背景:成纤维细胞生长因子21(FGF21),主要由胰腺分泌,肝脏,和脂肪组织,在调节糖脂代谢中起着举足轻重的作用。急性胰腺炎(AP)是一种常见的炎症性疾病,临床表现特殊。许多糖尿病患者出现并发炎症症状。糖尿病会加剧肠道通透性和肠道炎症,从而导致进展为AP。我们先前的研究表明FGF21显著减弱小鼠对AP的易感性。
目的:探讨FGF21对糖尿病小鼠AP的保护作用。
方法:在本研究中,通过注射ceruletide在糖尿病(db)/db糖尿病小鼠中建立了AP小鼠模型。此后,评价重组FGF21蛋白对AP的保护作用,重点检查血清淀粉酶(AMS)水平和胰腺和肠道炎症细胞因子[白细胞介素(IL)-6,肿瘤坏死因子-α(TNF-),和肠道IL-1β]。此外,本研究检测了该治疗对胰腺和小肠组织病理学改变的影响,以阐明FGF21在糖尿病合并AP小鼠中的作用.将抗生素(Abx)混合物与FGF21疗法组合施用以研究FGF21对患有AP的糖尿病小鼠中的AP的作用是否通过调节肠道微生物群介导。随后,通过重建不受保护的国家对群落进行系统发育调查(PICRUSt),生物信息学软件包,用于预测群体之间的不同途径,并探索肠道微生物群影响FGF21保护作用的潜在机制。
结果:结果表明,FGF21显着降低了血清AMS(944.5±15.9vs1732±83.9,P<0.01)和包括IL-6在内的炎症因子(0.2400±0.55vs1.233±0.053,P<0.01),肿瘤坏死因子-(0.7067±0.22vs1.433±0.051,P<0.01),糖尿病合并AP小鼠的IL-1β(1.377±0.069vs0.3328±0.02542,P<0.01)。此外,在小鼠的胰腺结构中观察到明显的恢复迹象。小肠炎症的组织学证据,包括水肿和绒毛损伤,显着缓解。FGF21还显著改变了肠道微生物群的组成,重新建立拟杆菌/厚壁菌比率。用Abx鸡尾酒治疗以耗尽肠道微生物群,FGF21+Abx组血清AMS(0.9328±0.075vs0.2249±0.023,P<0.01)和炎症因子(1.083±0.12vs0.2799±0.032,P<0.01)水平低于FGF21组。此外,FGF21+Abx组对胰腺和小肠组织的损伤减少,伴随着血糖水平的显着下降(17.50±1.1vs9.817±0.69mmol/L,P<0.001)。这些发现强调了在患有AP的糖尿病小鼠中,涉及Abx混合物与FGF21的联合治疗优于单独的FGF21治疗的保护作用。对不同群体的肠道微生物群组成进行了进一步表征,并使用PICRUSt2预测方法进行了基因功能的差异表达分析。这些发现表明,FGF21可能通过调节肠道微生物群中硫酸盐还原I途径和n-乙酰神经酰胺降解的超途径,对患有AP的糖尿病小鼠产生治疗作用。
结论:这项研究揭示了FGF21在改善胰腺和肠道损伤恢复方面的潜力,降低血糖水平,重塑患有AP的糖尿病小鼠的肠道菌群组成。值得注意的是,当与Abx鸡尾酒组合时,FGF21的保护作用增强。
BACKGROUND: Fibroblast growth factor 21 (FGF21), primarily secreted by the pancreas, liver, and adipose tissues, plays a pivotal role in regulating glucose and lipid metabolism. Acute pancreatitis (AP) is a common inflammatory disease with specific clinical manifestations. Many patients with diabetes present with concurrent inflammatory symptoms. Diabetes exacerbates intestinal permeability and intestinal inflammation, thus leading to the progression to AP. Our previous study indicated that FGF21 significantly attenuated susceptibility to AP in mice.
OBJECTIVE: To investigate the potential protective role of FGF21 against AP in diabetic mice.
METHODS: In the present study, a mouse model of AP was established in diabetic (db)/db diabetic mice through ceruletide injections. Thereafter, the protective effects of recombinant FGF21 protein against AP were evaluated, with an emphasis on examining serum amylase (AMS) levels and pancreatic and intestinal inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor-alpha (TNF-), and intestinal IL-1β]. Additionally, the impact of this treatment on the histopathologic changes of the pancreas and small intestinal was examined to elucidate the role of FGF21 in diabetic mice with AP. An antibiotic (Abx) cocktail was administered in combination with FGF21 therapy to investigate whether the effect of FGF21 on AP in diabetic mice with AP was mediated through the modulation of the gut microbiota. Subsequently, the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), a bioinformatics software package, was used to predict different pathways between the groups and to explore the potential mechanisms by which the gut microbiota influenced the protective effect of FGF21.
RESULTS: The results indicated that FGF21 notably diminished the levels of serum AMS (944.5 ± 15.9 vs 1732 ± 83.9, P < 0.01) and inflammatory factors including IL-6 (0.2400 ± 0.55 vs 1.233 ± 0.053, P < 0.01), TNF- (0.7067 ± 0.22 vs 1.433 ± 0.051, P < 0.01), and IL-1β (1.377 ± 0.069 vs 0.3328 ± 0.02542, P < 0.01) in diabetic mice with AP. Moreover, notable signs of recovery were observed in the pancreatic structure of the mice. The histologic evidence of inflammation in the small intestine, including edema and villous damage, was significantly alleviated. FGF21 also significantly altered the composition of the gut microbiota, reestablishing the Bacteroidetes/Firmicutes ratio. Upon treatment with an Abx cocktail to deplete the gut microbiota, the FGF21 + Abx group showed lower levels of serum AMS (0.9328 ± 0.075 vs 0.2249 ± 0.023, P < 0.01) and inflammatory factors (1.083 ± 0.12 vs 0.2799 ± 0.032, p < 0.01) than the FGF21 group. Furthermore, the FGF21 + Abx group exhibited diminished injury to the pancreatic and small intestinal tissues, accompanied by a significant decrease in blood glucose levels (17.50 ± 1.1 vs 9.817 ± 0.69 mmol/L, P < 0.001). These findings underscored the superior protective effects of the combination therapy involving an Abx cocktail with FGF21 over the FGF21 treatment alone in diabetic mice with AP. The gut microbiota composition across different groups was further characterized, and a differential expression analysis of gene functions was undertaken using the
PICRUSt2 prediction method. These findings suggested that FGF21 could potentially confer therapeutic effects on diabetic mice with AP by modulating the sulfate reduction I pathway and the superpathway of n-acetylceramide degradation in the gut microbiota.
CONCLUSIONS: This study reveals the potential of FGF21 in improving pancreatic and intestinal damage recovery, reducing blood glucose levels, and reshaping gut microbiota composition in diabetic mice with AP. Notably, the protective effects of FGF21 are augmented when combined with the Abx cocktail.