Short-chain fatty acids in cancer pathogenesis

Abstract

Cancer is a multi-step process that can be viewed as a cellular and immunological shift away from homeostasis in response to selected infectious agents, mutations, diet, and environmental carcinogens. Homeostasis, which contributes importantly to the definition of “health,” is maintained, in part by the production of short-chain fatty acids (SCFAs), which are metabolites of specific gut bacteria. Alteration in the composition of gut bacteria, or dysbiosis, is often a major risk factor for some two dozen tumor types. Dysbiosis is often characterized by diminished levels of SCFAs in the stool, and the presence of a “leaky gut,” permitting the penetration of microbes and microbial derived molecules (e.g., lipopolysaccharides) through the gut wall, thereby triggering chronic inflammation. SCFAs attenuate inflammation by inhibiting the activation of nuclear factor kappa B, by decreasing the expression of pro-inflammatory cytokines such as tumor necrosis factor alpha, by stimulating the expression of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor beta, and by promoting the differentiation of naïve T cells into T regulatory cells, which down-regulate immune responses by immunomodulation. SCFA function epigenetically by inhibiting selected histone acetyltransferases that alter the expression of multiple genes and the activity of many signaling pathways (e.g., Wnt, Hedgehog, Hippo, and Notch) that contribute to the pathogenesis of cancer. SCFAs block cancer stem cell proliferation, thereby potentially delaying or inhibiting cancer development or relapse by targeting genes and pathways that are mutated in tumors (e.g., epidermal growth factor receptor, hepatocyte growth factor, and MET) and by promoting the expression of tumor suppressors (e.g., by up-regulating PTEN and p53). When administered properly, SCFAs have many advantages compared to probiotic bacteria and fecal transplants. In carcinogenesis, SCFAs are toxic against tumor cells but not to surrounding tissue due to differences in their metabolic fate. Multiple hallmarks of cancer are also targets of SCFAs. These data suggest that SCFAs may re-establish homeostasis without overt toxicity and either delay or prevent the development of various tumor types.

Short-chain fatty acids induced lung tumor cell death and increased peripheral blood CD4+ T cells in NSCLC and control patients ex vivo

“…The observed increase in the expression of the stem cell marker expression CD90 in our experiments could potentially result from the reprogramming of SB-induced senescent cells into a stem-cell-like phenotype, which might help overcome and survive the external stress from SB treatment. A previous study highlighted an involvement of SCFA in blockade of cancer stem cell proliferation by altering the gene expression in the Wnt-ß-catenin pathway ( 41 ). Additional research is required to elucidate the precise mechanism and potential involvement of SB’s HDAC-inhibition in the upregulation of CD90 and the remaining effects of the increased stem cell population on cancer survival and progression.…”

Microbial metabolites affect tumor progression, immunity and therapy prediction by reshaping the tumor microenvironment (Review)

“…SCFAs have been shown to possess antitumor capabilities ( 40 ). However, SCFAs may also promote tumor progression and metastasis via immunomodulatory effects, signal transduction regulation and inflammation modulation, all of which can remodel the TME.…”

The Role of Short-Chain Fatty Acids, Particularly Butyrate, in Oncological Immunotherapy with Checkpoint Inhibitors: The Effectiveness of Complementary Treatment with Clostridium butyricum 588

“…Indeed, among the many actions of butyrate [ 24 ] (e.g., action on the intestinal barrier, energy production for enterocytes, participation in maintaining glycemic homeostasis, inhibition of histone deacetylase (HDAC)), it also plays a crucial regulatory role in immune system function and, thus, in the immune response to carcinogenic processes. Feitelson et al [ 41 ] suggested that SCFAs, particularly butyrate, can influence gene expression and cancer-associated signaling pathways, promoting cellular differentiation and apoptosis in tumor cells, as well as reducing the inflammation often associated with cancer development. There is now abundant scientific evidence available regarding how disturbances in the intestinal microbiota, particularly affecting the quota of butyrate-producing bacteria, impact both intestinal pathophysiology and the genesis of significant inflammatory effects, contributing to the onset of important pathologies, such as IBD [ 42 ], and the ability to maintain an active and balanced immune response.…”