What if an inflammatory molecule linked to multiple sclerosis (MS) could change disease not only by acting on immune cells, but also by reshaping the bacteria living in the gut?
A new study from Ashutosh Mangalam, PhD’s laboratory shows that IL-17A, a key inflammatory cytokine, can alter the gut microbiome in ways that influence regulatory immune responses and neuroinflammation.
The study, “IL-17A deficiency in HLA-DR3 transgenic mice enriches beneficial Prevotella species in gut to promote Tregs and reduce CNS autoimmunity,” published in Microbiome, found that removing IL-17A in mice carrying the human MS-associated HLA-DR3 gene led to enrichment of beneficial gut bacteria, particularly Prevotella species. These changes were accompanied by increased regulatory T cells, higher production of the anti-inflammatory cytokine IL-10, and milder experimental autoimmune encephalomyelitis (EAE), a widely used model of MS.
The study was led by co-first authors Drs. Shailesh Shahi and Sudeep Ghimire, working with a multidisciplinary team that included investigators from the University of Iowa Department of Pathology, Graduate Program in Immunology, College of Dentistry, and collaborating institutions. Dr. Mangalam led the study with Nitin Karandikar, MD, PhD, with additional contributions from Samantha Jensen, PhD; Peter Lehman, MS; Allison Rux, BS; Souradip Sinha, MSc; Nicholas Borcherding, MD, PhD; Munir Tanas, MD; Katherine Gibson-Corley, DVM, PhD; and Sukirth Ganesan, DDS, PhD, MPH.
The researchers also uncovered a mechanistic link between these microbial changes and immune regulation. IL-17A-deficient mice showed increased activation of the PPAR signaling pathway in the intestine. When the team administered the human gut commensal Prevotella copri to HLA-DR3 mice, P. copri reproduced key features of this regulatory environment, increasing PPAR pathway activity as well as FoxP3 and IL-10 expression.
Perhaps most strikingly, the protective effect could be transferred through the microbiome. When IL-17A-sufficient mice were exposed to microbiota from IL-17A-deficient mice, Prevotella-related bacteria were transferred, regulatory T-cell levels increased, and disease severity decreased. Together, the findings reveal an interconnected IL-17A–gut microbiome–Treg axis, showing that inflammatory signaling can reshape the gut microbial community, which in turn feeds back on the immune system to influence neuroinflammation.
The study builds on previous work from the Mangalam lab showing that P. copri is more abundant in healthy individuals than in people with MS and can protect against MS-like disease in experimental models. These findings raise the possibility that future microbiome-directed approaches could complement therapies targeting inflammatory pathways by promoting beneficial bacteria and strengthening regulatory immune responses.