Bile-Salt-Hydrolases from the Probiotic Strain Lactobacillus johnsonii La1 Mediate Anti-giardial Activity in Vitro and in Vivo

Abstract

Giardia duodenalis (syn. G. lamblia, G. intestinalis) is the protozoan parasite responsible for giardiasis, the most common and widely spread intestinal parasitic disease worldwide, affecting both humans and animals. After cysts ingestion (through either contaminated food or water), Giardia excysts in the upper intestinal tract to release replicating trophozoites that are responsible for the production of symptoms. In the gut, Giardia cohabits with the host's microbiota, and several studies have revealed the importance of this gut ecosystem and/or some probiotic bacteria in providing protection against G. duodenalis infection through mechanisms that remain incompletely understood. Recent findings suggest that Bile-Salt-Hydrolase (BSH)-like activities from the probiotic strain of Lactobacillus johnsonii La1 may contribute to the anti-giardial activity displayed by this strain. Here, we cloned and expressed each of the three bsh genes present in the L. johnsonii La1 genome to study their enzymatic and biological properties. While BSH47 and BSH56 were expressed as recombinant active enzymes, no significant enzymatic activity was detected with BSH12. In vitro assays allowed determining the substrate specificities of both BSH47 and BSH56, which were different. Modeling of these BSHs indicated a strong conservation of their 3-D structures despite low conservation of their primary structures. Both recombinant enzymes were able to mediate anti-giardial biological activity against Giardia trophozoites in vitro. Moreover, BSH47 exerted significant anti-giardial effects when tested in a murine model of giardiasis. These results shed new light on the mechanism, whereby active BSH derived from the probiotic strain Lactobacillus johnsonii La1 may yield anti-giardial effects in vitro and in vivo. These findings pave the way toward novel approaches for the treatment of this widely spread but neglected infectious disease, both in human and in veterinary medicine.

Understanding the Physiological Functions of the Host Xenobiotic-sensing Nuclear Receptors PXR and CAR on the Gut Microbiome using Genetically Modified Mice

“…Especially, the markedly higher proportion of Lactobacillus genus in the PXR-CAR-double null mice consistently correspond to a markedly decrease in major T-BAs in feces. Many species and strains of the Lactobacillus genus carry BSH that deconjugates the taurine and glycine molecules from BAs [68,69,[90][91][92][93][94][95]; in mice, the predominant effect is expected to be T-BA deconjugation, because taurine conjugation is a predominant pathway in mice over glycine conjugation.…”

Giardia spp. and the Gut Microbiota: Dangerous Liaisons

“…Susceptibility to Giardia infection varies significantly among different age groups in humans and in animal models, which is likely due at least in part to age-related shifts in microbiota composition, as well as changes in host immune factors. Several studies have shown the efficacy of using a suckling mouse model to study infection with Giardia isolates that do not typically infect adult mice ( Hill et al, 1983 ; Allain et al, 2017 , 2018a ; Riba et al, 2020 ). Shifts in the microbiota that occur upon weaning may be responsible for this increased resistance to Giardia infection ( Hill et al, 1983 ).…”

Bile salt hydrolases: Gatekeepers of bile acid metabolism and host-microbiome crosstalk in the gastrointestinal tract

“…Microbiome-encoded BSHs and secondary bile acid metabolism are associated with colonization resistance against pathogens such as Clostridioides difficile , which can use taurocholate (TCA) as a spore germinant, but vegetative cells are sensitive to most secondary bile acids [30]. Similarly, Lactobacillus johnsonii BSH activity has been shown to limit the eukaryotic pathogen Giardia duodenalis in vivo [31]. The variety of functions that BSH activity provides is unique to the biology of each organism and the niche it inhabits throughout the GIT, therefore warranting a better understanding of their utility for shaping the microbiota.…”