Oral Akkermansia muciniphila may ameliorates immune dysregulation in a murine model of streptozotocin-induced type 1 diabetes

Abstract

BACKGROUND

Akkermansia muciniphila (A. muciniphila) has been shown to have positive effects on various metabolic diseases and partially prevent the onset of spontaneous type 1 diabetes mellitus (T1DM) in nonobese diabetic mice; however, its therapeutic efficacy in T1DM mice that have already developed T1DM remains unclear.

AIM

To assess the effects of A. muciniphila intervention on the intestinal barrier, immune parameters [regulatory T (Tregs) cells/T helper 1 cells balance, signal transducer and activator of transcription 1 (STAT1)/nuclear factor kappa-B (NF-κB) signal] and intestinal flora in a streptozotocin (STZ)-induced mouse model of T1DM.

METHODS

Thirty male C57BL/6 mice were randomized into three groups (n = 10 for each): Normal control (NC group), STZ-induced T1DM (STZ group), and A. muciniphila-treated T1DM (A. muciniphila group). T1DM was induced with STZ (50 mg/kg/day intraperitoneally, 5 days). Body weight, blood glucose, and water intake were monitored weekly. T1DM was modelled in all STZ- and A. muciniphila-treated mice (random blood glucose > 16.7 mmol/L). A. muciniphila group mice received oral A. muciniphila (5 × 10⁷ colony-forming units/mouse) for 3 days. Following sacrifice, pancreatic histopathology, cytokines in splenic tissue, colonic zonula occludens-1 (ZO-1)/zonulin expression, cluster of differentiation (CD) 4⁺/CD8⁺ T-cell ratios, forkhead box P3 (FoxP3⁺) Tregs, STAT1/NF-κB p65 signaling, and gut microbiota composition were analyzed.

RESULTS

Compared with STZ group alone, A. muciniphila group did not affect metabolic parameters. Histopathologically, STZ group and A. muciniphila group pancreatic islet cells underwent vacuolar degeneration and necrosis, exhibiting reduced counts and significantly decreased insulin positivity (P < 0.05 vs NC), with no intergroup differences. Flow cytometry and enzyme-linked immunosorbent assay revealed elevated tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), and zonulin levels and decreased ZO-1 expression in STZ vs NC mice (P < 0.05). Compared with STZ alone, A. muciniphila group reduced TNF-α, TGF-β, and zonulin levels while increasing the CD4⁺/CD8⁺ ratio, FoxP3⁺ Tregs, interleukin-4, and ZO-1 (P < 0.05). Colonic NF-κB p65 expression was higher in STZ vs NC mice (P < 0.05), with no significant A. muciniphila group/NC difference after the intervention of A. muciniphila. The expression of NF-κB p65 in A. muciniphila group was lower than that in STZ group. STAT1 expression was lower in A. muciniphila vs STZ mice (P < 0.05). 16S sequencing revealed reduced Actinobacteria abundance in A. muciniphila vs STZ mice (P < 0.05).

CONCLUSION

Short-term intervention with A. muciniphila has shown positive effects on immune response parameters, exemplified by Treg-mediated restoration of immune tolerance, which may be associated with intestinal barrier enhancement and the decreased abundance of intestinal Actinobacteria.

Keywords: Type 1 diabetes; Streptozotocin; Akkermansia muciniphila; Autoimmune; Intestinal barrier

Core Tip: This study pioneers Akkermansia muciniphila (A. muciniphila) intervention evaluation in streptozotocin-induced type 1 diabetes mellitus (T1DM) mice. Despite no reversal of hyperglycemia or islet damage after short-term (3-day) oral administration, A. muciniphila ameliorated immune imbalance by enhancing intestinal barrier function (increased zonula occludens-1, decreased zonulin), suppressing pro-inflammatory cytokines (tumor necrosis factor-alpha, interferon-gamma), increasing anti-inflammatory interleukin-4 and regulatory T cells, modulating signaling pathways (reduced signal transducer and activator of transcription 1, suppressed nuclear factor kappa-B p65), and decreasing intestinal Actinobacteria abundance. These findings highlight A. muciniphila’s potential for immune regulation in established T1DM by gut barrier repair and microbial shifts.