FMT to combat antibiotic-resistant bacteria colonization

Antibiotic-resistant bacteria (ARB) infections are becoming an increasingly intense problem for health care facilities worldwide. Multi-drug resistant organisms (MDRO) are prevalent, including methicillin-resistant Staphylococcus aureus (MRSA), Clostridioides difficile (C. difficile), Carbapenem-resistant Enterobacteriaceae (CRE), vancomycin-resistant Enterococci (VRE) and Gram-negative bacteria producing extended-spectrum β-lactamases (ESBL). These bacteria are resistant to more than three antibiotics, making treatment less effective and more toxic. This is especially important in immunocompromised patients, where mortality from ARB infections is the highest. In addition, antibiotic-resistant pathogens prolongate the patient’s hospitalization, significantly complicate and increase the cost of treatment. The overuse of antibiotics is blamed for creating such a vast group of antibiotic-resistant strains.

The gut lumen is a suitable environment for developing bacteria containing antimicrobial-resistant genes (ARG). Some appropriate procedures have been taken in hospitals to prevent the spread of undesirable microorganisms, but alternatives have been searched for due to insufficient effectiveness. The use of probiotics and selective gastrointestinal tract decontamination showed first positive results. Treatment of ARB infections usually involves the administration of various combinations of antimicrobials chosen empirically by the physician. Due to their uncertain effectiveness, attempts are made to introduce new drugs, including combination therapy with β-lactamase inhibitors or isolation of strains with a specific resistance mechanisms.

Role of the gut microbiota

The gut microbiota generates a phenomenon called ‘colonization resistance’, a condition in which the correct composition of the gut microbiota protects against the implantation of a pathogen. Commensal bacteria produce antimicrobial peptides (AMP) and proteins that destroy the pathogen’s cell wall. Bacteroidetes are known for inhibiting functions of the penetrating microorganisms and depriving their ability to colonize. Healthy microbiota displaces the penetrating pathogens, competing with them for many resources. This gave rise to the thesis that the correct composition of the intestinal microbiota could displace pathogenic bacteria. Eubiosis (proper taxonomy and functional capacity of the gut microbiota) prevents the colonization of antibiotic-resistant bacteria and regulates the immune system’s response. Moreover, intestinal bacteria metabolites, such as short-chain fatty acids (SCFA), bile acids, and tryptophan metabolites, support the production of AMP, maintain the integrity of the intestinal barrier and prevent the development of pathogenic bacterial flora. Some commensal bacteria, such as Bifidobacterium longum, are responsible for the growth of mucin, which maintains the function of the intestinal barrier.

Microbiota exhibits immunomodulatory activity by secreting MSM and MAMPs (microbially-secreted metabolites and microbial-associated molecular patterns) molecules. Toll-like receptors and dendritic cells prevent the development of diseases in the presence of diverse bacterial flora. Additionally, the SCFAs are a source of energy for enterocytes and induce a T-helper lymphocyte response.

FMT in antibiotic- resistant bacteria GI tract colonization

Research conducted in the last five years shows that FMT (fecal microbiota transplantation) could be an effective method of decolonizing antibiotic-resistant bacteria. FMT is the transfer of intestinal microbiota from a healthy donor to the recipient’s digestive system. Scientists have shown that FMT helps restore and maintain homeostasis within the gut microbiota composition and ensures microbiota diversity. In addition, FMT causes an immediate and permanent reconstruction of the microbiome, making the microbiome similar to the donor taxonomic profile.

Our team has published the world’s first prospective study using FMT to decolonize antibiotic-resistant bacteria from the gastrointestinal tract of patients (https://doi.org/10.1093/cid/cix252). We showed decolonization up to 60-100% depending on the type of bacteria and the clinical situation. Further studies also give hope and confirm our reports. In patients with confirmed colonization of Enterobacteriaceae resistant to carbapenems (CRE), decolonization occurred in 78.7% of people within a year, most of them within the first month after FMT. The dominant strains were Klebsiella pneumoniae and Escherichia coli, producing the carbapenemases KPC, OXA-48, and NDM. In animal models and our study, it was shown that the presence of Barnesiella in the administered FMT preparation allowed for the decolonization of vancomycin-resistant Enterococci (VRE) and K. pneumoniae NDM. Multiple studies in patients with recurrent Clostridioides difficile infection showed that FMT caused a reduction in the bacterial population with resistance genes (ARGs). Similar studies have been conducted in patients suffering from hepatocirrhosis with equally positive results.

FMT is perceived as a suitable procedure for decolonizing the intestine with multi-drug resistant pathogens, confirmed by numerous clinical studies, which showed efficacy results at the level of 70-80%. FMT is considered a safe therapy and is well tolerated even among immunocompromised patients and other diseases. Only few severe events have been reported in patients after FMT.

References

Ghani R, Mullish BH, Roberts LA, Davies FJ, Marchesi JR. The potential utility of fecal (or intestinal) microbiota transplantation in controlling infectious diseases. Gut Microbes. 2022 Jan-Dec;14(1):2038856. doi: 10.1080/19490976.2022.2038856. PMID: 35230889; PMCID: PMC8890388.

Macareño-Castro J, Solano-Salazar A, Dong LT, Mohiuddin M, Espinoza JL. Fecal microbiota transplantation for Carbapenem-Resistant Enterobacteriaceae: A systematic review. J Infect. 2022 Jun;84(6):749-759. doi: 10.1016/j.jinf.2022.04.028. Epub 2022 Apr 21. PMID: 35461908

Jaroslaw Bilinski, Pawel Grzesiowski, Nikolaj Sorensen, Krzysztof Madry, Jacek Muszynski, Katarzyna Robak, Marta Wroblewska, Tomasz Dzieciatkowski, Grazyna Dulny, Jadwiga Dwilewicz-Trojaczek, Wieslaw Wiktor-Jedrzejczak, Grzegorz W. Basak, Fecal Microbiota Transplantation in Patients With Blood Disorders Inhibits Gut Colonization With Antibiotic-Resistant Bacteria: Results of a Prospective, Single-Center Study, Clinical Infectious Diseases, Volume 65, Issue 3, 1 August 2017, Pages 364–370, https://doi.org/10.1093/cid/cix252