Patients With Early vs Advanced HCC Show Distinct Gut Microbiota Alterations

A recent study found that patients with early-stage hepatocellular carcinoma (HCC) and those with advanced-stage disease exhibited distinct gut microbiota diversity and composition alterations, although future studies are warranted to investigate the mechanisms underlying the interactions between gut microbiota and HCC progression. The findings were published in Advances in Digestive Medicine.

Illustration of hepatocellular carcinoma | Image credit: Crystal light - stock.adobe.com

Gut microbiota alterations are known to play a role in the development of HCC, but the changes that take place in gut microbiota throughout the progression of HCC are not well described. Therefore, the study authors assessed differences in the fecal microbiota of patients with early- and advanced-stage HCC to characterize these groups.

The cross-sectional study, which was conducted in Taiwan, examined stool samples from 31 patients with early-stage HCC and 44 patients with advanced-stage HCC. The groups were similar in terms of the age and sex of patients, with a mean (SD) age of 66.1 (9.1) years in the early-stage cohort and 66.7 (8.9) years in the advanced-stage cohort. Patients’ gut microbiota composition was determined by 16S ribosomal RNA gene sequencing using the 16S Metagenomic Sequencing Library Preparation method.

While the alpha-diversity and species richness of the gut microbiota were similar between groups, there was significantly different beta-diversity between the gut microbiota of patients with early- vs advanced-stage HCC. In the 75 samples, the researchers identified 16 bacterial phyla, 24 classes, 41 orders, 70 families, and 228 genera. The main phyla seen were Bacteroidetes and Firmicutes, accounting for nearly 80% of all sequences, the authors noted.

The most prevalent classes seen were Bacteroidia, Clostridia, Negativicutes, and Gammaproteobacteria. Regarding orders, Bacteroidales, Clostridiales, Selenomonadales, Betaproteobacteriales, and Enterobacteriales were the most prevalent. Bacteroidaceae, Prevotellaceae, Ruminococcaceae, Lachnospiraceae, Veillonellaceae, Acidaminococcaceae, Burkholderiaceae, and Enterobacteriaceae were the most prominent families. The most prominent genera were Bacteroides, Prevotella, and Facecalibacterium.

In patients with advanced-stage HCC, the genus Veillonella, family Enterobacteriaceae, order Enterobactriales, and class Gammaproteobacteria were more enriched than in the microbiota of the early-stage cohort. In the advanced-stage cohort, Proteobacteria abundance was significantly higher compared with the early-stage cohort (P < .01).

The authors noted that there was no significant difference between groups regarding the Firmicutes to Bacteroidetes ratio, which previous research has reported to be a biomarker of obesity.

“To the best of our knowledge, this is the first study to compare the composition of the [gut microbiota] in patients with different stages of HCC,” the authors wrote. “The present work demonstrates that patients with early-stage HCC and advanced-stage HCC exhibit distinct alterations to the diversity and composition of the [gut microbiota].”

Recent research suggests increased intestinal permeability may allow bacteria and products of bacteria, like lipopolysaccharides (LPSs), to move from the intestines to the liver, the authors explained. The bacteria and products might exacerbate inflammation, liver injury, and fibrosis, potentially promoting hepatocarcinogenesis. Therefore, the gut microbiota may play substantial roles in HCC development and progress. The authors highlighted previous research indicating that Escherichia coli, a member of the Enterobacteriaceae family, is associated with increased LPS. Veillonella and Gammaproteobacteria, both potential human pathogens, have also been shown to produce LPS and induce cytokine release.

“Therefore, reshaping the gut microbiota to a healthy state through fecal microbiota transplantation (FMT) may potentially slow down the progression of HCC,” the authors wrote. “Thus, whether FMT may have a beneficial role in patients with early-stage and advanced-stage HCC warrants further investigation.”

The study was limited by its use of 16S rRNA gene sequencing vs metagenomic sequencing, limiting species-level interpretation of data and the ability to perform functional analyses, the authors noted. Additionally, confounders such as age, dietary intake, and medication may have influenced the findings. The study was also conducted in mainly ethnic Taiwanese patients, potentially limiting the generalizability of the findings.

In future analyses, the researchers plan to include all stages of HCC to more comprehensively analyze gut microbiota alterations.

“Our results suggest that patients with early-stage and advanced-stage HCC have distinct patterns of changes in [gut microbiota] diversity. Furthermore, we found that some taxa, including Veillonella, Enterobacteriaceae, Enterobacteriales, and Gammaproteobacteria, are enriched in the [gut microbiota] of patients with advanced-staged HCC,” the authors concluded. “Future studies are required to investigate the biofunctional effects and mechanisms that underlie the interaction between [gut microbiota] alterations and the progression of HCC.”

Reference

Tsai MC, Kuo YH, Tai WC, et al. Distinct gut microbiota alterations in patients with early-stage and advanced-stage hepatocellular carcinoma. Adv Digest Med. Published online February 1, 2024. doi:10.1002/aid2.13385