Hepatocellular Carcinoma: Understanding the Inflammatory Implications of the Microbiome

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. It is well known that repeated inflammatory insults in the liver can cause hepatic cellular injury that lead to cirrhosis and, ultimately, hepatocellular carcinoma. Furthermore, the microbiome has been implicated in multiple inflammatory conditions which predispose patients to malignancy. With this in mind, we explore the inflammatory implications of the microbiome on pathways that lead to HCC. We also focus on how an understanding of these underlying inflammatory principles lead to a more wholistic understanding of this deadly disease, as well as potential therapeutic implications.

Keywords: NAFLD; alcoholic liver disease; hepatitis B; hepatitis C; hepatocellular carcinoma; single cell.

Figure 1

Table depicting the role of leaky gut, endotoxin translocation, bile acid metabolism, choline, and vLDL duality in NAFLD. ^a Lam et al., 2012 [18], ^b Lam et al., 2015 [19], ^c Kolodziejczyk et al., 2019 [20], ^d Dapito et al., 2012 [21], ^e Schwab et al., 2020 [22], ^f Raza et al., 2019 [23], ^g Yoshimoto et al., 2013 [24], ^h Takahashi et al., 2018 [25], ⁱ Spencer et al., 2011 [28], ^j Chu et al., 2018 [29].

Figure 2

Upregulation and downregulation of microbes and their factors related to hepatitis B and C. ^a Mohamadkhani et al., 2018 [32], ^b Palsson McDermott et al., 2014 [33], ^c Milosevic et al., 2019 [36], ^d Lu et al., 2011 [30], ^e Wang et al., 2017 [31], ^f Ma et al., 2015 [34], ^g Roderburg et al. 2014 [35], ^h El-Mowafy et al., 2021 [39], ⁱ Aly et al., 2016 [40], ^j Qin et al., 2018 [41]., ^k Giannakoulis et al., 2021 [43].

Figure 3

Inflammatory implications of bacteria on immune cells and metabolic pathways in conditions associated with HCC. $\uparrow =\mathrm{upregulated},$ ↓ = downregulated.

Figure 4

Effect of bile acids and short chain fatty acids on upregulation and downregulation of inflammatory processes which lead to HCC. ^a Su et al., 2012 [74], ^b Zhang et al., 2012 [75], ^c Yamada et al., 2018 [76], ^d Xie et al., 2017 [77], ^e Xie et al., 2021 [78], ^f Ma et al., 2018 [79], ^g Singh et al., 2018 [80], ^h Lee et al., 2020 [82], ⁱ Janssen et al., 2017 [83], ^j Gupta et al., 2019 [84], ^k Wang et al., 2013 [85], ^l Matsui-Yuasa et al., 2016 [86].

Figure 5

Schematic depiction of single cell technology and how it can potentially be used for targeted, individualized treatment of HCC based on immune cell, and HCC risk factor phenotype.