Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice

Abstract

Vertebrates typically harbor a rich gastrointestinal microbiota, which has coevolved with the host over millennia and is essential for several host physiological functions, in particular maturation of the immune system. Recent studies have highlighted the importance of a single bacterial species, segmented filamentous bacteria (SFB), in inducing a robust T-helper cell type 17 (Th17) population in the small-intestinal lamina propria (SI-LP) of the mouse gut. Consequently, SFB can promote IL-17-dependent immune and autoimmune responses, gut-associated as well as systemic, including inflammatory arthritis and experimental autoimmune encephalomyelitis. Here, we exploit the incomplete penetrance of SFB colonization of NOD mice in our animal facility to explore its impact on the incidence and course of type 1 diabetes in this prototypical, spontaneous model. There was a strong cosegregation of SFB positivity and diabetes protection in females, but not in males, which remained relatively disease-free regardless of the SFB status. In contrast, insulitis did not depend on SFB colonization. SFBpositive, but not SFB-negative, females had a substantial population of Th17 cells in the SI-LP, which was the only significant, repeatable difference in the examined T-cell compartments of the gut, pancreas, or systemic lymphoid tissues. Th17-signature transcripts dominated the very limited SFB-induced molecular changes detected in SI-LP CD4 + T cells. Thus, a single bacterium, and the gut immune system alterations associated with it, can either promote or protect from autoimmunity in predisposed mouse models, probably reflecting their variable dependence on different Th subsets.gender | microbiome | T lymphocyte | autoimmune disease

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD Mice

“…3,6 For example, a recent study highlighted the diabetes protective association with presence of segmented filamentous bacteria (SFB) in NOD mice from different facilities. 7 In a recent study, SFB was however only found to protect NOD males in contrast to females when mono-colonized, and the mice therefore regained the diabetes gender bias which is lost in germ-free conditions. 8 Moreover, Lactobacillus and Bifidobacterium were found in higher abundance in feces from bio-breeding diabetes-resistant (BB-DR) rats before clinical onset of T1D compared with bio-breeding diabetes-prone (BB-DP) rats, which contained more Bacteroides, Eubacterium, and Ruminococcus ssp.…”

Reciprocity in Microbiome and Immune System Interactions and its Implications in Disease and Health

“…In a mouse model of autoimmune arthritis, germ free mice show attenuation of disease accompanied with lower Th17 cell frequency [26], whereas SFB monocolonization in those mice leads to an increase in Th17 cell numbers in the lamina propria and exacerbation of disease [26]. Contrary to clinical manifestations in EAE and arthritis models [26,27], the presence of SFB-induced lamina propria resident Th17 cells in NOD mice protect mice from diabetes [24]. This might occur as a result of the regulation of Th17 cells in the small intestine [39].…”

“…While SFB is associated with Th17 cells in NOD mice, no immunopathology is observed in these mice [24]. Th17 cells are not always pathogenic [19,39].…”

“…However, the role of SFB in shaping immune response is much broader than mere induction of one specific subset and it contributes to full maturation of gut immune response [22] and induction of a wide range of T cell responses comprising of Th17, Th1, Th2 and Treg cells [23]. This might explain why SFB colonization is associated with protection in some experimental models of disease such as the NOD mouse model of type 1 diabetes [24,25], while it is pathogenic in other experimental settings such as EAE and arthritis [26,27]. One possible mechanism for a protective role of IL-17 in a mouse colitis model is through modulation of Th1 response [28].…”

“…Presence of SFB in the gastrointestinal tract of NOD mice is associated with protection from diabetes [24]. While SFB is associated with Th17 cells in NOD mice, no immunopathology is observed in these mice [24].…”