The interaction of gut microbiota with parasitic protozoa

Abstract

The human intestinal microbiota is composed of a complex combination of microorganisms including bacteria, virus, and eukaryotes. The microbiota plays a critical role in homeostasis through creating a mucosal barrier, providing protective responses to pathogens, and affecting the immune system and metabolism of the host. Molecules secreted by parasites can alter composition of microbiota both by acting directly on the microbial community and indirectly by affecting the host physiology. On the other hand, the microbiota composition can affect the survival, physiology, and virulence of many parasitic protozoa. Explanation of possible interactions between the microbiota, immune response, and protozoa may further clarify the underlying mechanisms of infectivity, clinical variations, and life-cycle of protozoa.

The microbiota, which has significant effects on human health, is the sum of different microorganisms that include bacteria, fungi, viruses and protozoa and all the genomes of these are collectively called microbiome (O’Hara and Shanahan 2006). The human body is widely colonized by the microbiota including skin, genitourinary system, respiratory tracts, and gastrointestinal system (GIS), which is the most heavily colonized system (Sekirov et al. 2010). GIS microbiome, which can adapt to environmental changes, creates a mucosal barrier in the intestines, prevents the invasion of pathogenic microorganisms, and positively affects the development of the immune system and metabolism of the host (Shanahan 2002). However, disruption of the microbiome has a major role in the etiopathogenesis of many diseases (inflammatory diseases, diabetes, and cancer) and affects the treatment responses and drug resistance in diseases (Fulbright et al. 2017).

It has been recently highlighted that the commensal bacteria found in microbiota have defensive roles against parasitic protozoa (Bär et al. 2015). Potential contribution of the bacterial microbiome to the body's defense against protozoa infections is not only limited to the intestine, but may also affect tissue and blood parasites. In this review, we aim to shed light on the potential influence of the microbiota on the most prevalent parasitic protozoa.

The microbiota and protozoa may interplay in a variety of ways including alteration of protozoa virulence, modulation of host immunity against the parasite, and rivalry for the niche in the intestinal lumen (Bashey 2015). The microbiota may affect the courses of parasite infections of mucosa, blood and tissue while protozoa may also alter the content of the microbiota. All these effects could be diagnostic markers for a wide variety of parasitic diseases. Protozoa cause a wide spectrum of diseases, ranging from asymptomatic to invasive infection. According to literature-based studies, it is thought that one of the reasons for clinical variation in protozoa infections may be the intestinal microbiota. Bacterial microbiota may impact the protozoa virulence and potentially cause variability in clinical manifestation or symptoms with infected individuals (Marie and Petri 2014; Bär et al. 2015). Protozoa living in the human body may be affected by the interaction between the intestinal microflora and the host immune system, and the disrupting of this balance plays a vital role in the growth and death of protozoa.

Immunity-microbiota interactions occurring in the early period of life have long-lasting impacts on immune homeostasis and vulnerability to infections and inflammatory diseases later in life (Zhang et al. 2020). Optimal unity of the immune system-microbiota contributes to induction of the protective responses to pathogens and maintenance of molecular signaling pathways including tolerance to innocuous antigens (Belkaid and Hand 2014). Alterations in the content of the microbiota can impact systemic immunity against protozoa and decrease resistance to infection in intestinal lumen (Burgess et al. 2017), and thus influence the progression of both the intestinal and blood-borne parasitic diseases (Buffie and Pamer 2013; Yooseph et al. 2015). It has been noticed that the dynamic modulation between the microbiota, protozoa, and host immune system shapes the clinic manifestation of parasitic infections. Therefore, a better understanding of the mechanisms underlying interaction with microbiota-protozoa in hosts may help to diagnose, and treat protozoa infections, and elucidate clinical variations.

Entamoeba, Giardia, and Cryptosporidium spp., which are common enteric pathogens and have clinical spectra varying from moderate to severe infection, reside in mucosa where they are surrounded by the gut-associated microbiota (Fig. 1) (Kosek et al. 2001; Haque et al. 2003; Solaymani-Mohammadi and Singer 2010; Villarino et al. 2016). It has been clearly shown that commensal microorganisms in the intestine influence the degree of infectivity and infection with the enteric protozoa (Bär et al. 2015). Entamoeba is considerably associated with gut microbiota composition and diversity. Studies showed that Entamoeba spp. infection was predicted with 79% accuracy by the composition of an individual’s gut microbiota (Morton et al. 2015) and associated with Prevotellaceae, anaerobic gram-negative bacteria, which is one of the most important taxa (Gilchrist et al. 2016). Also, in vivo studies reported that segmented filamentous bacteria (SFB) colonizing the intestine protected from amebiasis by producing high levels of IL-23 from bone marrow dendritic cells and recruiting more neutrophils to the intestine (Burgess et al. 2014; Fujimura and Lynch 2015). These studies have underscored the potential contribution of microbiota-driven inflammation in switching outcomes of parasite infections.

Fig. 1.

The interaction between gut microbiota and enteric parasites

Cryptosporidium and Giardia protoza may also be influenced by the intestinal microbiota. Cryptosporidium infectivity can depend on the association between the relative abundances of some bacterial communities found widespread in adult intestines (Morton et al. 2015). Interestingly, the indole-producing bacteria provide a protection against Cryptosporidium infection, although this mechanism of indole is not exactly understood. However, this could be explained by the effect of indole in both increasing epitelial integrity (Morton et al. 2015) and stimulating anti-inflammatory pathways (Jin et al. 2014; Chappell et al. 2016). Previous studies reported that patients infected with Giardia had intestinal dysbiosis for a long time after the infection had been completely eliminated from the body (Wensaas et al. 2012; Hanevik et al. 2014). Besides, the abundance of Bifidobacterium significantly increases in Giardia-positive patients, suggesting that enteric protozoa can induce essential alterations in the microbiota, which result in substantially different bacterial taxa (Iebba et al. 2016). As in vitro culture models provide the analysis of interactions between infection and individual components of the microbiota, a study showed that Lactobacillus johnsonii considerably inhibited the proliferation of Giardia in vitro. Also, this protective role of L. johnsonii was confirmed by in vivo studies, showing that it prevented Giardia infection and mucosal damage (Pérez et al. 2001; Berrilli et al. 2012).

Intestinal bacteria may also influence extra-intestinal protozoa in a variety of ways, such as regulation of signaling pathways, stimulating innate or adaptive immunity and producing microbiota-derived metabolites (Netea et al. 2016). However, mechanisms underlying these effects are still poorly understood. Blood-stage protozoa can be significantly affected by microbial components in the intestine (Mukherjee et al. 2020). Recent studies support that the bacterial community affects protozoa burden and mortality rates of Plasmodium infection and regulates the severity of disease. Perhaps, these perturbs in the microbiota may explain why some individuals have more severe disease than others and have clinical variations, such as cerebral and intestinal pathologies (Yooseph et al. 2015; Mukherjee et al. 2020). Further studies in both humans and mice have shown that certain bacterial communities are correlated with risk of Plasmodium infection while some provide protection against Plasmodium (Yooseph et al. 2015). In addition, Plasmodium infections can cause significant alterations in the composition of microbiota and may alter the host immune system, thus, indicating an interesting presence of three-way crosstalk between Plasmodium-microbiota-host immunity (Mooney et al. 2015; Taniguchi et al. 2015).

Trichomonas vaginalis, an urogenital system protozoon, is the most prevalent non-viral sexually transmitted infection in the world (“WHO | Prevalence and incidence of selected sexually transmitted infections,” 2014). Clinical variation of infection may be impacted by the microbiota composition in the vagina. Specially, vaginal bacteria play an important role in the binding of the protozoa to the mucosal surface and the maintenance of parasite life-cycle. T. vaginalis is associated with the low proportions of Lactobacilli species, providing further interactions between human cells and the protozoon (“WHO | Prevalence and incidence of selected sexually transmitted infections,” 2014; Hinderfeld and Simoes-Barbosa 2020). Also, studies have shown that T. vaginalis infection is accompanied by a dysbiotic microbiota consisting mostly of anaerobic bacteria, increasing the pathogenicity of protozoa (Hinderfeld and Simoes-Barbosa 2020).

By understanding the impact of the microbiota on both parasitic protozoa and the host immune system, the fundamental mechanisms underlying infectivity, clinical variations, and life-cycle of protozoa have become increasingly apparent. Ultimately, further investigation of interplays between the intestinal microbiota and protozoa will provide new approaches in the diagnosis and treatment of parasitic infections.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.