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The Microbiome and Autoimmune Disease: 'Are We Not Men?'

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In this issue, Healio Rheumatology covers the expanding implications of the microbiome in autoimmune disease as the notion of the microbiome is now widespread and is heard across multiple disciplines. Nobel Laureate Joshua Lederberg has coined the microbiome “the ecological community of commensal, symbiotic and pathogenic microorganisms that literally share our body space.”

Leonard Calabrese

One cannot read a newspaper or magazine without being inundated with the implications of the microbiome on health and disease. While the concept that our body’s cells are vastly outnumbered by our prokaryotic brethren is now accepted, the complexities of this vast system are continuously being revealed. It now seems certain that popping a probiotic or eating yogurt will not alter the incidence or natural history of autoimmune disease. In fact, I believe the Human Microbiome Project, which was launched in 2008 with laudatory goals including stimulating research in the field, is highly reminiscent of its parent, the Human Genome Project, which in 2003 completed the sequencing of the human genome. This feat promised to provide the blueprint for health and disease. While remarkable, it scientifically has left us with a seemingly endless series of complex unanswered questions.

Disease Onset Pathogenesis

For rheumatologists, it appears clear the microbiome is in some way integral to affecting both disease onset and pathogenesis. Early work in animal models, especially using genetically manipulated gnonobiotic mice subsequently undergoing microbiomic manipulation, has clearly demonstrated the importance of the microbiome in shaping the immune response and influencing the development and course of numerous autoimmune diseases. In humans, advances in the lab, especially targeted and even metagenomic sequencing, coupled with dramatic advances in informatics, has allowed new and innovative research – some of which is highlighted in this issue.

I would like to point out two intriguing observations to support the importance and potential of microbiomics in autoimmunity as well the dramatic complexities we must hurdle to have a clearer understanding of the field. First, what are the evidence in humans that the microbiome may be a driver of autoimmunity? Consider that Finland has one of the highest incidences of type 1 diabetes in the world and studies have previously demonstrated that the microbiome of children developing the disease appear to change in a predictable way in the year preceding the disease. This observation raised the question of possible causality, yet the evidence was incomplete.

Important Study

In an important recently published study, Vatanen and colleagues compared the microbiome of children genetically at risk for type 1 diabetes in Finland and Estonia to the microbiome of children from neighboring Russia, a country and region with a dramatically lower incidence of type 1 diabetes. In this elegant prospective study, they demonstrated that the type 1 diabetes predisposed children of Finland had microbiomes skewed to Bacteroides species while the Russian children were skewed to Escherichia coli. They then demonstrated the lipopolysaccharides from these respective bacteria were differentially capable of inducing inflammation as demonstrated by the capacity of respective lipopolysaccharides moieties to stimulate nuclear factor-kappaB dependent cytokines. They subsequently demonstrated in the animal model of non-obese mice, which are predisposed to type 1 diabetes, E. coli but not Bacteroides species were capable of decreasing the incidence of type 1 diabetes, suggesting an immunologically silencing microbiota may thus preclude aspects of immune education and subsequent disease. This, of course, is all consistent with the hygiene hypothesis, which has had its ups and downs for more than 25 years. I find this comforting.

Image: Janel Macoska 1978; Courtesy of Michael Pilmer at Club Devo. We are at the beginning of a remarkable journey. If anyone, such as the band Devo, asks you “Are we not men?” the correct response is “We are a metagenomic community.”

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Second, in case we are tempted to become smug about the new microbiomics and the promise of our ability to manipulate bacterial colonization as potential therapies or preventative measure for autoimmunity, it is only the tip of the iceberg. Moving forward, there is increasing interest in the expanded metagenome, including the prokaryotic and eukaryotic microviromes which vastly outnumber the prokaryotic communities. This community is only now being to be studied in detail and the data on the inter-kingdom effects (ie, viral and bacterial interactions) are highly provocative, as shown by Norman and colleagues.

Beginning of a Journey

We should not examine the “microbiome” without also examining the influence of the meiofaunal community, which is comprised of metazoans, including helminths. This latter community has been clearly demonstrated to influence the onset and course of autoimmunity in preclinical models and is being utilized in clinical trials for numerous diseases including arthritis, as shown by Hembly.

We are only at the beginning of a remarkable journey. If anyone, such as the band Devo or Dr. Moreau asks you “Are we not men?” the correct response is “We are a metagenomic community.”

Thank you for reading. I look forward to receiving your comments at calabrl@ccf.org or on Twitter @LCalabreseDO.

References:

Helmby H. BMC Immunol. 2015;doi:10.1186/s12865-015-0074-3.

Norman JM, et al. Gastroenterology. 2014;doi:10.1053/j.gastro.2014.02.001.

Vatanen T, et al. Cell 2016;165:842-853.

For more information:

Leonard H. Calabrese, DO, is the Chief Medical Editor, Healio Rheumatology, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic.

Disclosure: Calabrese reports he is a consultant for Genentech, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Sanofi, Jansen and AbbVie; and is on the speakers bureau for Genentech, AbbVie and Bristol-Myers Squibb and Crescendo Bioscience.

Editor’s Note

On a related note, I recommend the book An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases by Moises Velasquez-Mannon. Velasquez-Mannon is a terrific science and environmental writer who appears in The New York Times and other influential publications. I read this book 2 years ago and it kindled a strong interest in metagenomic immune interactions, which I now incorporate in my lectures and yearly Immunology Boot Camp.

– Leonard H. Calabrese, DO

Chief Medical Editor

Healio Rheumatology