Targeting gut microbiota and barrier function with prebiotics to alleviate autoimmune manifestations in NOD mice

Abstract

Aims/hypothesis Adopting a diet containing indigestible fibre compounds such as prebiotics to fuel advantageous bacteria has proven beneficial for alleviating inflammation. The effect of the microbial changes on autoimmunity, however, remains unknown. We studied the effects of prebiotic xylooligosaccharides (XOS) on pancreatic islet and salivary gland inflammation in NOD mice and tested whether these were mediated by the gut microbiota. Methods Mother and offspring mice were fed an XOS-supplemented diet until diabetes onset or weaning and were compared with a control-fed group. Diabetes incidence was monitored, insulitis and sialadenitis were scored in histological sections from adult mice, and several metabolic and immune variables were analysed in mice before the development of diabetes. Gut barrier function was assessed using an in vivo FITC-dextran permeability test. The importance of XOS-mediated gut microbial changes were evaluated in antibiotic-treated mice fed either XOS or control diet or given a faecal microbiota transplant from test animals. Results Diabetes onset was delayed in the XOS-fed mice, which also had fewer cellular infiltrations in their pancreatic islets and salivary glands. Interestingly, insulitis was most reduced in the XOS-fed groups when the mice were also treated with an antibiotic cocktail. There was no difference in sialadenitis between the dietary groups treated with antibiotics; the mice were protected by microbiota depletion regardless of diet. Faecal microbiota transplantation was not able to transfer protection. No major differences in glucose-insulin regulation, glucagon-like peptide-1, or short-chain fatty acid production were related to the XOS diet. The XOS diet did, however, reduce gut permeability markers in the small and large intestine. This was accompanied by a more anti-inflammatory environment locally and systemically, dominated by a shift from M1 to M2 macrophages, a higher abundance of activated regulatory T cells, and lower levels of induction of natural killer T cells and cytotoxic T cells. Conclusions/interpretation Prebiotic XOS have microbiota-dependent effects on salivary gland inflammation and microbiotaindependent effects on pancreatic islet pathology that are accompanied by an improved gut barrier that seems able to heighten control of intestinal diabetogenic antigens that have the potential to penetrate the mucosa to activate autoreactive immune responses.

Prebiotics Regulation of Intestinal Microbiota Attenuates Cognitive Dysfunction Induced by Surgery Stimulation in APP/PS1 Mice

“…Although TNF-α was slightly upregulated after surgery, there was no significant difference among four groups, which indicated that TNFα may not be the major inflammatory cytokines for the postoperative neuroinflammatory response and cognitive dysfunction in the present model. Furthermore, intestinal barrier damage and increased inflammation response can be attenuated by XOS intervention through modulating the intestinal microbiota, which is consistent with the anti-autoimmune effect of XOS in non-obesity-diabetes mice [53]. Evidence has proven that XOS intervention can reduce intestinal permeability markers and inflammatory response through inhibiting of natural killer T cells and cytotoxic T cells [53], which require further investigations in the perioperative context.…”

Intestinal Flora and Disease Mutually Shape the Regional Immune System in the Intestinal Tract

“…A more pronounced regional and systemic anti-inflammatory environment was also observed compared with the control group (105)(106)(107)(108)(109)(110). Hence, this treatment may serve to improve gut barrier and, thus, has the potential to activate autoreactive immune responses (104).…”

“…The mechanism by which intestinal flora affects the regional immune system includes secretion of metabolic products (6), expression of PAMPs (9), and prevention of pathogen adhesion (103). For example, probiotics including bifidobacteria and lactobacilli, affect autoimmunity (104). This has been supported by a study that fed non-obese diabetic mouse a xylooligosaccharide diet and observed a subsequent reduction in intestinal marker permeability, primarily from M1 to M2 macrophages, an increase in the activation of regulatory T cells, and a reduction in the levels of activated cytotoxic T cells and NKT cells.…”

Intestinal Permeability in Children with Celiac Disease after the Administration of Oligofructose-Enriched Inulin into a Gluten-Free Diet—Results of a Randomized, Placebo-Controlled, Pilot Trial

“…Therefore, prebiotics, the substrates that are selectively utilized by host microorganisms conferring a health benefit [ 21 ], were proposed as a promising intervention for gut barrier improvement [ 22 , 23 ]. The positive effects of prebiotics and prebiotic-derived metabolites on the gut barrier functions have been repeatedly confirmed by in vitro and in vivo studies [ 24 , 25 , 26 ]. However, there is no agreement in the influence of prebiotics in clinical trials.…”