The Interplay between Immunity and Microbiota at Intestinal Immunological Niche: The Case of Cancer

Abstract

The gut microbiota is central to the pathogenesis of several inflammatory and autoimmune diseases. While multiple mechanisms are involved, the immune system clearly plays a special role. Indeed, the breakdown of the physiological balance in gut microbial composition leads to dysbiosis, which is then able to enhance inflammation and to influence gene expression. At the same time, there is an intense cross-talk between the microbiota and the immunological niche in the intestinal mucosa. These interactions may pave the way to the development, growth and spreading of cancer, especially in the gastro-intestinal system. Here, we review the changes in microbiota composition, how they relate to the immunological imbalance, influencing the onset of different types of cancer and the impact of these mechanisms on the efficacy of traditional and upcoming cancer treatments.

Keywords: cancer; dysbiosis; gut microbiota; immune system; immunological niche.

Figure 1

The complex interplay among gut lumen environment, mucosal barrier, immunological niche in oncogenesis. The failure of maintaining homeostatic equilibrium between commensals and pathogens at gut lumen level leads to dysbiosis. The bacterial products enhance the gut permeability leading to bacterial and toxins translocation. Toll-like receptors (TLRs) expressed on activated dendritic cells (aDC) are able to recognize pathogen-associated molecular patterns (PAMPs) and can activate the NF-κB, JNK and p38 mitogen-activated protein kinases. JNK promotes the activation of pro-oncogenic Ras. Other receptors situated on several types of immune cells are represented by nucleotide-binding oligomerization domain-like receptors (NLRs), which are pattern recognition receptors (PRRs) that can activate NF-κB and promote inflammasomes. Other carcinogenetic agents, like nitrous compounds and secondary bile acids, can act respectively as alkylating mediators or via reactive oxygen species at a DNA level. Furthermore, high doses of butyrate inhibit histone deacetylase (HDAC) that is able to inactivate many oncogenic signaling pathways. The presence of pro-inflammatory T-cells can induce pro-inflammatory cytokines at tumor site. The concomitant action of T-regs creates a state of immunosuppression at tumor level.