Clinical And Gut Microbiota Study Of QSHY Decoction In The Treatment For Patients With Damp Heat Syndrome Of Non-alcoholic Fat Liver Disease

Objective:To evaluate safety and effectiveness of traditional Chinese medicine compound QSHY for patients with damp heat syndrome of nonalcoholic fat liver disease.Exploring the curative effect mechanism of QSHY decoction from the perspective of gut microbiota.Methods:(1)Carry out a multi-center,randomized,double-blind,double-simulated controlled clinical trial to collect 246 patients of NAFLD with damp heat syndrome.There are 123 cases in the test group of "QSHY Granule+Dangfei Liganning Capsule Simulator" and 123 cases in the control group of "QSHY Granule Simulator+Dangfei Liganning Capsule".The course of treatment is 24 weeks,with 0 weeks,12 weeks,and 24 weeks as follow-up points.Simultaneous curative effect analysis with FAS set and PPS set.Primary outcome indicator:CAP values,ALT,GGT.Secondary outcome indicators:TCM syndromes,related laboratory indicators,and imaging indicators before and after treatment are observed.Safety evaluation index.(2)And 16S rRNA sequencing is used to screen the difference in gut microbiota before and after treatment.Stool samples of patients in the test group are tested at 0 weeks(67 cases),3 weeks(24 cases),12 weeks(38 cases),and 24 weeks(67 cases).Combining with clinical curative effect,explore the changes of microbiota related to QSHY recipe.Results:Primary outcome indicator:The CAP value,serum ALT and GGT levels of the test group in different follow-up periods were lower than before treatment(all P<0.05),and after 24W treatment,the test group was better than the control group in terms of the improvement of CAP value(P<0.05),it has a tendency to be better than the control group in reducing the serum ALT level(PPS set P=0.056),and it is better than the control group in reducing the serum GGT level(P<0.05).Secondary outcome indicators:(1)TCM syndrome:After 24W treatment,the total score of TCM syndromes and the total score of main syndromes in the test group were lower than before treatment,and the test group was lower than the control group(all P<0.05).The test group is better than the control group in the effective rate of the main symptoms of TCM at 24W(PPS set P=0.044).After 24 weeks treatment,the individual indicators of TCM syndromes including right flank pain,heavy sleepiness,fullness or pain in the abdominal abdomen,sticky and uncomfortable stools,yellow urine,sticky mouth,dry mouth and bitter mouth all were improved(all P<0.05),and the test group was better than the control group in improving the score of stool stickiness(P<0.05).At the same time,there is a trend of differences between the two groups in the disappearance of the positive symptoms of sticky stools,and the test group has a tendency to be better than the control group(PPS set P=0.056).There was a significant difference in the disappearance of positive symptoms of yellow urine,the test group was better than the control group(P<0.05).(2)Imaging aspects:After 24W treatment,the CT ratio of liver and spleen in the test group was higher than before treatment,MRI-PDFF level(single center),liver stiffness under elastic ultrasound were lower than before treatment,and the degree of fatty liver under ultrasound was better than before treatment(all P<0.05),but there was no statistical difference between the groups(all P>0.05).(3)General indicators:The weight,BMI,waist circumference and waist-hip ratio of the test group at different followup points were lower than before treatment(all P<0.05),but there was no statistical difference between the two groups(all P>0.05).(4)In terms of secondary liver function indicators:Serum DBiL and AST level in the test group at different follow-up points were lower than before treatment,and the AST level in the test group was lower than the control group at 24W(P<0.05),but there was no statistical difference in DBiL between the two groups(all P>0.05).The absolute value of ALP of the test group at 12W and 24W was lower than that of the control group(P<0.05),and the test group was better than the control group in reducing the serum ALP level.(5)blood lipid and blood glucose:Serum HbAlc in the test group at different follow-up points was lower than before treatment,but there was a statistical difference between the two groups only at 12W(PPS set P<0.05).After the intervention of QSHY decoction,the blood lipid-related indexes TG,TC,HDL-C,LDL-C and blood glucose-related indexes FPG,FINS,HOMA-IR of the test group at different follow-up points were not statistically different from before treatment.There was no statistical difference between the two group(all P>0.05).(6):The LJDQ score of the test group at 24W was higher than that before treatment(P<0.05),but there was no statistical difference from the control group(P>0.05).(7):Among the safety evaluation indexes,in the test group,except for SBP,RBC,and UA which were lower than before treatment(P<0.05),the other safety evaluation indexes did not change significantly(all P>0.05).The early changes in QSHY treatment of NAFLD damp-heat syndrome patients were mainly reflected in the increasing the abundance of Firmicutes,and the long-term changes were the common changes of Firmicutes,Bacteroides and Proteobacteria(all P<0.05)).Corresponding early change genus are Butyricicoccus,Lachnoclostridium,Tyzzerella,Lachnospira,Lachnospiraceae_ND3007_group,Lachnospiraceae_UCG-004 which were increased after treatment.Long-term change genus include the same bacteria as the early changes,as well as Blautia,Escherichia-Shigella which were decreased,Parabacteroides and Bacteroides which were increased(all P<0.05).The correlation analysis with clinical factors shows that the difference of microbiota before and after treatment is closely related to the changes of ALT and GGT levels.Among them,the related microbiota that QSHY reduces serum liver enzyme ALT and GGT levels in NAFLD patients with damp-heat syndrome were Blautia,Escherichia-Shigella,Parabacteroides and Lachnospiraceae_NC2004_group.Conclusion:1.The TCM compound QSHY decoction can effectively reduce the serum liver enzyme ALT and GGT levels and liver fat content under imaging,and improve the TCM syndromes and syndrome-related clinical symptoms of NAFLD patients with damp-heat syndrome.And it is better than the positive control drug Dangfei Liganning Capsule in improving the serum GGT level,the score of TCM syndromes and the TCM symptom of sticky and uncomfortable stools.The curative effect is safe,with no adverse reactions..2.The TCM compound QSHY decoction can correct the structural disorder of the gut microbiota of NAFLD patients with damp-heat syndrome,in which the decrease in the abundance of Escherichia-Shigella and the increase in the abundance of Lachnoclostridium,Butyricicoccus,Tyzzerella,Lachnospira,Lachnospiraceae_ND3007_group,Lachnospiraceae_UCG-004 may be the target of QSHY decoction to improve NAFLD patients with damp-heat syndrome.The decrease in the abundance of Blautia,Escherichia-Shigella and the increase in the abundance of Parabacteroides and Lachnospiraceae_NC2004_group are related to the efficacy of serum liver enzyme ALT/GGT.