The human microbiota is an invisible universe of bacteria, viruses, and other organisms (their genes are collectively known as the microbiome) that live in close association with the human body. Microbial species and their products influence many critical functions of their hosts, including digestion, the supply of essential nutrients and vitamins, and the regulation of immune functions. We are only beginning to understand the scope of human interactions with the microbiome and their interdependence. Recently, the field of microbiome research has been transformed by the development of two major enabling technologies. The first is parallel DNA sequencing technologies that permit the genes of many thousands of organisms residing in our gut and skin to be rapidly identified, quantitated, and followed over time within individuals, and across populations. The second advance is the development of germ-free (gnotobiotic) mouse colonies, permitting the effects of defined bacteria to be studied in a living animal. Although the field is still in its infancy, dramatic findings have already been obtained that have generated great optimism that understanding the microbiome in detail will have profound implications for understanding human disease, and for improving the management of many human health problems. It is likely – in fact, certain – that the composition of the microbiome contributes to the development many autoimmune diseases, which in aggregate affect more than 10% of the population. Data has also implicated the microbiome in many other conditions including obesity, cardiovascular diseases, anxiety, depression and other behavioral disorders; as well as in cancer.

As a prototypic autoimmune disease, multiple sclerosis (MS) is ideally suited for a deep exploration of the role of the microbiome. A profound environmental contribution to MS is well-established; microbial organisms and chemical messengers that can either produce or protect against MS attacks have been identified, and excellent mouse models for MS exist. Given the promise of microbiome studies in MS, we propose forming a collaborative research effort to investigate the relationship between gut commensal microbiota^{^[1]} and MS susceptibility, progression, and therapeutic response. The initiative we propose could be transformational and result in a paradigm shift in how we understand the microbiome and its relation to MS. Given the groundwork that has already been laid and the promise of the initial research findings, now is an opportune time to invest in this area to unlock potential treatments or ways to prevent MS.

The overall goal is to develop disease biomarkers and novel therapeutics based on modulation of the gut immune system/brain axis, including the targeted use of pre-biotic, pro-biotic or anti-biotic therapies. In order to accomplish this goal, we aim to:

Create a highly collaborative “Center of Excellence Without Walls” in which outstanding scientists and clinical MS experts from many institutions and regions of the world form a single interactive team dedicated to solving this problem as quickly as possible.
Develop a sufficient gnotobiotic mouse^[2] capacity to enable studies in animal models.
Develop a therapeutics discovery program based on microbiota modulation.
Lay the groundwork for clinical trials aimed at testing the most promising therapeutic candidates within 4-5 years.

By identifying infectious agents at play in MS, it is likely that we will clarify some of the most important and interesting questions in the field, including: how does MS develop in the first place; what determines whether a patient will have a benign or severe clinical course; and why has MS increased in frequency in recent years?

Our proposed collaboration will be one of the largest disease-specific projects in microbiome research worldwide. As this group leads the way, it will set the stage for future projects that will capitalize on these achievements. We anticipate that a whole new field of research and therapeutics for autoimmune diseases, and possibly for other conditions, will be developed in the coming years.

^{^[1]} Gut commensal microbiota refers to the aggregate organisms that live in the human gut and are not inherently harmful to the human body.

^[2]Gnotobiotic mice are mice that are either germ-free or only have specific strains of bacteria and other microorganisms.

Program components and goals

Our program has four components that will advance our understanding of the impact that bacteria – both beneficial and harmful – have on the immune system, and our ability to develop and test therapies that will modulate these bacteria for the benefit of patients and those at risk of MS.

Screening of Microbiota Composition in MS

The goal of this first component is to characterize the microbiota present in the gut of people with MS at the beginning of the illness, throughout the course of the disease, and in response to therapy.

Bacterial Transfer into Gnotobiotic Mice

A second goal is to develop an efficient animal model that reflects the microbiotic composition found in patients and to test which bacteria are beneficial and which are harmful.

Immunological and Molecular Studies of the Gut-immune System/Brain Axis

Once the first two components are well underway, we will embark on a series of comprehensive immunological studies to understand the cross-talk between bacterial populations of interest and the immune system.

Clinical Trials

The fourth and most important goal is to harmonize all of the above information for the purpose of designing clinical trials to assess our ability to eliminate harmful bacteria and encourage beneficial bacteria.