Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans

Abstract

Summary 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 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.

Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice

“…Moreover, the abundance of Bacteroides species has been associated with the appearance of diabetes-related autoantibodies 2 7 22 32. Loss of immune tolerance due to substantial overgrowth of Bacteroidetes was recently proposed to associate with the inferior capacity of LPS/endotoxin of Bacteroides dorei to establish LPS tolerance 7. On the other hand, B. fragilis and other Bacteroides species induce IL-10-secreting and Foxp3 expressing regulatory Tr1 and Treg cells in gnotobiotic mice and suppress induction of inflammatory colitis 17 18.…”

“…In addition, a decline in the overall diversity of microbiota was found to associate with an increased risk to develop clinical disease 3. Some of the proposed mechanisms relate to local immune homeostasis and gut barrier integrity,4 5 activation of the adaptive immune responses interfering with peripheral tolerance to tissue antigens such as beta-cell antigens6 or immune suppression driven by lipopolysaccharide (LPS) produced by specific gut bacteria 7. However, a causal relation between intestinal microbes and T1D has not been established, and hence, the ways in which the intestinal microbiota may affect T1D development are mostly speculative.…”

Antibiotic perturbation of the preterm infant gut microbiome and resistome

“…3,[6][7][8] Perturbation of the gut microbiota during this key developmental window can have lasting effects on host physiology and disease risk. [9][10][11][12][13][14] One of the most common perturbations during this period, antibiotic therapy, 13,15 can substantially alter the gut microbiota and infant physiology. 10,[16][17][18][19][20][21] Because preterm infants are at high risk for infection, antibiotics are the most commonly prescribed medications in neonatal intensive care units (NICUs) in the United States ( Fig.…”

Participation of the microbiome in the pathogenesis of diabetes mellitus

“…Very broad observations pertaining to differences in the composition of the bacterial microbiome and the incidence of early-onset autoimmune diseases which are common in Finland and Estonia, but less prevalent in Russia, have been presented by Vatanen et al [25]. They have pointed to the fact that changes in the bacterial microflora can be detected even before any clinical symptoms of the type 1 diabetes are observable [33].…”

“…The agenda of these studies covers multiple directions of the pathogenesis of such metabolic disorders as changes in the immunological reactions contributing to the incidence of diabetes, as well as pathogenetic significance of inflammations in these diseases [12,[21][22][23][24][25].…”