Commensal Intestinal Protozoa-Underestimated Members of the Gut Microbial Community

Abstract

The human gastrointestinal microbiota contains a diverse consortium of microbes, including bacteria, protozoa, viruses, and fungi. Through millennia of co-evolution, the host-microbiota interactions have shaped the immune system to both tolerate and maintain the symbiotic relationship with commensal microbiota, while exerting protective responses against invading pathogens. Microbiome research is dominated by studies describing the impact of prokaryotic bacteria on gut immunity with a limited understanding of their relationship with other integral microbiota constituents. However, converging evidence shows that eukaryotic organisms, such as commensal protozoa, can play an important role in modulating intestinal immune responses as well as influencing the overall health of the host. The presence of several protozoa species has recently been shown to be a common occurrence in healthy populations worldwide, suggesting that many of these are commensals rather than invading pathogens. This review aims to discuss the most recent, conflicting findings regarding the role of intestinal protozoa in gut homeostasis, interactions between intestinal protozoa and the bacterial microbiota, as well as potential immunological consequences of protozoa colonization.

Keywords: Blastocystis; Dientamoeba; Entamoeba; SCFA; bacteria; gut immunity; inflammatory bowel disease; intestinal protozoa; microbiota.

Figure 1

The impact of intestinal protozoa colonization on gut immunity and bacterial composition. (A) Colonization with commensal protozoa species (e.g., Entamoeba spp. besides Entamoeba histolytica) leads to increased microbial diversity and remodeling of bacterial communities in the gut. SCFA (short-chain fatty acids) producers are enriched, and pathogenic bacterial species such as Escherichia coli and Proteobacteria are reduced. SCFAs in the intestinal lumen are absorbed by epithelial cells for energy production, while unmetabolized SCFAs enter the systemic circulation. Outside the gut, SCFAs facilitate generation of extrathymic Tregs via enhanced acetylation of Foxp3 locus in CD4⁺ T cells as well as directly affect gene expression in dendritic cells, thus prompting Treg differentiation and consequently IL-10 production. Colonization with commensal protozoa strains leads to polarization of T cell responses towards Th2-dominated profile characterized by IL-4, IL-5, and IL-13 secretion as well as downregulation of TNF. Overall, this results in decreased pro-inflammatory response within the intestines. (B) Colonization with pathogenic protozoa species (such as Cryptosporidium and Entamoeba histolytica) can lead to decreased microbiota diversity, enrichment of pathogenic bacterial species, and a decline in abundance of beneficial bacteria. Cysteine proteases produced by pathogenic protozoa compromise the intestinal epithelial barrier by depleting colonic mucin and create gaps between colonocytes, enabling the parasites to breach the epithelial barrier and invade the tissue. Cysteine proteases also degrade IgA, IgG and IL-18, as well as inhibit Th1-type responses. Pathogenic protozoa also upregulate IL-1B, IL-6, and TNF in the intestines. Overall, these triggers aggravated inflammatory response within the gut. SCFA: Short chain fatty acid, IL: Interleukin, Tregs: T regulatory Th: T helper, TNF: tumor necrosis factor.