Abstract
Intestinal homeostasis underpins the development of type 1 diabetes (T1D), and dietary manipulations to enhance intestinal homeostasis have been proposed to prevent T1D. The current study aimed to investigate the efficacy of supplementing a novel specific low-methoxyl pectin (LMP) dietary fiber in preventing T1D development. Female NOD mice were weaned onto control or 5% (wt/wt) LMP supplemented diets for up to 40 weeks of age, overt diabetes incidence and blood glucose were monitored. Then broad-spectrum antibiotics (ABX) treatment per os for 7 days followed by gut microbiota transfer was performed to demonstrate gut microbiota-dependent effects. Next-generation sequencing was used for analyzing the composition of microbiota in caecum. Concentration of short chain fatty acids were determined by GC-MS. The barrier reinforcing tight junction proteins zonula occludens-2 (ZO-2), claudin-1 and NOD like receptor protein 3 (NLRP3) inflammasome activation were determined by Western blot. The proportion of CD25+Foxp3+CD4+ regulatory T cell (Foxp3+ Treg) in the pancreas, pancreatic and mesenteric lymph nodes was analyzed by flow cytometry. We found that LMP supplementation ameliorated T1D development in non-obese diabetic (NOD) mice, as evidenced by decreasing diabetes incidence and fasting glucose levels in LMP fed NOD mice. Further microbiota analysis revealed that LMP supplementation prevented T1D-associated caecal dysbiosis and selectively enriched caecal bacterial species to produce more SCFAs. The LMP-mediated microbial balance further enhanced caecal barrier function and shaped gut-pancreatic immune environment, as characterized by higher expression of tight junction proteins claudin-1, ZO-2 in caecum, increased Foxp3+ Treg population and decreased NLRP3 inflammasome activation in both caecum and pancreas. The microbiota-dependent beneficial effect of LMP on T1D was further proven by the fact that aberration of caecal microbiota by ABX treatment worsened T1D autoimmunity and could be restored with transfer of feces of LMP-fed NOD mice. These data demonstrate that this novel LMP limits T1D development by inducing caecal homeostasis to shape pancreatic immune environment. This finding opens a realistic option for gut microbiota manipulation and prevention of T1D in humans.
Highlights
Type 1 diabetes (T1D) is characterized by autoreactive T cell-mediated selective destruction of pancreatic beta-cells in genetically predisposed individuals [1]
Gut dysbiosis is frequently associated with gut barrier dysfunction, resulting in increased gut permeability and translocation of diabetogenic proteins and macromolecular structures in T1D susceptible animal models and in humans to contribute to the disease development [4, 10, 11]
We investigated whether Low-methoxyl pectin (LMP) supplementation influenced T1D development in nonobese diabetic (NOD) mice
Summary
Type 1 diabetes (T1D) is characterized by autoreactive T cell-mediated selective destruction of pancreatic beta-cells in genetically predisposed individuals [1]. Gut microbiota affects fermentation of food components and production of metabolites [5] and influences host immune status and gut permeability, impacting autoimmune processes during T1D [6]. It has been proven that when the mutualistic relation between host immunity and the microbiota is compromised, alterations in bacteria function and diversity, a process called dysbiosis, may cause or contribute to T1D development [2, 3, 6, 7]. The same studies showing the involvement of gut dysbiosis in T1D demonstrate the flexibility of the gut microbial communities for manipulation by food components, which opens new venues to treat or prevent T1D [5, 9, 12]
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