LAUSR

Simple Summary Gut-associated protozoa are a heterogenous group of microbes that frequently reside within humans. The role of commensal intestinal protozoa and their interaction with the human organism is a highly complex topic, and an area of research that has been largely neglected. We argue that some protozoa species might be beneficial inhabitants of the gut that can significantly impact human health and disease. Here, we aimed to comprehensively review existing literature on the conflicting outcomes of protozoa colonization, their interaction with the bacterial microbiota, and the crosstalk between the protozoa and the host immune system. Moreover, we emphasize the importance for future studies to investigate these aspects of protozoa colonization that will undoubtedly increase our understanding of complex interactions between intestinal protozoa, other microbiota organisms, and the human host. 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.