A diet enriched in omega-3 PUFA and inulin prevents type 1 diabetes by restoring gut barrier integrity and immune homeostasis in NOD mice

Abstract

IntroductionThe integrity of the gut barrier (GB) is fundamental to regulate the crosstalk between the microbiota and the immune system and to prevent inflammation and autoimmunity at the intestinal level but also in organs distal from the gut such as the pancreatic islets. In support to this idea, we recently demonstrated that breakage of GB integrity leads to activation of islet-reactive T cells and triggers autoimmune Type 1 Diabetes (T1D). In T1D patients as in the NOD mice, the spontaneous model of autoimmune diabetes, there are alterations of the GB that specifically affect structure and composition of the mucus layer; however, it is yet to be determined whether a causal link between breakage of the GB integrity and occurrence of autoimmune T1D exists.MethodsHere we restored GB integrity in the NOD mice through administration of an anti-inflammatory diet (AID- enriched in soluble fiber inulin and omega 3-PUFA) and tested the effect on T1D pathogenesis.ResultsWe found that the AID prevented T1D in NOD mice by restoring GB integrity with increased mucus layer thickness and higher mRNA transcripts of structural (Muc2) and immunoregulatory mucins (Muc1 and Muc3) as well as of tight junction proteins (claudin1). Restoration of GB integrity was linked to reduction of intestinal inflammation (i.e., reduced expression of IL-1β, IL-23 and IL-17 transcripts) and expansion of regulatory T cells (FoxP3+ Treg cells and IL-10+ Tr1 cells) at the expenses of effector Th1/Th17 cells in the intestine, pancreatic lymph nodes (PLN) and intra-islet lymphocytes (IIL) of AID-fed NOD mice. Importantly, the restoration of GB integrity and immune homeostasis were associated with enhanced concentrations of anti-inflammatory metabolites of the ω3/ω6 polyunsaturated fatty acids (PUFA) and arachidonic pathways and modifications of the microbiome profile with increased relative abundance of mucus-modulating bacterial species such as Akkermansia muciniphila and Akkermansia glycaniphila.DiscussionOur data provide evidence that the restoration of GB integrity and intestinal immune homeostasis through administration of a tolerogenic AID that changed the gut microbial and metabolic profiles prevents autoimmune T1D in preclinical models.

Efficacy of an elemental diet in achieving clinical remission in dogs with chronic enteropathy

“…Given the well‐recognized benefit of diet modification in CE in dogs, 1,5,6,12,33 other factors correlating food components to GI‐related clinical signs should be considered. Much data supports the ability of diet to modulate the GI immune system, with an indisputable role of the gut microbiome 32,34,35 . Recent studies indicate that the antigenic target in dogs with CE may be the intestinal microbiota rather than food components, 11 raising the possibility that microbiome shifts may underlie clinical improvement.…”

“…Much data supports the ability of diet to modulate the GI immune system, with an indisputable role of the gut microbiome. 32,34,35 Recent studies indicate that the antigenic target in dogs with CE may be the intestinal microbiota rather than food components, 11 raising the possibility that microbiome shifts may underlie clinical improvement. Feeding EL had significant effects on the fecal microbiome, which varied based on T2 clinical response (Figures 4 and 5).…”

Age-related loss of intestinal barrier integrity plays an integral role in Thymic involution and T cell ageing

“…Furthermore, high intake of dietary bre and omega-3 polyunsaturated fatty acids (both enriched in MedDiet foods like fruits, vegetables, sh and nuts) has been shown to restore gut barrier function in non-obese diabetic mice, thereby restoring intestinal immune homeostasis (i.e. reduced gut in ammation, expansion of IL10-producing Tregs, decline in pro-in ammatory Th17 cells) [44]. However, these bene cial effects on the immune system have yet to be con rmed in aged humans.…”

High Fat Diet–Wheat Gliadin Interaction and its Implication for Obesity and Celiac Disease Onset: In Vivo Studies

“…More recently in NOD mice, a model of autoimmune diabetes, a diet enriched in inulin and ω3‐PUFAs restored the integrity of gut barrier along with reduced transcript levels of IL‐1β, IL‐23, and IL‐17, and expansion of Treg cells. [ 71 ]…”