Regulation of disease progression and therapeutic response in multiple sclerosis by the GUT microbiota

The National Institute of Allergy and Infectious Diseases awarded Oklahoma Medical Research Foundation $258,584 on July 9, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the regulation of disease progression and therapeutic response in multiple sclerosis by the gut microbiota.

The research examines how the gut microbiome influences multiple sclerosis progression and treatment outcomes, with specific focus on the costimulatory molecule CD40/CD40L interaction and changes in Akkermansia muciniphila abundance. The project leverages longitudinal microbiota data from people with multiple sclerosis, using 16S sequencing and baseline microbiota composition analysis to identify biomarkers and mechanisms that distinguish disease progressors from non-progressors, enabling personalized therapeutic approaches for early aggressive intervention.

Performance runs through June 30, 2028, at Oklahoma Medical Research Foundation's Oklahoma City, Oklahoma location.

Abstract

/summary multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) driven by a combination of both genetic and environmental risk factors including vitamin d intake, epstein-barr viral infection, and the GUT microbiome. In recent years, the treatment paradigm for MS has shifted towards early aggressive intervention to prevent disease progression and irreversible CNS damage. Given that not all people with MS (pwms) experience disease progression and that early aggressive medicines potentially pose a greater risk for side effects, IT is imperative to identify biomarkers and mechanisms unique to progression - to serve as prognostic indicators to provide personalized therapeutic approaches. The interaction between the membrane-bound costimulatory molecule CD40 and its ligand CD40L broadly regulate inflammation. CD40L is increased in pwms as compared to healthy controls and increased in progressive forms of disease. Second-generation anti-CD40L MAB therapeutics are well tolerated in pwms, cross the blood-brain barrier unlike other mabs and are highly efficacious, with current phase II trials underway. A number of case-control studies identified changes in GUT microbiome composition between pwms and healthy controls, including altered akkermansia muciniphila (a. Muciniphila). A. Muciniphila abundance is increased in pwms, but paradoxically decreased with elevated disease activity or severity. A major confounder in identifying microbiota signatures specific to MS disease progression is the inability to detect relevant changes prior to disease onset or progression, in part due to the overreliance on cross-sectional case-control MS cohort studies. Thus, we performed a ~5 year longitudinal study in pwms, interrogating baseline microbiota composition by 16S sequencing. Disease progressors displayed a distinct baseline GUT microbiome compared to non- progressors, including decreased akkermansia, correlating with elevated serum levels of soluble CD40L at baseline. We therefore hypothesize that integration of microbial and immunological signatures of disease progression has prognostic value. Further, we hypothesize that the restoration of a. Muciniphila levels will synergize with anti-CD40L MAB treatment to modulate therapeutic responses in pwms. We will test these hypotheses using two complementary approaches: 1) multimodal microbiomics and immunoprofiling studies in pwms, and 2) mechanistic studies in the primary autoimmune mouse model of MS, experimental autoimmune encephalomyelitis (EAE) leveraging novel genetic models of relapsing-remitting and progressive disease, commensal colonization and probiotic administration of a. Muciniphila and tandem therapeutic CD40L blockade.