Lloyd H. Kasper

The role of microbiome in central nervous system disorders

Mammals live in a co-evolutionary association with the plethora of microorganisms that reside at a variety of tissue microenvironments. The microbiome represents the collective genomes of these co-existing microorganisms, which is shaped by host factors such as genetics and nutrients but in turn is able to influence host biology in health and disease. Niche-specific microbiome, prominently the gut microbiome, has the capacity to effect both local and distal sites within the host. The gut microbiome has played a crucial role in the bidirectional gut-brain axis that integrates the gut and central nervous system (CNS) activities, and thus the concept of microbiome-gut-brain axis is emerging. Studies are revealing how diverse forms of neuro-immune and neuro-psychiatric disorders are correlated with or modulated by variations of microbiome, microbiota-derived products and exogenous antibiotics and probiotics. The microbiome poises the peripheral immune homeostasis and predisposes host susceptibility to CNS autoimmune diseases such as multiple sclerosis. Neural, endocrine and metabolic mechanisms are also critical mediators of the microbiome-CNS signaling, which are more involved in neuro-psychiatric disorders such as autism, depression, anxiety, stress. Research on the role of microbiome in CNS disorders deepens our academic knowledge about host-microbiome commensalism in central regulation and in practicality, holds conceivable promise for developing novel prognostic and therapeutic avenues for CNS disorders.

An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signalling

The mammalian immune system constitutively senses vast quantities of commensal bacteria and their products through pattern recognition receptors, yet excessive immune reactivity is prevented under homeostasis. Intestinal microbiome can influence host susceptibility to extra-intestine autoimmune disorders. Here we report that polysaccharide A (PSA), a symbiosis factor for human intestinal commensal Bacteroides fragilis, protects against central nervous system demyelination and inflammation during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, through toll-like receptor 2 (TLR2). TLR2 mediates tissue-specific expansion of a critical regulatory CD39+ CD4 T cell subset by PSA. Ablation of CD39 signaling abrogates PSA control of EAE manifestations and inflammatory cytokine responses. Further, CD39 confers immune-regulatory phenotypes to total CD4 T cells and Foxp3+ CD4 Tregs. Importantly, CD39-deficient CD4 T cells show an enhanced capability to drive EAE progression. Our results demonstrate the therapeutic potential and underlying mechanism by which an intestinal symbiont product modulates CNS-targeted demyelination.

A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39+Foxp3+ T cells and Treg function

Polysaccharide A (PSA) derived from the human commensal Bacteroides fragilis is a symbiosis factor that stimulates immunologic development within mammalian hosts. PSA rebalances skewed systemic T helper responses and promotes T regulatory cells (Tregs). However, PSA-mediated induction of Foxp3 in humans has not been reported. In mice, PSA-generated Foxp3+ Tregs dampen Th17 activity thereby facilitating bacterial intestinal colonization while the increased presence and function of these regulatory cells may guard against pathological organ-specific inflammation in hosts. We herein demonstrate that PSA induces expression of Foxp3 along with CD39 among naïve CD4 T cells in vitro while promoting IL-10 secretion. PSA-activated dendritic cells are essential for the mediation of this regulatory response. When cultured with isolated Foxp3+ Tregs, PSA enriched Foxp3 expression, enhanced the frequency of CD39+HLA-DR+ cells, and increased suppressive function as measured by decreased TNFα expression by LPS-stimulated monocytes. Our findings are the first to demonstrate in vitro induction of human CD4+Foxp3+ T cells and enhanced suppressive function of circulating Foxp3+ Tregs by a human commensal bacterial symbiotic factor. Use of PSA for the treatment of human autoimmune diseases, in particular multiple sclerosis and inflammatory bowel disease, may represent a new paradigm in the approach to treating autoimmune disease.

The Gut Microbiome in Multiple Sclerosis

Opinion statementThe gut microbiome is made up of a wide range of (chiefly) bacterial species that colonize the small and large intestine. The human gut microbiome contains a subset of thousands of bacterial species, with up to 1014 total bacteria. Studies examining this bacterial content have shown wide variations in which species are present between individuals. The gut microbiome has been shown to have profound effects on the development and maintenance of immune system in both animal models and in humans. A growing body of evidence has implicated the human gut microbiome in a range of disorders, including obesity, inflammatory bowel diseases, and cardiovascular disease. Animal studies present compelling evidence that the gut microbiome plays a significant role in the progression of demyelinating disease, and that modulation of the microbiome can lead to either exacerbation or amelioration of symptoms. Differences in diet, vitamin D insufficiency, smoking, and alcohol use have all been implicated as risk factors in MS, and all have the ability to affect the composition of the gut microbiota. Preliminary clinical trials aimed at modulating the gut microbiota in MS patients are underway and may prove to be a promising and lower-risk treatment option in the future.

A commensal bacterial product elicits and modulates migratory capacity of CD39+ CD4 T regulatory subsets in the suppression of neuroinflammation

Tolerance established by host-commensal interactions regulates host immunity at both local mucosal and systemic levels. The intestinal commensal strain Bacteroides fragilis elicits immune tolerance, at least in part, via the expression capsular polysaccharide A (PSA). How such niche-specific commensal microbial elements regulate extra-intestinal immune responses, as in the brain, remains largely unknown. We have recently shown that oral treatment with PSA suppresses neuro-inflammation elicited during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. This protection is dependent upon the expansion of immune-regulatory CD4 T cells (Treg) expressing CD39, an ectonucleotidase. Here, we further show that CD39 modulation of purinergic signals enhances migratory phenotypes of both total CD4 T cells and Foxp3+ CD4 Tregs at central nervous system (CNS) lymphoid-draining sites in EAE in vivo and promotes their migration in vitro. These changes are noted during PSA treatment, which leads to heightened accumulation of CD39+ CD4 Tregs in the CNS. Deficiency of CD39 abrogates accumulation of Treg during EAE, and is accompanied by elevated Th1/Th17 signals in the CNS and in gut-associated lymphoid tissues. Our results demonstrate that immune-modulatory commensal bacterial products impact the migratory patterns of CD4 Treg during CNS autoimmunity via the regulation of CD39. These observations provide clues as to how intestinal commensal microbiome is able to modulate Treg functions and impact host immunity in the distal site.

Immunomodulatory activity of interferon-beta

Multiple sclerosis (MS) is a complex disorder of the central nervous system that appears to be driven by a shift in immune functioning toward excess inflammation that results in demyelination and axonal loss. Beta interferons were the first class of disease‐modifying therapies to be approved for patients with MS after treatment with this type I interferon improved the course of MS on both clinical and radiological measures in clinical trials. The mechanism of action of interferon‐beta appears to be driven by influencing the immune system at many levels, including antigen‐presenting cells, T cells, and B cells. One effect of these interactions is to shift cytokine networks in favor of an anti‐inflammatory effect. The pleiotropic mechanism of action may be a critical factor in determining the efficacy of interferon‐beta in MS. This review will focus on select immunological mechanisms that are influenced by this type I cytokine.

Gut microbiome and the risk factors in central nervous system autoimmunity

Humans are colonized after birth by microbial organisms that form a heterogeneous community, collectively termed microbiota. The genomic pool of this macro‐community is named microbiome. The gut microbiota is essential for the complete development of the immune system, representing a binary network in which the microbiota interact with the host providing important immune and physiologic function and conversely the bacteria protect themselves from host immune defense. Alterations in the balance of the gut microbiome due to a combination of environmental and genetic factors can now be associated with detrimental or protective effects in experimental autoimmune diseases. These gut microbiome alterations can unbalance the gastrointestinal immune responses and influence distal effector sites leading to CNS disease including both demyelination and affective disorders. The current range of risk factors for MS includes genetic makeup and environmental elements. Of interest to this review is the consistency between this range of MS risk factors and the gut microbiome. We postulate that the gut microbiome serves as the niche where different MS risk factors merge, thereby influencing the disease process.

Digesting the emerging role for the gut microbiome in central nervous system demyelination

The fields of microbiology, immunology, neurology and nutrition are rapidly converging, as advanced sequencing and genomics-based methodologies have enabled the mapping out of the microbial diversity of humans for the first time. Bugs, guts, brains and behavior were once believed to be separate domains of clinical practice and research; however, recent observations in our understanding of the microbiome indicate that the boundaries between domains are becoming permeable. This permeability is multidirectional: Biological systems are operating simultaneously in a vastly complex and interconnected web. Understanding the microbiome-gut-brain axis will entail fleshing out the mechanisms by which transduction across each domain occurs, allowing us ultimately to appreciate the role of commensal organisms in shaping and modulating host immunity. This article will highlight animal and human research to date, as well as highlight directions for future research. We speculate that the gut microbiome is potentially the premier environmental risk factor mediating inflammatory central nervous system demyelination, in particular multiple sclerosis.

Gut Commensalism, Cytokines, and Central Nervous System Demyelination

There is increasing support for the importance of risk factors such as genetic makeup, obesity, smoking, vitamin D insufficiency, and antibiotic exposure contributing to the development of autoimmune diseases, including human multiple sclerosis (MS). Perhaps the greatest environmental risk factor associated with the development of immune-mediated conditions is the gut microbiome. Microbial and helminthic agents are active participants in shaping the immune systems of their hosts. This concept is continually reinforced by studies in the burgeoning area of commensal-mediated immunomodulation. The clinical importance of these findings for MS is suggested by both their participation in disease and, perhaps of greater clinical importance, attenuation of disease severity. Observations made in murine models of central nervous system demyelinating disease and a limited number of small studies in human MS suggest that immune homeostasis within the gut microbiome may be of paramount importance in maintaining a disease-free state. This review describes three immunological factors associated with the gut microbiome that are central to cytokine network activities in MS pathogenesis: T helper cell polarization, T regulatory cell function, and B cell activity. Comparisons are drawn between the regulatory mechanisms attributed to first-line therapies and those described in commensal-mediated amelioration of central nervous system demyelination.

The evolving role of the gut microbiome in human disease

http://dx.doi.org/10.1016/j.febslet.2014.09.015 0014-5793/ 2014 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. We are delighted to introduce this Special Issue, which summarizes the current understanding of the complex relationship between the gut microbiome and the host. Animals and humans have evolved a digestive system that allows them to walk, swim or fly free of the constraints of terra firma. The gut is a remarkably complex organ involved in both homeostasis and susceptibility to disease. The importance of commensal microbial populations in human health and disease was first suggested by Joshua Lederberg (Science 288 (5464): 291, 2000). Lederberg introduced the term microbiome to describe the community of all microorganisms residing in the human body, and their collective genome. Later, Lora Hooper and Jeff Gordon proposed that the microbiome should be viewed as part of the total human genome (Science 292 (5519): 1115–1118, 2001). The adult human intestine harbors a population of up to 100 trillion bacteria cells. This number is over ten-fold the total number of human somatic and germ cells. Impressively, the gut microbiome weighs nearly 2.5 kg dry weight. The collective genome of the gut microbiome exceeds by over 300 times the size of the human genome, and provides additional functional features that mammals have not evolved. The symbiotic relationship that has evolved between the gut microbiome and the host shapes immune and digestive functions of the host, and allows the organism to adjust to environmental cues. Thus, the gut microbiome has multiple physiological functions. Among others, it is involved in defense against pathogen colonization; fortification of the intestinal epithelial barrier; digestion of nutrients and dietary fibers; and maturation and functionality of the intestinal immune system. Notably, there is a binary interaction between the host and commensal microorganisms that dwell within each of us. Not only does the gut microbiome contribute important functions to the host, but also the host immune system is conditioned from birth on to tolerate the vast array of microorganisms that compose the microbiome. As discussed by several articles in this Special Issue, a wide variety of factors — both endogenous (such as host and microorganism genetics, developmental stage, hormone signaling and immune cell populations) and exogenous (such as dietary habits, medical treatment, exposure to antibiotics, vitamin insufficiency, environmental pollutants and vaccination) — can influence the composition of the gut microbiome. All these factors are implicated in dysbiosis that is the loss of microbiome homeostasis. Dysbiosis may influence susceptibility to disease. Several articles in this Special Issue examine how changes in the gut microbiome composition might be associated with diseases, including obesity, type I diabetes, autoimmunity, affective disorders, neural degeneration, and cardiovascular disease. The impact of dysbiosis on susceptibility to disease is just beginning to be appreciated and will be reflected in time with significant changes in approaches to develop disease treatments. Overall, it can be proposed that understanding the gut microbiome may lead to the realization that changes in its composition may represent the greatest environmental risk factor to our health. So, we hope that you will enjoy reading the articles of this Special Issue, which collectively illustrate an emerging new ‘‘treasure trove’’ for understanding and treating human disease.