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Microbial therapy against gut inflammation

Periodic Reporting for period 1 - MAGI (Microbial therapy against gut inflammation)

Reporting period: 2019-10-01 to 2021-09-30

Gut microbial dysbiosis have been associated with IBD, metabolic disorders and expansion of specific microbiota resident members that can drive inflammation (pathobionts). IBD affects over 5 million people world-wide, with estimate costs to healthcare of 4.6-5.6 thousand million Euros/year. We aim to develop biotherapies that in the long-term can be applied to tackle symptoms (inflammation) and harmful outcomes (hospitalization, surgery, risk of cancer or infections) that would greatly increase patients quality of life, while decreasing time and costs of hospitalizations and medication. Also, the QS-based therapy and the safe-to use engineered biotherapy agent here applied to an IBD mouse model as a proof-of-concept can lead to new prevention and treatment strategies for other microbiota-related diseases associated with gut dysbiosis including infectious diseases, neurological and metabolic disorders, or cancer.

The grant MAGI had the overall objective of taking advantage of microbial interactions mediated by quorum sensing (QS) to tackle gut microbial imbalances (dysbiosis) in inflammatory bowel diseases (IBD).
IBD is characterized by a dysbiotic microbiota and consequent inflammation and loss of protection against pathogenic bacteria. Recovery from dysbiosis into a balanced microbiota can revert these detrimental effects, and QS has been shown to be able to ameliorate dysbiotic microbiota.

In the proposed action we intended to favor beneficial interactions among members of the microbiota in order to promote resilience and re-establishment of normal functions, therefore aiming at an effective therapy to counteract IBD dysbiosis, inflammation, loss of protection against expansion of pathobionts and susceptibility to pathogens. The project was founded on two major pillars:
1. Use an engineered bacterial microbiota strain to manipulate levels of the quorum sensing molecule Auto-inducer 2 (AI-2) in a dysbiotic murine gut;
2. Promote colonization resistance / displacement of IBD-related pathogens or pathobionts and restore balance on an IBD dysbiotic microbiota

We have successfully used a native gut microbiota member as a biotherapy agent against AIEC infection in IBD context, not only capable of displacing the pathobiont, but also of promoting gut microbiota recovery after antibiotic-induced dysbiosis, therefore potentially protecting from subsequent recurrent infections. Hence, we have achieved the proposed main objective of identifying and testing a potential biotherapy to resolve IBD-related symptoms.
During the period of MAGI we have established an IBD-prone mouse model of Nod2-/- mutants in our facility and country, that we have compared to other mouse models for their intestinal inflammation profile (characteristic of IBD). We have then used this murine model of IBD to test the capacity of a gut microbiota isolate, that we have shown in vitro to be able to inhibit the IBD-relevant pathobiont AIEC.
We have shown that our protective microbiota member is able to promote displacement of AIEC from antibiotic-induced dysbiotic Nod2-/- mice, promoting gut microbiota compositional recovery in the process.
Our in vitro and in vivo results have led to the ongoing study of the microbial interactions involved in the displacement of AIEC from the gut and microbiota recovery of diversity promoted by our protective microbiota isolate.

These results are being included in a manuscript in preparation dedicated to the study of this protective phenotype against AIEC in IBD context, while the potential use of the protective microbiota isolate as a biotherapy against IBD-related AIEC infections is being evaluated.
MAGI has allowed us to improve on the current state of the art regarding AIEC infections in IBD context, providing a potentially suitable biotherapeutic agent to displace ongoing AIEC infection, while promoting microbial diversity recovery in IBD microbiota after antibiotic treatment. These results open the door to a potential therapeutic approach that can tackle both current infections and promote protection from future infections by the common IBD pathobiont AIEC. Having such a therapy available to IBD patients would greatly increase the quality of life and allow for antibiotic treatments to be done when needed, decreasing the risk of developing infections due to the untargeted effect of antibiotics of reducing native microbiota diversity and consequently protection, therefore reducing the vast cost with IBD patients' hospitalisations due to recurrent infections.
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