Effect Of Adropin On Colonic Imflammation In Colitis Mice And Its Association With The Clinical Characteristics In Patients With Crohn’s Disease

Background: It has been found that intestinal immune imbalance is one of important pathogenesis of inflammatory bowel disease(IBD)and the energy metabolism involves in the immune balance.However,IBD patients(especially in Crohn’s disease)showed significant disorder in the energy metabolism.Adropin,one of energy regulating factors,distributes widely in various tissues,and has effcets on regulating the metabolism of glucose and lipid,and also has anti-inflammatory.Objectives: To investigate the effect of adropin on colonic imflammation in colitis mice and its association with the clinical characteristics in patients with Crohn’s disease.Methods:(1)In total,24 Male 8-week-old SPF adropin +/-heterozygote mice(KET)were randomly divided into 4 groups: blank control(group KET-Cont)、colitis mice(group KET-coli)、colitis mice treated by adropin ip.(group KET-coli-Adr)、colitis mice treated by placebo ip(group KET-coli-Plac).12 male wild-type(WT)mice were randomly divided into 2 groups: black control(group WT-Cont)and colitis mice(group WT-coli).The colitis was induced by drinking 2% DSS solution for 7 days.Adropin(450mmol/g/d/per)was intraperitoneally injected in the mice in group KET-coli-Adr.General conditions were observed daily.The colonic histopathologic changes were evaluated by HE staining,and the expressions of adropin,PGC-1α and Sirt1 in colonic tissues were detected respectively by immunohistochemistry.The serum concentrations of adropin,IL-1β and TNF-α were measured with ELISA,and the expressions of some proteins(adropin、Sirt1、PGC-1α、NF-κB)involving in the adropin-Sirt1/PGC-1α signal pathway detected by Western blot.(2)The serum levels of adropin were measured in 60 Crohn’s disease(CD)patients and 36 healthy controls,and then the correlation between serum adropin and clinical parameters were analyzed.The colonic tissue and mesenteric fat were collected respectively from 8 CD cases and 6patients with colon cancer who received surgical treatment,and then the expressions of adropin,PGC-1α and Sirt1 in these tissues were detected with immunofluorescence.Results:(1)In healthy mice,adropin was expressed in the muscular and mucosal layers of colon.(1)The expression of adropin was significantly higher in group KET-coli(80.98±1.10pg/ml)than in group KET-Cont(107.20±3.32pg/ml)(P<0.05).It was also higher in WT-coli group(120.80±5.07pg/ml)than that in WT-Cont group(92.68±2.61pg/ml)(P<0.05).Then the expression of adropin was higher in group WT-coli than in group KET-coli.(2)Compared with those in WT-coli group,the DAIs,serum IL-1β and colon histopathologic scores were increased,and colon length was shorter in group KET-coli(P<0.05).(3)Compared with those in group KET-coli-Plac,the colon length was longer,and serum TNF-α and IL-1β levlels were decreased significantly in group KET-coli-Adr(P<0.05).(4)The expressions of Sirt1,PGC-1α,NF-κB in colonic tissues in group KET-coli and in group WT-coli were significantly higher than those in group KET-Cont and in group WT-Cont(P<0.05).They were also higher in group KET-coli than in group WT-coli.(5)Compared with those in group KET-coli-Plac and in group KET-coli,the expressions of Sirt1,PGC-1α in colonic tissues were upregulated,and NF-κB was decreased in group KET-coli-Adr.(2)Adropin was expressed in the colonic muscular and mucosal layers,and in the mesentery fat in CD patients.(1)The serum adropin concentration was no difference between in group CD and in healthy controls.However,it’s lower in patients with active CD than in patients with remission CD(3629.81±931.49 vs 4322.47±1194.69,P<0.05).And the serum adropin levels showed negative correlation with ESR and CDAI in CD patients.(2)Compared with those in patients with colon cancer,the expressions of adropin,Sirt1 and PGC-1α in colonic tissues were upregulated respectively in CD patients(Padropin=0.034 、 PSirt1=0.023 、 PPGC-1α=0.000).(3)The expressions of adropin and PGC-1α in the mesenteric adipose tissue in CD patients were also higher respectively than in patients with colon cancer(Padropin=0.000,PPGC-1α=0.000).Conclusion: Adropin may activate the Sirt1/ PGC-1α pathway and then inhibits inflammatory factors(such as NF-κB,IL-1β and TNF-α)release,resulting in improvement of intestinal inflammation.Adropin gene deficiency may aggravated intestinal inflammation in DSS-induced mice.