from the intestinal epithelium, about five lymphocyte diameters, Dr. Wu said. But some species that can get really close or even attach to intestinal epithelium exert immunomodulatory effects that allow them to dictate host health and disease status. Her collaboration with Randy Longman, MD, PhD, an Assistant Professor of Medicine at Weill Cornell Medicine, New York, NY, has demonstrated that bugs with close proximity to host isolated from spondyloarthritis patients indeed cause arthritis development in the mouse arthritis model.

“If you look at the immune system, the gut mucosal surface is the only place where you have constant antigen stimulus,” Dr. Wu said. “Microbial infection followed by autoimmune reaction, people have known about that phenomenon for a long time. But few have dug into the mucosal side. The field of microbiome and mucosal immunity is one of the hottest areas right now because their interactions affect all sorts of disease and health. Autoimmune arthritis-related lung disease is one defined area, but the same thing is happening in cancer, the central nervous, and the rest of the body.”