Depletion of gut microbiota facilitates fibroblast growth factor 21-mediated protection against acute pancreatitis in diabetic mice.

BACKGROUND

Fibroblast growth factor 21 (), 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.

AIM

To investigate the potential protective role of 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 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 in diabetic mice with AP. An antibiotic (Abx) cocktail was administered in combination with therapy to investigate whether the effect of 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 .

RESULTS

The results indicated that notably diminished the levels of serum AMS (944.5 ± 15.9 1732 ± 83.9, 0.01) and inflammatory factors including IL-6 (0.2400 ± 0.55 1.233 ± 0.053, 0.01), TNF- (0.7067 ± 0.22 1.433 ± 0.051, 0.01), and IL-1β (1.377 ± 0.069 0.3328 ± 0.02542, 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. also significantly altered the composition of the gut microbiota, reestablishing the ratio. Upon treatment with an Abx cocktail to deplete the gut microbiota, the + Abx group showed lower levels of serum AMS (0.9328 ± 0.075 0.2249 ± 0.023, 0.01) and inflammatory factors (1.083 ± 0.12 0.2799 ± 0.032, 0.01) than the group. Furthermore, the + 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 9.817 ± 0.69 mmol/L, 0.001). These findings underscored the superior protective effects of the combination therapy involving an Abx cocktail with over the 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 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.

CONCLUSION

This study reveals the potential of 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 are augmented when combined with the Abx cocktail.