Effects Of Intestinal Microbial Dysbiosis On Chronic Pancreatitis

Chronic pancreatitis(CP)is defined as a pathological fibro-inflammatory syndrome of the pancreas with genetic,environmental or other risk factors and develops persistent pathological responses to parenchymal injury or stress.However,its pathogenesis still remains unclear.Besides alcohol and biliary diseases,the recurrent of acute pancreatitis(AP)can also lead to the occurrence of CP due to the clinical observation.Earlier studies have shown that antibiotic treatment to decrease intestinal flora can effectively alleviate AP in mice.Additionally,salivary and intestinal microorganisms significant changed in CP patients compared with healthy.However,the role of intestinal microbiota in CP is still unclear.Therefore,we used the ceruleininduced CP model in mice to investigate the effects on decrease of intestinal flora by antibiotics on CP and its possible mechanism and represents a promising therapeutic strategy of CP.8-week-old male C57BL/6J mice were randomly divided into four groups,control group,antibiotic control group,CP model group,and antibiotic treatment group.Mice administered with antibiotic gavage for 1 week before modeling,then challenged with repeated intraperitoneal injection of cerulein(50 ?g/kg)for four weeks to establish CP with antibiotic treatment throughout.Mice were killed 3 days after the last cerulein injection,then gathered serum and pancreas.The weights of pancreas were measured,histological changes analyzed by H&E staining,and the expression of pancreatic inflammatory factors and fibrosis-related genes were detected by quantitative polymerase chain reaction(qPCR).The expression of fibrosisrelated proteins,HDACs and GPCR were measured by Western-blot,the content of short chain fatty acids(SCFAs)in feces were detected by GC-MS.The results showed that antibiotic treatment can aggravate CP by intensifying pancreatic atrophy,inflammation and fibrosis.Besides,the antibiotic treatment also significantly reduced the SCFAs in feces and increased the expression of HDAC1 in pancreas.To further elucidate the mechanism of antibiotic treatment on CP,8-week-old male C57BL/6J mice were randomly divided into four group,including control group,CP model group,antibiotic treatment group and SCFAs treatment group.Antibiotic treatment and CP model were administrated as previously.Mice were treated with SCFAs mix(67.5 mM Acetate,40 mM Butyrate,25.9 mM Propionate)in the drinking water and water solutions were prepared and changed weekly.Then the pancreatic weight,morphological changes and the expression of fibrosis-related protein were determined in the same way.The results showed that the administration of drinking water containing SCFAs can effectively alleviate the pancreatic atrophy and fibrosis which aggravated by antibiotic treatment,indicating that decreased intestinal flora aggravated CP are partly due to the decreased concentration of SCFAs.In summary,intestinal microbial dysbiosis induced by antibiotics significantly decrease SCFAs concentration in colon,which attenuates the inhibitory effect on HDAC1 and ultimately aggravates CP in mice.This study for the first time demonstrates that antibiotics-induced intestinal microbial dysbiosis can promote CP development in mice.Indicating that intestinal flora and its metabolite may play an important role in CP and offer theoretical basis on clinical treatment of CP.