the potential of gut microbiota therapeutics

In the latest narrative review published in Nutrientsresearchers are gathering evidence of the curative potential and limitations of gut microbiome-based therapies in critical diseases to inform strategies for their future optimization.

Study: Gut microbiome-based therapies in critically ill adult patients: a narrative review. Image credits: SewCreamStudio/Shutterstock.com

Background

There are several reasons why restoring gut microbial diversity using gut microbiome-based therapies, for example fecal microbiota transplantation (FMT) and selective digestive decontamination (SDD), could help prevent or even treat critical diseases.

When broad-spectrum antibiotics help treat critical illness, they deplete the commensal microbiota in the gut, leading to overgrowth of potentially pathogenic bacteria.

The colonization of potential pathogens in the intestinal epithelium disrupts the diversity of the microbiota that regulates the host immune system, as shown in several studies conducted in critically ill human subjects.

For example, one study showed a higher relative abundance of gram-negative bacteria, e.g. Staphylococcus aureus, in patients with sepsis.

Furthermore, a greater relative abundance of potentially pathogenic bacteria reduces the production of short-chain fatty acids (SCFAs) in the intestines; furthermore, they hinder the production of immunoglobulins A (IgA), antimicrobial peptides and defensins, collectively exacerbating the imbalance between the host immune system and the gut microbiota.

Interestingly, the gut microbiota communicates with other organs including the lungs, kidneys, brain, heart, etc.

Thus, restoring the gut microbiota and its metabolites could be of enormous therapeutic value in critical diseases, such as sepsis, ventilator-associated pneumonia (VAP), and coronavirus disease 2019 (COVID-19).

About the study

To analyze relevant literature suggesting that gut microbiome-based therapies benefit adult patients with critical illnesses, the researchers conducted a thorough search of the Pubmed index journals and identified all English-language articles published before September 2023.

They specifically identified suitable situations for the application of several gut microbiome-based therapeutic approaches, including FMT, SDD, probiotics, prebiotics and synbiotics, as well as microbiota-derived metabolites, such as short-chain fatty acids. (SCFAs), flavonoids, aromatic microbial metabolites (AMMs) and indole-3-propionic acid (IPA).

Current evidence of the usefulness and limitations of all gut microbiome-based therapies

FMT involves the transfer of engineered microbiota from a healthy donor’s feces to a patient’s intestine to help restore normal function of the intestinal microbiota.

In mouse models, early application of FMT reduced mortality from myocardial infarction and alleviated acute lung injury (ALI) by altering the gut microbiota. Similarly, in mice with sepsis, FMT restored the abundance of several commensal bacteria, including Firmicutes. Escherichia Shigella, Lactobacillus, and Proteobacteria.

Furthermore, clinical studies in human subjects have demonstrated the ability of FMT in the treatment of melanoma and transient inhibition of systemic immune cytotoxicity.

Moreover, FMT is the most effective therapeutic approach

antibiotic resistant Clostridium difficile infection (CDI) in patients with hematological malignancies. Thus, it prevents recurrent infections by various types of multidrug-resistant organisms (MDROs), especially after long-term antibiotic treatment.

Limitations of FMT include the lack of large randomized clinical trials (RCTs) and the lack of visibility of bacteria it inhibits. The unavailability of a suitable method to screen for potentially pathogenic bacteria in human donated fecal samples for FMT is another limitation of this approach.

SDD has long been used to improve the prognosis of intensive care unit (ICU) patients and reduce the incidence of intensive care unit-acquired infections due to intestinal colonization by gram-negative bacteria, such as S. aureus.

Several RCTs have demonstrated the effectiveness of SDD in reducing mortality in ICU patients. Yet, the effect of SDD on the incidence of antimicrobial resistant (AMR) organisms remains unresolved.

Probiotics are ‘live microorganisms’ that, when properly dosed, protect intestinal integrity, reduce bacterial translocation, prevent pathogen overgrowth, reduce pro-inflammatory cytokines and increase anti-inflammatory cytokine levels.

They can also act via pharmacokinetics; for example, an E. coli-based one probiotic called Nissle 1917 improves the absorption of amiodarone, an antiarrhythmic drug.

Complementary to probiotic therapy Akkermansia muciniphila (A. muciniphila) bacteria can help treat ALI. Furthermore, the combination of probiotics is based on Lactobacillus, BifidobacteriumAnd Streptococci was effective as an adjunctive therapy in severe COVID-19 patients, as it helped reduce the inflammatory index, for example that of C-reactive protein (CRP).

Likewise, L. reuteri-probiotics can reduce mortality rates in acute respiratory distress syndrome.

Clinical studies have not validated specific formulations of probiotics for every dysbiosis situation; thus, they do not fully support their preventive role in critically ill patients, especially as a stand-alone treatment.

Furthermore, overuse of synbiotics has been shown in some cases to lead to infectious complications in critically ill patients instead of treating their nosocomial infections.

Prebiotics are substrates that intestinal microbes use selectively to maintain intestinal homeostasis; for example, dietary fiber (DF) promotes the production of SCFAs. They also work by lowering levels of the intestinal metabolite trimethylamine N-oxide (TMAO).

In intensive care, DF has also been shown to improve clinical outcomes in critically ill patients, shortening their hospital stay and reducing morbidity and mortality.

They also reduce the systemic inflammatory response, such as in COVID-19, by providing anti-inflammatory nutrition and accentuating immunity through the gut-lung microbial axis.

Clinical studies have also shown that plant secondary metabolites, flavonoids, promote SCFA production and upregulate the abundance of probiotics, e.g. Lactobacillus, and downregulating pathogenic bacteria, e.g. S. aureus.

Synbiotics are probiotics that are stimulated by prebiotics and have various beneficial effects on the host. They modulate the innate and adaptive arms of immunity to reduce systemic inflammation and promote the function of other organs. In addition, they reduce the concentrations of harmful metabolites in the intestines.

For critically ill patients suffering from nosocomial infections, synbiotics provide a safe method to reduce endotoxins, serum inflammatory markers and sepsis-related complications.

Prophylactic synbiotics (e.g. Yakult combined with Shiorta) increase the number of probiotic strains (e.g. Bifidobacterium) in fecal bacteria and intestinal SCFAs, especially acetic acid, which have protective effects against enterocolitis and VAP in sepsis patients.

Probiotics, prebiotics and synbiotics are suitable for use as nutritional supplements in patients with intestinal microbiota dysbiosis.

Acetic acid, propionic acid and butyric acid are the most important SCFAs for intestinal health. They regulate myocardial tissue repair and support the activity of innate lymphocytes and B&T cells, strengthening the function of the intestinal immune barrier to remove pathogens.

However, currently available evidence for their therapeutic effectiveness in critically ill patients is small.

Furthermore, studies have shown that its high levels can exert direct cytotoxic effects on pathogens and contribute to Multiple Organ Dysfunction Syndrome (MODS).

Conclusions

Further studies should continue to investigate mechanisms by which gut microbiome-based therapies benefit critically ill patients and validate their toxicities and appropriate therapeutic doses in inappropriate human and mouse models.

Studies should also evaluate more types of critical illness, establish the appropriate composition of FMT grafts to ensure patient safety, and validate new methodologies such as engineered symbiotic bacteria.