Effects of Bacillus Calmette-Guérin on immunometabolism, microbiome and liver diseases⋆

Abstract

Metabolic diseases have overtaken infectious diseases as the most serious public health issue and economic burden in most countries. Moreover, metabolic diseases increase the risk of having infectious diseases. The treatment of metabolic disease may require a long-term strategy of taking multiple medications, which can be costly and have side effects. Attempts to expand the therapeutic use of vaccination to prevent or treat metabolic diseases have attracted significant interest. A growing body of evidence indicates that Bacillus Calmette-Guérin (BCG) offers protection against non-infectious diseases. The non-specific effects of BCG occur likely due to the induction of trained immunity. In this regard, understanding how BCG influences the development of chronic metabolic health including liver diseases would be important. This review focuses on research on BCG, the constellation of disorders associated with metabolic health issues including liver diseases and diabetes as well as how BCG affects the gut microbiome, immunity, and metabolism.

Keywords: Bacillus Calmette-Guérin (BCG); Diabetes; Gut microbiota; Liver disease; Metabolic diseases; Trained immunity; Vaccination.

Fig. 1

BCG induces trained immunity which has effects on metabolic activity and epigenetic rewiring. Increased glycolysis, glutaminolysis, and cholesterol synthesis are essential for BCG-induced trained immunity development in the monocytes. In addition, when trained immunity occurs, monocytes undergo epigenetic rewiring. H3K4me3, an activating histone modification, is prevalent in the proximal regulatory areas of pro-inflammatory cytokine genes including TNF-α and IL-6 in trained monocytes. Another sign of BCG-induced trained immunity is reduced H3K9me3 at the promoters of TNF-α and IL-6. Importantly, metabolites such as acetyl-CoA in trained monocytes serve as cofactors for acetyltransferases. Collectively, the integration of metabolism and epigenetic rewiring occurs during BCG-induced trained immunity. Abbreviations: α-KG, alpha-ketoglutarate; ATP, adenosine triphosphate; BCG, Bacillus Calmette-Guérin; H3K4me3, trimethylated histone H3 lysine 4; H3K9me3, trimethylated histone H3 lysine 9; IL-6, interleukin-6; TCA, tricarboxylic acid; TNF-α, tumor necrosis factor-alpha.

Fig. 2

Effects of BCG on metabolic diseases. (A) Intravenous administration of BCG in ob/ob mice prevents NAFLD development by altering the physiological condition of both adipocytes and hepatocytes. BCG reduces fatty acid-induced ER stress in the livers of ob/ob mouse model. (B) BCG vaccination inhibits T cells from destroying insulin-secreting cells, allowing the pancreas to regenerate and begin producing insulin in animal models. (C) In hyperlipidemic E3L.CETP mice, BCG reduces plasma non-HDL cholesterol levels by improving hepatic cholesterol clearance. BCG can delay atherosclerosis progression by decreasing foam cells and plaque formations in mice. (D) BCG reduces systemic inflammation in humans and the effects are stronger in men than in women. How BCG vaccine lowers inflammation while enhancing trained immunity is still unknown. (E) BCG induces trained immunity in monocytes via epigenetic rewiring. Abbreviations: BCG, Bacillus Calmette-Guérin; E3L.CETP, APOE∗3-Leiden cholesteryl ester transfer protein; ER, endoplasmic reticulum; HDL, high-density lipoprotein; NAFLD, non-alcoholic fatty liver disease; NOD, nonobese diabetic.