AUTHOR=Wu Zhaozhen , Zhang Sujie , Li Lingling , Huang Ziwei , Huang Di , Hu Yi 

TITLE=The gut microbiota modulates responses to anti–PD-1 and chemotherapy combination therapy and related adverse events in patients with advanced solid tumors

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.887383

DOI=10.3389/fonc.2022.887383

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have been widely used in treating different malignancies. Several studies have reported that the gut microbiota modulates the response and adverse events (AEs) to ICIs in melanoma, non–small cell lung cancer (NSCLC), renal cell cancer and hepatocellular carcinoma, but data on other cancer types and ICI combination therapy are limited.</p></sec><sec><title>Methods</title><p>Stool samples were collected from patients with cancer who received anti–PD-1 and chemotherapy combination treatment and were analyzed by fecal metagenomic sequencing. The microbiota diversity and composition were compared between the responder (R) and non-responder (NR) groups and the AE vs. the non-AE (NAE) groups. In addition, associated functional genes and metabolic pathways were identified.</p></sec><sec><title>Results</title><p>At baseline, the microbiota diversity of the groups was similar, but the genera <italic>Parabacteroides</italic>, <italic>Clostridia bacterium UC5.1_2F7</italic>, and <italic>Bifidobacterium dentium</italic> were enriched in the R group, whereas <italic>Bacteroides dorei</italic> and 11 species of <italic>Nocardia</italic> were enriched in the NR group. At 6 weeks, the beta diversity was significantly different between the R and NR groups. Further analysis found that 35 genera, such as <italic>Alipes</italic>, <italic>Parabacteroides</italic>, <italic>Phascolarctobacterium</italic>, <italic>Collinsella</italic>, <italic>Ruminiclostridium</italic>, <italic>Porphyromonas</italic>, and <italic>Butyricimonas</italic> and several genera of the <italic>Fibrobacteraceae</italic> family, were frequently distributed in the R group, whereas 17 genera, including <italic>Enterococcus</italic>, <italic>Lachnoclostridium</italic>, <italic>Hungatella</italic>, and <italic>Bilophila</italic> and several genera of the <italic>Pseudonocardiaceae</italic> and <italic>Beijerinckiaceae</italic> families, were more abundant in the NR group. A total of 66 and 52 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologs (KOs) were significantly enriched in the R and NR groups, respectively. In addition, pathway analysis revealed functional differences in the gut microbacteria in the R group, including the enrichment of anabolic pathways and DNA damage repair (DDR) pathways. Dynamic comparisons of the bacterial composition at baseline, 6 weeks, and 12 weeks showed that the abundance of <italic>Weissella</italic> significantly increased in the R group at 6 weeks and the abundance of <italic>Fusobacterium</italic> and <italic>Anaerotruncus</italic> significantly increased in the NR group at 12 weeks. Linear discriminant analysis effect size analysis indicated that bacteria of <italic>Bacteroidetes</italic>, especially <italic>Bacteroides</italic>, were enriched in the NAE group, whereas flora of <italic>Firmcutes</italic>, such as <italic>Faecalibacterium prausnitzii</italic>, <italic>Bacteroides fragilis</italic>, and <italic>Ruminococcus lactaris</italic>, were enriched in the AE group.</p></sec><sec><title>Conclusion</title><p>Beta diversity and differences in the gut microbiota modulated AEs and the response to anti–PD-1 blockade combined with chemotherapy, by regulating related anabolic and DDR pathways. Dynamic changes in the intestinal microbiome may predict the efficacy of PD-1 inhibitor–based therapy.</p></sec>