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BileBaG

Bile Salt Hydrolases (BSHs) – based biotherapies to fight giardiasis
Funder: French National Research Agency (ANR)Project code: ANR-23-CE18-0022
Funder Contribution: 459,877 EUR
Description

Giardiasis is a widespread intestinal parasitic disease caused by the protozoan Giardia intestinalis. This digestive parasitosis is considered a neglected disease by the World Health Organization (WHO). Giardiasis is very common, affecting children in particular, and can go unnoticed in some patients. Symptoms include mild to severe or even chronic diarrhea, vomiting, abdominal pain, fatigue and weight loss in case of massive infections. Giardiasis also affects many mammals, including pets such as dogs and cats as well as livestock (ruminants, pigs, etc.). Current treatments are limited to a few anti-infective drugs, but the emergence and spread of resistant strains pose problems for human and animal health. New means of control, such as the use of probiotics, are therefore necessary. Probiotics are "live microorganisms that, when ingested in sufficient quantities, exert positive health effects beyond the traditional nutritional effects". Although they are used in human and veterinary medicine, probiotics remain largely unstudied in the fight against parasitic diseases, even though they represent promising therapeutic alternatives. Several studies have described the ability of certain strains of probiotics to control Giardia proliferation with beneficial effects on the hosts, but their mechanisms of action remain poorly elucidated. Our interdisciplinary consortium of parasitologists, microbiologists and veterinarians has discovered a molecular mechanism based on the action of enzymes produced by certain probiotic strains, bile-salt hydrolases (BSH), which are able to control the growth of Giardia in culture by metabolizing certain non-toxic bile components into their deconjugated derivatives that are toxic to the parasite. In particular, we found that probiotic strains of lactobacilli naturally rich in BSH activities were able to better control the proliferation of Giardia, both in culture, in experimentally infected mice and in puppies naturally infected with Giardia. In these animals, the parasite load and the cyst excretion were reduced. This parasite load could also be reduced by directly using recombinant BSH enzymes (rBSH). We have patented this discovery and wish to continue to explore the use of probiotic lactobacilli BSH as an innovative therapeutic solution for the control of giardiasis in human and veterinary medicine. Although in culture, BSH act against Giardia indirectly via the production of deconjugated bile acids, delivering a signal to the parasite leading to its death, the actual effects and safety of BSH-based therapies in the infected animal are unknown. BileBaG aims to test the effects of these therapies on parasite survival and the host-microbiota-parasite interaction using a mouse model infected with different strains of Giardia. The therapeutic approaches we are considering include improving the anti-Giardia properties of current probiotic candidates by enhancing their BSH activities/stabilities and developing recombinant probiotics. These studies are essential before considering the use of BSH-producing probiotics or recombinant BSH (rBSH), to control this parasite. The BileBaG results could potentially be also be extended to other enteric pathogens that occupy a similar gut environment to Giardia and are potentially controlled in the same manner.

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