Gut Microbial Dysbiosis Due to Helicobacter Drives an Increase in Marginal Zone B Cells in the Absence of IL-10 Signaling in Macrophages

Abstract

It is clear that IL-10 plays an essential role in maintaining homeostasis in the gut in response to the microbiome. However, it is unknown whether IL-10 also facilitates immune homeostasis at distal sites. To address this question, we asked whether splenic immune populations were altered in IL-10-deficient (Il10−/−) mice in which differences in animal husbandry history were associated with susceptibility to spontaneous enterocolitis that is microbiome-dependent. The susceptible mice exhibited a significant increase in splenic macrophages, neutrophils and marginal zone (MZ) B cells that was inhibited by IL-10 signaling in myeloid, but not B cells. The increase in macrophages was due to increased proliferation that correlated with a subsequent enhancement in MZ B cell differentiation. Cohousing and antibiotic treatment studies suggested that the alteration in immune homeostasis in the spleen was microbiome-dependent. 16S rRNA sequencing revealed that susceptible mice harbored a different microbiome with a significant increase in the abundance of the bacterial genus Helicobacter. The introduction of H. hepaticus to the gut of nonsusceptible mice was sufficient to drive macrophage expansion and MZ B cell development. Given that myeloid cells and MZ B cells are part of the first line of defense against blood-borne-pathogens, their increase following a breach in the gut epithelial barrier would be protective. Thus IL-10 is an essential gatekeeper that maintains immune homeostasis at distal sites that can become functionally imbalanced upon the introduction of specific pathogenic bacteria to the intestinal track.

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

“…For this reason, we cohoused both the control and Mpo −/− mice with mice from the Dittel colony prior to EAE induction to equilibrate their microbiomes. In support of this EAE induction protocol is our studies in Il10 −/− mice where we found that their T-independent immune responses were altered in a microbiome-dependent manner due to a significant increase in marginal zone B cells (Ray et al 2015). We also found that Il10 −/− mice from our colony harbored a different microbiome as compared to similar mice purchased directly from The Jackson Laboratory (Jax) and upon cohousing with mice from the Dittel colony their microbiomes shifted to that of the home colony (Ray et al 2015).…”

“…In support of this EAE induction protocol is our studies in Il10 −/− mice where we found that their T-independent immune responses were altered in a microbiome-dependent manner due to a significant increase in marginal zone B cells (Ray et al 2015). We also found that Il10 −/− mice from our colony harbored a different microbiome as compared to similar mice purchased directly from The Jackson Laboratory (Jax) and upon cohousing with mice from the Dittel colony their microbiomes shifted to that of the home colony (Ray et al 2015). From these data and other studies in the literature demonstrating that immunodeficiencies can alter the penetrance of disease in a putatively microbiome-dependent manner (Ray et al 2015, Ray & Dittel 2015), it is probable that since MPO is required for controlling certain bacterial and fungal infections, its absence could lead to a change in the composition of the microbiota altering EAE severity (Aratani et al 2000).…”

“…We also found that Il10 −/− mice from our colony harbored a different microbiome as compared to similar mice purchased directly from The Jackson Laboratory (Jax) and upon cohousing with mice from the Dittel colony their microbiomes shifted to that of the home colony (Ray et al 2015). From these data and other studies in the literature demonstrating that immunodeficiencies can alter the penetrance of disease in a putatively microbiome-dependent manner (Ray et al 2015, Ray & Dittel 2015), it is probable that since MPO is required for controlling certain bacterial and fungal infections, its absence could lead to a change in the composition of the microbiota altering EAE severity (Aratani et al 2000). Given that the gut microbiome is now thought to modulate MS pathogenesis examining the impact of MPO-deficiency on the composition of the gut microbiota and EAE disease penetrance is of particular interest (Mielcarz & Kasper 2015).…”

Psychobiotics and the Manipulation of Bacteria–Gut–Brain Signals

“…Exogenous bacteria can also trigger the development of immunogenic responses under certain conditions. For instance, the introduction of Helicobacter hepaticus in the presence of genetically-deficient interleukin-10 signalling systems led to an increase in pro-inflammatory marginal zone B cells (in the category of white blood cells, expressing antibodies) of the spleen [112]. The microbiome also controls the development of appropriate immunosuppression in response to dietary antigens through the production of immunosuppressive regulatory T-cells [113].…”

Helicobacter saguini, a Novel Helicobacter Isolated from Cotton-Top Tamarins with Ulcerative Colitis, Has Proinflammatory Properties and Induces Typhlocolitis and Dysplasia in Gnotobiotic IL-10 −/− Mice

“…Thus, without the anti-inflammatory actions of IL-10, an unregulated Th1-mediated immune response against selected enteric bacteria ensues and precipitates colitis characterized histologically by epithelial hyperplasia, mucosal and submucosal inflammation, and ulcerative lesions in the cecal-colonic junction (26,(34)(35)(36)(37)(38). EHS infection exacerbates the onset of disease in IL-10 Ϫ/Ϫ mice and thus is a frequently used model to study pathogen-induced IBD and colon cancer.…”