Intestinal Microbiota Predicts Lung Cancer Patients At Risk For Immune-related Diarrhea

[Background]Anti-programmed cell death 1(PD-1)inhibitors,which enhance immunity via blockade of PD-1,represent an effective option for the treatment of lung cancer and have shown some impressive efficacy.However,the inhibitors can also result in immune-related adverse events,such as immune-related diarrhea.Researches have shown that intestinal microbiota plays a vital role in gastrointestinal.Whereas,the relationship between PD-1 inhibitors and immune-related diarrhea is still elusive.In our study,we aim to identify the correlation of intestinal microbiota and immune-related diarrhea,and hope to find specific bacteria as potential biomarkers of immune-related diarrhea.[Methods]This retrospective study enrolled in 26 lung cancer patients who were treated with PD-1 inhibitors in Chinese PLA General Hospital from January 2017 to June 2017.All patients have received intravenous infusion treatment,method:Nivolumab 3mg/kg,every two weeks;Pembrolizumab 2mg/kg,every three weeks.And the fecal samples were obtained from patients before the first dose of PD-1 inhibitor.Based on whether they develop diarrhea or not,the patients were subgroup into progressed to diarrhea(PtD)group and diarrhea-free(D-F)group.Immune-related diarrhea was graded according to the National Cancer Institute Common Toxicity Criteria(CTC,version 4.0).And 16S rRNA sequencing was used to profile fecal bacterial composition.The onset of diarrhea and fecal bacterial composition were retrospectively analyzed.We used the R programming language 3.1.1 for statistical analysis.[Results]Of the 26 patients,8 patients experienced diarrhea between 1 and 10 weeks after the using of PD-1 inhibitor.There were no significant differences in baseline characteristics between PtD group and D-F group(P>0.05).The two groups had similar microbial richness and diversity before the initiation of immune-related diarrhea based on Alpha diversity indices.While referring to Beta diversity,weighted-UniFrac PCoA analysis demonstrated significant differences in bacterial composition among the two group.Besides,At the phylum level,Bacteroidetes were richer in D-F group than that in PtD group,while Firmicutes were poorer than that in PtD group.At the genus level,two families of the Bacteroidetes phylum(Bacteroides and Parabacteroides)and a family of the Firmicutes phylum(Phascolarctobacterium)were more abundant in D-F group.Veillonella from Proteobacteria phylum was lower in D-F group than that in PtD group.(all P<0.05)[Conclusions]Microbiota changing participates in the onset of immune-related diarrhea.Identifying these biomarkers may help us to diagnose the side effect earlier,and it also provides a new method of treatment for us.