Association Of Gut Microbiota And Sunitinib-induced Diarrhea In Metastatic Renal Cell Carcinoma

Purpose:Vascular endothelial growth factor-tyrosine kinase inhibitors(VEGF-TKIs)induced diarrhea seriously affects the quality of life and prognosis of patients with metastatic renal cell carcinoma(mRCC).We aim to assess the relationship between sunitinib-induced diarrhea and gut microbiota by 16 S rRNA sequencing,and then preliminarily screen potential microbial markers for treatment of sunitinib-induced diarrhea.Experimental Design:1.Determination of Research Objects and Collection of Samples.To collect participants ‘demographics,clinicopathological data,treatment-related side effects,probiotics and antibiotics usage were collected from of patients with mRCC who received at least two weeks sunitinib treatment in Fuzhou General Hospital or Fujian Medical University Union Hospital from May 2017 to March 2018.2.Subject grouping.The patients were divided into diarrhea group and non-diarrhea group according to diarrhea classification.In subgroup analysis,the patients were divided into mild diarrhea group(1-2 grade diarrhea)and severe diarrhea group(3-4 grade diarrhea),pre-treatment of sunitinib(sunitinib-pre)and post-treatment of sunitinib(sunitinib-post).To compare the composition and difference of gut microbiota in each group.3.Sample analysis.The stool bacteriomic profiling of patients was characterized with use of the V3-V4 region of 16 S rRNA sequencing for ? diversity,microbial community distribution,? diversity and the changed gut microbiota that differed between groups with vs without diarrhea.4.All data were analyzed by IBM SPSS 20.0 software.Results:1.A total of 31 patients were consented and enrolled(13 samples fromFuzhou General Hospital and 18 samples from Fujian Medical University Union Hospital).Finally,33 fecal samples were collected(31 samples after sunitinib treatment and 2 samples before sunitinib treatment).64.5% of study subjects had sunitinib-induced diarrhea and 35.5% did not.There was no difference in age,sex and body mass index between diarrhea group and non-diarrhea group.2.Gut microbial diversity decreased in diarrhea group,especially in patients with severe diarrhea.3.At phylum level,the community structure of intestinal flora in the two groups was similar.Firmicutes,Bacteroidetes and Proteobacteria were the three dominant bacteria in the two groups,accounting for about 90%.4.The abundance of Ruminococcaceae(from Firmicutes)was the most significant difference between diarrhea group and non-diarrhea group,indicating that Firmicutes was the most closely related to sunitinib-induced diarrhea.5.The microbial composition with lower abundance of Fecalibacterium?Oscillospira ? Ruminococcaceae ? Eubacterium ? Lachnospiraceae and Coriobacteriaceae(belong to butyrate-producing bacteria)were found in patients with diarrhea.6.Compared with sunitinib-pre group,the diversity of gut microbiota was increased,while Bacteroides decreased in sunitinib-post group.Conclusions:This study confirms the connection between gut microbiota and sunitinib-induced diarrhea.Sunitinib-induced diarrhea was negatively correlated with the diversity of gut microbiota.Defects of the butyrate-producing bacteria,Firmicutes and Bacteroides may be the physiological basis of sunitinib-induced diarrhea,which could be potential therapeutic targets for sunitinib-induced diarrhea.