Dynamic microbiome and metabolome analyses reveal the interaction between gut microbiota andanti‐PD‐1 based immunotherapy in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a severe disease with high mortality and global incidence. However, the interaction between the gut microbiome and combined immunotherapy for HCC is yet unclear. In this prospective clinical study, patients with unresectable HCC who had not received systemic treatment previously were recruited. Fecal and serum samples were collected at the baseline point and before each subsequent administration as specified. Between 20 October 2019 and 2 February 2021, 61 patients were screened for eligibility, of whom 35 patients were finally included in this study. Alpha diversity of fecal samples from patients who responded to immunotherapy was higher than that of nonresponders at baseline. However, the prominent alpha‐diversity between responders and nonresponders became similar as early as week 6 after treatment. The beta diversity of intergroup did not show significant difference at the ninth week after treatment. Alpha‐d‐Glucose was the only serum metabolite that differed between the responders and nonresponders after 3 months. Responder‐enriched Ruminococcus showed a positive correlation with serum galactaric acid, while Klebsiella was positively associated with 3‐methylindole and lenticin (all P < .01). The machine learning classifier based on serum metabolites were more able to discriminate HCC patients who potentially benefited from immunotherapy at baseline (AUC 0.793, 95% CI: 0.632‐0.954) than the classifier of gut microbiome. In conclusion, gut microbiome biomarkers are associated with the response to anti‐PD‐1 based immunotherapy in HCC patients. Classifiers based on gut microbiota and serum metabolites are feasible.

Qingyi granules ameliorate severe acute pancreatitis in rats by modulating the gut microbiota and serum metabolic aberrations

“…Serum galactaric acid was shown to be positively correlated with Ruminococcus abundance in hepatocellular carcinoma patients responding to immunotherapy (Wu et al. 2022 ). This suggests that high galactaric acid levels are related to abnormal microbiota activities in SAP.…”

Modulating gut microbiome in cancer immunotherapy: Harnessing microbes to enhance treatment efficacy

“… 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 The enrichment of Faecalibacterium was also associated with ICB responsiveness in different cancers, involving melanoma, HCC, and NSCLC. 36 , 41 , 42 , 43 , 44 , 45 , 46 For a specific cancer type, a meta-analysis of melanoma patients revealed that the presence of Lachnospiraceae species is associated with a more favorable clinical response, while the presence of Streptococcaceae species is linked to an unfavorable response. 47 In another study, several bacterial taxa were found to be differentially enriched in melanoma patients who were responders to combined CTLA-4 and PD-1 blockade, including Bacteroides stercoris , Parabacteroides distasonis , and Fournierella massiliensis.…”

“… 52 HCC Faecalibacterium , Blautia , Lachnospiracea incertae Sedis, Megamonas , Ruminococcus , Coprococcus , Dorea , Haemophilus anti-PD-1 16S rRNA (V3-V4) 35 China Wu et al. 36 , 41 , 42 , 43 , 44 , 45 , 46 Hepatobiliary Lachnospiraceae bacterium GAM79, Alistipes sp. Marseille-P5997, Ruminococcus calidus , Erysipelotichaceae bacterium GAM147 anti-PD-1 metagenomic 65 China Mao et al.…”

“… 53 Melanoma Faecalibacterium , Firmicutes ipilimumab 16S rRNA (V3-V4) 26 France Chaput et al. 36 , 41 , 42 , 43 , 44 , 45 , 46 Melanoma Bacteroides caccae ipilimumab, nivolumab, ipilimumab plus nivolumab, or pembrolizumab metagenomic 39 USA Frankel et al. 36 , 41 , 42 , 43 , 44 , 45 , 46 Melanoma Faecalibacterium prausnitzii , Bacteroides thetaiotaomicron , Holdemania filiformis ipilimumab plus nivolumab metagenomic 24 USA Frankel et al.…”

Gut dysbiosis in nonalcoholic fatty liver disease: pathogenesis, diagnosis, and therapeutic implications

“…The gut microbiota also has been demonstrated to enhance the therapeutic response to immune checkpoint inhibitors though targeting immunomodulatory molecules or their ligands on the surfaces of T cells ( McCulloch et al., 2022 ; Wu et al., 2022 ; Zhang et al., 2022 ; Zhao et al., 2022 ). The combination has been approved for treating various malignant tumors, including NAFLD-associated HCC ( Baruch et al., 2021 ; Davar et al., 2021 ; Shiraishi et al., 2022 ).…”