Study On The Interaction Between Heparin Polysaccharides And Gut Microbiota

Heparin is one of the widely used anticoagulant and antithrombotic drugs in clinical practice.Due to its high electronegativity and low lipid solubility,Oral heparin bioavailability was poor.Heparin is always administered by injection in clinical practice,which is not convenient,and it is more convenient for patients with higher compliance to use it by oral administration.At present,there are few studies on oral heparin in the gastrointestinal tract.The gastrointestinal tract is a complex environment colonized with a large number of intestinal flora,which is closely related to the metabolism of the host.Study on the interaction between oral heparin and intestinal flora will promote the development of oral heparin drugs.In the analysis of the effects of gastrointestinal environment on oral heparin,we tested the fluorescent heparin in mice by gavage.And found that no fluorescent heparin was detected in heart,liver,spleen,lung and kidney,which is mainly distributed in the gastrointestinal of mice.By examining the stability of heparin in simulated gastrointestinal fluids,heparin was found to have better stability in the gastrointestinal tract without degradation.We detect the changes of heparin and its derivatives by high performance liquid chromatography after they was co-incubated with intestinal flora in vitro.It was found that heparin and heparin derivatives can degraded by the mouse fecal flora was cultured in heparin medium.The experiment found that heparin and heparin derivatives induced bacterial flora have different ability of degrade heparin and heparin derivatives.The ability of degradation heparin and heparin derivatives depending on the type of heparin added in the medium,we found that HP is better than NAHP,and the worest is LNA.Gut bacteria also has different degradation capabilities with heparin and heparin derivatives,we found that HP is the easiest to degrade than NAHP,and LNA is the most difficult to degrade.By measuring the effect of heparin on the structure of intestinal flora in vitro,we found that heparin can regulate the structure of cultured intestinal by enriching Bacteroides and inhibiting Shigella sp.in vitro.In investigating the effects of heparin on gut microbiota,high-throughput sequencing was used to detect changes in gut flora in the feces of mice.Analysis of mice body weight,colon structure and spleen weight index by continuous oral heparin for 30 days showed that long-term oral heparin had no obvious side effects on the body.And it was found that the biodiversity of the fecal microflora of the oral heparin mice(HP group)was decreased compared with the mice administered with physiological saline(WT group)during the oral administration of 30 days heparin to mice.We did not find the difference between the oral heparin group and wild type group at the phylum level.But at the genus level,the abundance of Alistipes,Parasutterella and Prevotellaceae-UCG-001 was increased in oral heparin mice compared with the WT group,while the relative abundances of ASF356,Dubosiella,Desulfovibrio,Odoribacter,Lachnospiraceae_NK4A136-group and Ruminococcaceae UCG-014 were decreased.These findings indicating that Oral administration of heparin has a certain regulatory effect on the intestinal flora of mice.In summary,the reduced bioavailability of oral administration of heparin may be related to the degradation of heparin byintestinal flora.Oral heparin has the ability to regulate the intestinal flora and have high safety.This finding will provide reference for the development of clinical oral heparin drugs.