Nutrient competition and metabolite production by the gut microbiota to reduce carbapenem-resistant Enterobacteriaceae growth in the human intestine

Antimicrobial resistance is a serious threat to human health, resulting in treatment failures, infection relapses, longer hospitalisations, and poor clinical outcomes. Treatment options are limited, frequently less effective, and involve administration of more toxic antibiotics. Antimicrobial-resistant infections are responsible for 700,000 deaths globally each year, and without the development of new treatments this figure is estimated to rise to 10 million deaths per year by 2050.

Outbreaks of antimicrobial-resistant infections are also very costly to the NHS. Therefore, there is an urgent need to develop new approaches to prevent and treat antimicrobial-resistant infections.

The intestine is the primary colonisation site and reservoir for pathogens called carbapenem-resistant Enterobacteriaceae (CRE). CRE intestinal colonisation precedes the development of other serious CRE infections, such as bloodstream infections. Patients would benefit from the removal of CRE from their intestines before they go on to develop these serious infections.

However, currently there are no clinical guidelines, standard of care, or management guidance for patients with intestinal CRE colonisation.

Studies have demonstrated that faecal microbiota transplantation (FMT) can remove CRE from the intestine, where faeces from a healthy donor are administered to the intestine of a CRE colonised patient. However, we do not understand the mechanisms that FMT uses to remove CRE from the intestine, and FMT is not a risk-free procedure. Examples of disadvantages of FMT include concerns treating immunocompromised patients, the risk of transmitting infections, and invasive administration routes.

Moreover, regulatory oversight is limited for FMT and protocols are not standardised. FMT needs to be replaced with new therapies that are more effective, safe, rationally designed, and doseable.

The healthy gut is colonised by a diverse collection of microbes collectively referred to as the gut microbiota. A healthy gut microbiota provides protection against intestinal colonisation with CRE. Nutrients are limited in the intestine and microbes must compete with each other to use these nutrients to support their growth.

A healthy gut microbiota outcompetes CRE for these nutrients and also produces compounds called metabolites that can inhibit CRE growth. However, antibiotic-mediated killing of gut microbiota members allows CRE to colonise and dominate the intestine. Antibiotics increase the concentration of nutrients available to support CRE growth coupled with a reduction in the concentration of metabolites that can inhibit CRE growth.

The goal of this proposal is to develop new microbiome therapeutics consisting of a synthetic microbial consortium (specific members of the gut microbiota) and inhibitory metabolites. The inhibitory metabolites will cause an initial reduction in CRE growth. The synthetic microbial consortium will colonise the intestine, outcompete CRE for nutrients, and inhibit CRE growth by producing inhibitory metabolites, resulting in a long-term reduction in CRE growth.

An artificial gut model of CRE intestinal colonisation will be used to determine the effects of antibiotics and FMT on nutrient competition, metabolite production, gut microbiota composition, and CRE growth. Synthetic microbial consortia will be designed consisting of gut microbiota members that outcompete CRE for nutrients and produce metabolites that inhibit CRE growth.

This new therapeutic will be tested in the artificial gut model to demonstrate its efficacy to inhibit CRE growth.

This study has the potential to significantly impact clinical practice by developing a new treatment that could be used to prevent or treat CRE intestinal colonisation, and therefore prevent other serious infections such as CRE bloodstream infections.