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Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.

ABSTRACT: According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Europe, where early-onset autoimmune diseases are common in Finland and Estonia but are less prevalent in Russia. We found that Bacteroides species are lowly abundant in Russians but dominate in Finnish and Estonian infants. Therefore, their lipopolysaccharide (LPS) exposures arose primarily from Bacteroides rather than from Escherichia coli, which is a potent innate immune activator. We show that Bacteroides LPS is structurally distinct from E. coli LPS and inhibits innate immune signaling and endotoxin tolerance; furthermore, unlike LPS from E. coli, B. dorei LPS does not decrease incidence of autoimmune diabetes in non-obese diabetic mice. Early colonization by immunologically silencing microbiota may thus preclude aspects of immune education.

SUBMITTER: Vatanen T

PROVIDER: S-EPMC4950857 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.

Vatanen Tommi T Kostic Aleksandar D AD d'Hennezel Eva E Siljander Heli H Franzosa Eric A EA Yassour Moran M Kolde Raivo R Vlamakis Hera H Arthur Timothy D TD Hämäläinen Anu-Maaria AM Peet Aleksandr A Tillmann Vallo V Uibo Raivo R Mokurov Sergei S Dorshakova Natalya N Ilonen Jorma J Virtanen Suvi M SM Szabo Susanne J SJ Porter Jeffrey A JA Lähdesmäki Harri H Huttenhower Curtis C Gevers Dirk D Cullen Thomas W TW Knip Mikael M Xavier Ramnik J RJ

Cell 20160428 4

According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Europe, where early-onset autoimmune diseases are common in Finland and Estonia but are less prevalent in Russia. We found that Bacteroides species are lowly abundant in Russians but dominate in Finnish and ...[more]

PMID: 27133167

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Project description:Autoimmune diseases (AIDs) refer to connective tissue inflammation caused by aberrant autoantibodies resulting from dysfunctional immune surveillance. Most of the current treatments for AIDs use non-selective immunosuppressive agents. Although these therapies successfully control the disease process, patients experience significant side effects, particularly an increased risk of infection. There is a great need to study the pathogenesis of AIDs to facilitate the development of selective inhibitors for inflammatory signaling to overcome the limitations of traditional therapies. Immune cells alter their predominant metabolic profile from mitochondrial respiration to glycolysis in AIDs. This metabolic reprogramming, known to occur in adaptive immune cells, i.e., B and T lymphocytes, is critical to the pathogenesis of connective tissue inflammation. At the cellular level, this metabolic switch involves multiple signaling molecules, including serine-threonine protein kinase, mammalian target of rapamycin, and phosphoinositide 3-kinase. Although glycolysis is less efficient than mitochondrial respiration in terms of ATP production, immune cells can promote disease progression by enhancing glycolysis to satisfy cellular functions. Recent studies have shown that active glycolytic metabolism may also account for the cellular physiology of innate immune cells in AIDs. However, the mechanism by which glycolysis affects innate immunity and participates in the pathogenesis of AIDs remains to be elucidated. Therefore, we reviewed the molecular mechanisms, including key enzymes, signaling pathways, and inflammatory factors, that could explain the relationship between glycolysis and the pro-inflammatory phenotype of innate immune cells such as neutrophils, macrophages, and dendritic cells. Additionally, we summarize the impact of glycolysis on the pathophysiological processes of AIDs, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and ankylosing spondylitis, and discuss potential therapeutic targets. The discovery that immune cell metabolism characterized by glycolysis may regulate inflammation broadens the avenues for treating AIDs by modulating immune cell metabolism.

Dataset Information

Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.

Publications

Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.

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