Butyrate as a promising therapeutic target in cancer: From pathogenesis to clinic (Review)

Abstract

Cancer is one of the leading causes of mortality worldwide. The etiology of cancer has not been fully elucidated yet, and further enhancements are necessary to optimize therapeutic efficacy. Butyrate, a short‑chain fatty acid, is generated through gut microbial fermentation of dietary fiber. Studies have unveiled the relevance of butyrate in malignant neoplasms, and a comprehensive understanding of its role in cancer is imperative for realizing its full potential in oncological treatment. Its full antineoplastic effects via the activation of G protein‑coupled receptors and the inhibition of histone deacetylases have been also confirmed. However, the underlying mechanistic details remain unclear. The present study aimed to review the involvement of butyrate in carcinogenesis and its molecular mechanisms, with a particular emphasis on its association with the efficacy of tumor immunotherapy, as well as discussing relevant clinical studies on butyrate as a therapeutic target for neoplastic diseases to provide new insights into cancer treatment.

Keywords: GPCR; HDACI; butyrate; cancer; treatment; tumor immunity.

Figure 1

Illustration of the pathways involved in the synthesis, absorption, and metabolism of butyrate. Glutarate, L-lysate, succinate and non-digestible carbohydrates are the four sources of butyrate that the gut bacteria use. It is absorbed and digested by the intestinal epithelial cells. Little amounts of butyrate enter the liver, where it regulates the metabolism of fatty acids.

Figure 2

The role of butyrate in tumorigenesis. SCFAs are produced by the intestinal microbiome in the fermentation of undigested food fiber, non-digestible carbohydrates, or resistant starch. Butyrate is one of the major SCFAs. The antitumor effect of butyrate is mainly reflected in four aspects: (A) Modulation of immune response; (B) Influences on the tumor inflammatory microenvironment; (C) Induction tumor cell apoptosis; (D) Enhancement of the immunotherapeutic effect and (E) Protection of the intestinal epithelial barrier function. SFCAs, short-chain fatty acids.

Figure 3

Butyrate plays an anticancer role within the human body through the activation of GPCRs. Its primary mode of action involves the regulation of cytokine production and immune cell functionality, achieved primarily by the activation of GPCRs. This activation serves to bolster intestinal barrier function, strengthen the immune system, mitigate inflammation, govern energy metabolism, and impede the progression of tumors. GPCR, G protein-coupled receptor.

Figure 4

Butyrate exerts anticarcinogenic effects through effecting acetylation. The main types of genes affected by butyrate include: (A) tumor immunity-related genes; (B) tumor apoptosis-related genes; (C) cell cycle control-related genes; (D) tumor-related miRNA; (E) tumor cell metabolism-related genes. miRNA or miR, microRNA; HK, hexokinase.