Conceptions in parasite-microbiota relationships

Abstract

Abundant information refers to the role of microbiota in maintaining homeostasis by assisting, improving, and regulating immunity in humans. Yet, the effect exerted by parasitic infections on the developing microbiota, is so far not recognized. Various parasites were related to specific alterations in the essential loads of developing microbiota. Additionally, modulation of immune functions was reported. This review aimed to present examples for the interaction between parasitic infections and microbial gut imbalance dubbed dysbiosis. This form of parasite-microbiota interaction seems to influence both the metabolism and the acquired immunity of the host. Consideration of this data will direct future studies to focus on the altered microbiota during various parasitic infections and to highlight the benefits of its re-enrichment in the therapeutic trials. PARASITOLOGISTS UNITED JOURNAL 134 levels like N oxides and S oxides, that act as a substrate for the expansion of facultative anaerobic bacteria[20]. Hatter et al.[15] noted an ominous outgrowth of Clostridia spp. that was sustained in chronic infection with toxoplasmosis. Also, Egan et al.[21] suggested that the depletion of gut flora reduces mice resistance to T. gondii-triggered ileitis. Likewise, Couturier-Maillard et al.[22] suggested that the collaboration between intestinal commensals and T. gondii in the development of small intestine inflammation increases the capability of the parasite to approach the epithelial cells and promotes its invasion to the mucosa. (2) Cryptosporidium parvum is another intracellular intestinal sporozoa that has been hypothesized to trigger dysbiosis indirectly by causing damage to the intestinal epithelium[23]. Fecal microbiota from mice infected with C. parvum were shown to differ significantly from that of non-infected controls. Amazingly, a recent study demonstrated that probiotics can significantly influence the intestinal microenvironment and the epithelial lining which promotes the proliferation of C. parvum[24]. (3) Leishmaniasis is caused by intracellular flagellates that were shown to trigger skin dysbiosis in humans and murine models. Cutaneous leishmaniasis is characterized by augmented Staphylococcus and/ or Streptococcus infections and skin inflammation. Interestingly, in murine models this dysbiosis was found to be transferable to naive mice[25]. Similarly, visceral leishmaniasis (VL) patients are more susceptible to fatal nosocomial secondary bacterial infections (Pseudomonas aeruginosa and Staphylococcus aureus)[26]. This was attributed to the suppressed status of T-helper 1 due to alterations in antigen presentation, MHC/HLA, antigen processing, T cell receptor recognition, and the myeloid derived suppressor cells[27-29]. However, establishment of VL infection in murine models with previously induced intestinal dysbiosis showed late onset and development of weight loss[30]. [II] Luminal (intestinal and genitourinary) parasites (1) Giardia duodenalis (G. lamblia) is an intestinal flagellate that inspires dysbiosis by overwhelming the physical mucus and epithelial barrier by several mechanisms. The trophozoite stage of the parasite is extremely motile via its flagella[31] and possesses proteolytic activity that disrupts the integrity of mucin-2 (MUC2) to yield a less viscous physical barrier[32-34]. In addition, it produces secretory/excretory cysteine proteases (CP)[35] (CP2, CP3, and CP16160[32,36]) that cause apoptosis of the epithelial lining of the intestine and disruption of the tight junctions[37]. Giardipain-1 is another virulent factor with proteolytic activity similar to cathepsin B-like protein. It induces the formation of pore-like defects and membrane blebs, reduces the trans-epithelial electrical resistance, and targets mainly the tight junction proteins (occludin and claudin-1). In addition, it stimulates the activation of caspase-3, the fragmentation of poly ADP ribose polymerase (PARP), and the exposure of phosphatidylserine causing apoptosis of the epithelial cells[38]. Consequently, the mucosal microbiota adjacent to the epithelial cells can penetrate the thin lining of the host-derived glycans, the cell surface glycocalyx and the extracellular secreted mucus[39]. The pathogenic dysbiotic microbiota associated with giardiasis in germ free mice, induces the signalling pathway of the toll-like receptor-4, and the production of the pro-inflammatory cytokine IL1β[37]. Gerbaba et al.[40] showed that G. lamblia induces functional alterations in the commensal microbiota, possibly transforming them into opportunistic pathogens, and altering the host-microbe homeostatic interactions. Interestingly, Allain et al.[32] demonstrated that the high proteolytic activity by G. lamblia is protective to the host against concurrent bacterial entero-pathogens by promoting bacterial killing and alleviating inflammation of the intestine. Bartelt et al.[41] assumed that in association with protein malnutrition the intestinal microbiota promoted persistent colonization by G. lamblia that led to growth impairment in experimentally infected mice. (2) Blastocystis spp. are the most common eukaryotic intestinal protozoa in human[42]. As an anaerobe, it lacks several definitive mitochondrial features and misses the standard mitochondrial electron transport chain and oxidative phosphorylation[43]. Notably in a healthy gut, oxygen concentration is extremely low[44] to promote the growth of obligate anaerobic microbiota from the Bacteroides and Firmicutes phyla[45]. In a dysbiotic gut, when the intestinal microbiota get disrupted and luminal bioavailability of oxygen increases, the resulting alteration in intestinal biodiversity promotes the growth of the facultative anaerobic Enterobacteriaceae[12,46,47]. A strict anaerobe such as Blastocystis spp. cannot sustain itself in this medium that is not its ideal ecosystem. In this context, in a well-established irritable bowel syndrome (IBS), dysbiosis Blastocystis spp. may be compelled out of the gut since the early stages of the disease[48]. On the other hand, Tsaousis et al.[49] suggested that Blastocystis spp. has an alternative oxidase nature that allows it to deal with fluctuating oxygen concentrations in the gut and should be better termed as a microaerophilic. Blastocystis infection in rats involved colon hypersensitivity and showed alterations in the composition of the microbiota and hence their metabolic shifts[50]. Conversely, two studies[51,52] reported the presence of healthy microbiota rather than dysbiosis in patients infected with Blastocystis spp. Moreover, Scanlan et al.[53] considered Blastocystis spp. a member of the Parasites and microbiota Elsaftawy and Wassef 135 healthy microbiota. However, in a previous study the genotype of the parasite appeared to play a hidden role in the capability of the parasite in contributing to disease[54]. In this context, the relationship between different genotypes of the parasite and dysbiosis seems to be a new point of research. (3) Entamoeba histolytica was previously shown to modify the tight junction proteins and disturb the permeability of the epithelial barrier, allowing translocation of intestinal microbiota into the mucosal surfaces and spread to the other organs[55,56]. Iyer et al.[57] reported that E. histolytica favours the phagocytosis of bacterial species such as Lactobacillus ruminus. Similarly, Verma et al.[58] revealed that E. histolytica associated dysbiosis was characterized by increased Bifidobacterium spp. in faecal samples, while other bacteria that are essential for the maintenance of intestinal homeostasis such as Bacteroides, Clostridia, Campylobacter, Lactobacillus, and Eubacterium were reduced as compared to healthy subjects. Interestingly, Sicard et al.[59] demonstrated that colonic microbiota break down complex carbohydrates into glycans that can act as a nutrient source for E. histolytica. With the absence of bacteria, E. histolytica is forced to be in close contact with the epithelium to feed and search for alternative sources of energy in the lumen[60]. Moreover, in germ free mice the MUC2 layer was found to be thinner and penetrable[59] with diminutive O-glycan monomers[52]. Additionally, it was postulated that the ratio of bacterial phyla present in the host microbiota may alter or influence the colonization of E. histolytica. For instance, Escherichia coli was found to protect E. histolytica against oxidative stress in two patterns[61] described in figure (1). However, in murine models Clostridium is defensive during E. histolytica infection through the increased production of interleukin 17A, dendritic cells, and neutrophils. Moreover, bone marrow-derived dendritic cells were reported to secrete elevated levels of IL-23[62]. Gilchrist et al.[63] showed that the expansion of Prevotella copri probiotic was associated with dysentery due to intestinal amoebiasis in infants from 600 to 800 days of age. Sarjapuram et al.[64] revealed that probiotics (specifically Lactobacillus casei) have an anti-proliferative effect on E. histolytica. Varet et al.[61] speculated this effect to be unrelated to alterations in the pH value of the media. (4) Trichuris trichiura is a round worm reported in a Malaysian study to be associated with shifts in the composition of the gut microbiota of infected patients especially with Paraprevotellaceae bacteria concerned with the breakdown of proteins and carbohydrates in food[65]. In general, helminthic infections may promote regulatory immune cell reactions that may suppress harmful allergic and inflammatory diseases. They are supposed to elicit regulatory T cells by altering the gut microbiota or via secretion of bioactive molecules. Hence, worms and their secretory molecules may be innovative treatments for allergic inflammation[1,66]. (5) Trichomonas vaginalis is a flagellate that causes the most common sexually transmitted disease (STD) during the child bearing p