PS1490 BERBERINE MAY CORRECT GUT MICROBIOTA‐INDUCED CORTICOSTEROID RESISTANCE AND MESENCHYMAL STEM CELL DYSFUNCTION IN IMMUNE THROMBOCYTOPENIA BY REGULATING GUT MICROBIOTA STRUCTURE
Authors: wang Y. , liu X. , he Y. , wang Q. , zhu X. , wang C. , fu H. , lv M. , chang Y. , zhao X. , zhao X. , xu L. , liu K. , huang X. , zhang X. 
Published: June 2019

Background:Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by abnormal immune response. Though many therapies have been used, corticosteroid‐resistance remains to be a challenge clinically. Extensive research shows that environmental factors affect the disease profile, such as Helicobacter pylori being proven to be associated with thrombocytopenia. Though evidence that the gut microbiota contributes to the development of auto‐immune disorders is accumulating, there is no information available on relationship between gut microbiome and ITP. Berberine(BBR), a traditional compound isolated from a Chinese herb, has been widely used as a nonprescription drug to treat diarrhea. Recently, BBR has been reported to modulate microbiota structure, which contributes to improving metabolic disorders. Here, we hypothesized that BBR might regulate gut microbiota thus enhancing bone marrow mesenchymal stem cell (MSC) function to treat ITP.Aims:To investigate the relationship between gut microbiota and ITP, and determine the mechanism of corticosteroid resistance induced by gut microbiota, as well as the effect of BBR on treating ITP.Methods:We performed deep shotgun sequencing on 151 fecal samples from 99 ITP patients and 52 healthy controls to characterize the gut microbiota and gene function of ITP. To better determine the relationship between gut microbiota and impaired MSCs function, we detected serum lipopolysaccharide (LPS) of ITP patients and healthy controls, and assessed MSCs function with and without LPS stimulation in vitro. Certainly, a pilot cohort study was performed to assess the efficacy of BBR in corticosteroid‐resistant ITP patients. To better characterize the role of gut microbiota in the development of ITP and its underling mechanism, as well as the effect of BBR, we performed colonization of mice with specific bacterium and established active ITP murine model.Results:We constructed a gene catalogue containing 3,548,820 non‐redundant genes totally and identified significant gut microbiota dysbiosis in ITP patients. The abundance of Flarobacterium succinicans (F. succinicans) was markedly increased in ITP especially in corticosteroid‐resistant ITP patients. Gene function annotation indicated that LPS biosynthesis was down‐regulated remarkably in corticosteroid‐resistant ITP patients. ELISA detection indicated that serum LPS was significantly lower in corticosteroid‐resistant ITP patients, which was consistent with the result of gene function annotation. LPS stimulation could restore the function of MSCs from corticosteroid‐resistant ITP patients in vitro. Colonization of F. succinicans altered gut microbiota structure and serum LPS level, impaired MSCs function and the response to corticosteroid therapy in active ITP model. Improving MSCs function induced by F. succinicans colonization by ARTA could enhance the response to corticosteroid therapy. Moreover, BBR treatment could modulate gut microbiota dysbiosis, thus reversing the effect of F. succinicans colonization, and eventually enhancing the response to corticosteroid therapy in ITP model. Pilot study validated the effect of BBR in corticosteroid‐resistant ITP patients.Summary/Conclusion:Our findings demonstrated that gut microbiome altered in ITP and might contribute to the development of corticosteroid‐resistance. Impaired MSC function induced by microbiota might mediated corticosteroid resistance in ITP. BBR might correct corticosteroid‐resistance by modulating gut microbiota structure, thus being a novel potential second‐line candidate to treat ITP.