Are Long-Chain Polyunsaturated Fatty Acids the Link between the Immune System and the Microbiome towards Modulating Cancer?

Abstract

Three recent studies revealed synergy between immune-checkpoint inhibitors and the microbiome as a new approach in the treatment of cancer. Incidentally, there has been significant progress in understanding the role of polyunsaturated fatty acids (PUFAs) in modulating cancer and the immune system, as well as in regulating the microbiome. Inflammation seems to be the common denominator among these seemingly unrelated biological entities-immune system, the microbiome, and long-chain polyunsaturated fatty acids (LC-PUFAs). This commentary presents a hypothesis proposing the existence of an optimal level of LC-PUFAs that nurtures the suitable gut microbiota preventing dysbiosis. This synergy between optimal LC-PUFAs and gut microbiota helps the immune system overcome the immunosuppressive tumour microenvironment including enhancing the efficacy of immune checkpoint inhibitors. A model on how LC-PUFAs (such as omega(n)-3 and n-6 fatty acids) forms a synergistic triad with the immune system and the microbiome in regulating inflammation to maintain homeostasis is presented. The principles underlying the hypothesis provide a basis in managing and even preventing cancer and other chronic diseases associated with inflammation.

Keywords: cancer; dysbiosis; gut health; immune checkpoint inhibitors; immunotherapy; inflammation; microbiome; omega-3 fatty acids; omega-6 fatty acids; polyunsaturated fatty acids.

Figure 1

The hypothesis. Inflammation is the central element in the relationship among LC-PUFAs, the gut microbiome and the tumour microenvironment/immune system. Inflammation is regulated by the interaction of the components of the triad. LC-PUFAs (n-3 and n-6 fatty acids) have been shown to directly regulate cancer cells and immune cells as well as modulating the inflammatory state that sustains the tumour microenvironment which promotes the growth and malignancy of tumours. Simultaneously, LC-PUFAs have a direct role on microbial growth in the gut, which has consequences to the inflammatory state of the gut. Gut dysbiosis has a direct consequence in promoting inflammation in the tumour microenvironment suppressing the anti-tumour activities of the immune cells and immune checkpoint inhibitors. The model supports the role of LC-PUFAs in regulating the progression of cancer directly and indirectly through the gut microbiome assisting in modifying the tumour microenvironment.