The influence of aging and the microbiome in multiple sclerosis and other neurologic diseases.

The human gut microbiome is well-recognized as a key player in maintaining health. However, it is a dynamic entity that changes across the lifespan. How the microbial changes that occur in later decades of life shape host health or impact age-associated inflammatory neurological diseases such as multiple sclerosis (MS) is still unclear. Current understanding of the aging gut microbiome is largely limited to cross-sectional observational studies. Moreover, studies in humans are limited by confounding host-intrinsic and extrinsic factors that are not easily disentangled from aging. This review provides a comprehensive summary of existing literature on the aging gut microbiome and its known relationships with neurological diseases, with a specific focus on MS. We will also discuss preclinical animal models and human studies that shed light on the complex microbiota-host interactions that have the potential to influence disease pathology and progression in aging individuals. Lastly, we propose potential avenues of investigation to deconvolute features of an aging microbiota that contribute to disease, or alternatively promote health in advanced age.

Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS.

While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts. Here, we directly compared CD11c+T-bet+ ABCs using models of Epstein-Barr virus (EBV), gammaherpesvirus 68 (γHV68), multiple sclerosis (MS), and experimental autoimmune encephalomyelitis (EAE), and found that each drives the ABC population to opposing phenotypes. EBV infection has long been implicated in MS, and we have previously shown that latent γHV68 infection exacerbates EAE. Here, we demonstrate that ABCs are required for γHV68-enhanced disease. We then show that the circulating ABC population is expanded and phenotypically altered in people with relapsing MS. In this study, we show that viral infection and autoimmunity differentially affect the phenotype of ABCs in humans and mice, and we identify ABCs as functional mediators of viral-enhanced autoimmunity.

Inhibition of Th1 activation and differentiation by dietary guar gum ameliorates experimental autoimmune encephalomyelitis.

Dietary fibers are potent modulators of immune responses that can restrain inflammation in multiple disease contexts. However, dietary fibers encompass a biochemically diverse family of carbohydrates, and it remains unknown how individual fiber sources influence immunity. In a direct comparison of four different high-fiber diets, we demonstrate a potent ability of guar gum to delay disease and neuroinflammation in experimental autoimmune encephalomyelitis, a T cell-mediated mouse model of multiple sclerosis. Guar gum-specific alterations to the microbiota are limited, and disease protection appears to be independent of fiber-induced increases in short-chain fatty acid levels or regulatory CD4+ T cells. Instead, CD4+ T cells of guar gum-supplemented mice are less encephalitogenic due to reduced activation, proliferation, Th1 differentiation, and altered migratory potential. These findings reveal specificity in the host response to fiber sources and define a pathway of fiber-induced immunomodulation that protects against pathologic neuroinflammation.

Age-dependent gray matter demyelination is associated with leptomeningeal neutrophil accumulation.

People living with multiple sclerosis (MS) experience episodic CNS white matter lesions instigated by autoreactive T cells. With age, patients with MS show evidence of gray matter demyelination and experience devastating nonremitting symptomology. What drives progression is unclear and studying this has been hampered by the lack of suitable animal models. Here, we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induced a nonremitting clinical phenotype that was associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young, SJL/J mice. Although the quantity and quality of T cells did not differ in the brains of old versus young EAE mice, an increase in neutrophils and a decrease in B cells were observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and gray matter pathology are dictated by age and associated with other immune cells, such as neutrophils.

Direct and indirect effects of microbiota-derived metabolites on neuroinflammation in multiple sclerosis.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) are highly influenced by changes in the microbiota and of microbiota-derived metabolites, including short chain fatty acids, bile acids, and tryptophan derivatives. This review will discuss the effects of microbiota-derived metabolites on neuroinflammation driven by central nervous system-resident cells and peripheral immune cells, and their influence on outcomes of EAE and MS.