In the latest narrative review published in Nutrients, researchers compile evidence of the curative potential and limitations of gut microbiome-based therapeutics in critical illnesses to inform strategies for their future optimization.
Study: Gut Microbiome-Based Therapeutics in Critically Ill Adult Patients—A Narrative Review. Image Credit: SewCreamStudio/Shutterstock.com
Background
There are several reasons why the restoration of the gut microbial diversity using gut microbiome-based therapeutics, e.g., fecal microbiota transplantation (FMT) and selective digestive decontamination (SDD), could help prevent or even treat critical illnesses.
When broad-spectrum antibiotics help treat critical illnesses, they deplete commensal microbiota in the gut, which leads to excessive growth of potentially pathogenic bacteria.
The colonization of potential pathogens in the intestinal epithelium disturbs the microbiota diversity that regulates the host immune system, as evidenced by several studies done in critically ill human subjects.
For instance, a study showed a higher relative abundance of gram-negative bacteria, e.g., Staphylococcus aureus, in patients with sepsis.
Furthermore, an increased relative abundance of potentially pathogenic bacteria reduces the production of short-chain fatty acids (SCFAs) in the gut; additionally, they hinder the production of immunoglobulins A (IgA), antimicrobial peptides, and defensins, which collectively aggravates the imbalance between the host immune system and the gut microbiota.
Interestingly, gut microbiota communicates with other organs, including the lungs, kidneys, brain, heart, etc.
Thus, restoring gut microbiota and its metabolites could be of immense therapeutic value in critical illnesses, such as sepsis, ventilator-associated pneumonia (VAP), and coronavirus disease 2019 (COVID-19).
About the study
For relevant literature to analyze current evidence suggesting that gut microbiome-based therapeutics benefit adult patients with critical illnesses, the researchers thoroughly searched Pubmed-index journals and identified all English-language articles published before September 2023.
They specifically identified apt situations for the application of different 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 the micro-manipulated microbiota from the feces of a healthy donor to a patient's intestine to help restore the normal function of gut microbiota.
In murine models, early application of FMT reduced mortality due to myocardial infarction and alleviated acute lung injury (ALI) through altering gut microbiota. Likewise, in mice with sepsis, FMT restored the abundance of several commensal bacteria, including Firmicutes, Escherichia Shigella, Lactobacillus, and Proteobacteria.
Furthermore, clinical trials with human subjects have demonstrated the ability of FMT in melanoma treatment and temporary inhibition of systemic immune cytotoxicity.
In addition, FMT is the most effective therapeutic approach in
antibiotic-resistant Clostridium difficile infection (CDI) in patients with hematological malignancies. Thus, it prevents recurrent infections from different multidrug-resistant organisms (MDROs) species, especially after prolonged antibiotic treatment.
Limitations of FMT include lack of large randomized clinical trials (RCTs) and no 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.
For a long time, SDD has been used to promote the prognosis of intensive care unit (ICU) patients and reduce the incidence of ICU-acquired infections by preventing colonization of the gut by gram-negative bacteria, such as S. aureus.
Several RCTs have demonstrated the effectiveness of SDD in reducing the mortality rate in ICU patients. Yet, the effect of SDD on the incidence of antimicrobial-resistant (AMR) organisms remains unresolved.
Probiotics are 'live microorganisms,' which, at appropriate dosages, protect intestinal integrity, decrease bacterial translocation, prevent pathogen overgrowth, reduce pro-inflammatory cytokine, and increase anti-inflammatory cytokine levels.
They can also act through pharmacokinetics; for instance, an E. coli-based probiotic called Nissle 1917 enhances the absorption of amiodarone, an antiarrhythmic drug.
Probiotic therapy supplementing Akkermansia muciniphila (A. muciniphila) bacteria could help treat ALI. Furthermore, the combination of probiotics based on Lactobacillus, Bifidobacterium, and Streptococcus was effective as adjuvant therapy in severe COVID-19 patients as it helped reduce the inflammatory index, e.g., that of C-reactive protein (CRP).
Likewise, L. reuteri-based probiotics can reduce mortality rates in acute respiratory distress syndrome.
Clinical trials have not validated specific formulations of probiotics for each dysbiosis situation; thus, they do not fully support their preventive role in critically ill patients, especially as a stand-alone treatment.
Moreover, overuse of synbiotics, in some cases, has been shown to lead to infectious complications in critically ill patients rather than treating their nosocomial infections.
Prebiotics are substrates that host gut microbes selectively use to maintain gut homeostasis; for instance, dietary fiber (DF) promotes the production of SCFAs. They also act by decreasing the levels of intestinal metabolite trimethylamine N-oxide (TMAO).
In intensive care, DF has also been shown to improve clinical outcomes in critically ill patients, shorten their hospital stay, and reduce morbidity and mortality.
They also reduce the systemic inflammatory response, like in COVID-19, by offering anti-inflammatory nutrition and accentuating immunity via the gut–lung microbial axis.
Clinical trials have also shown that plant secondary metabolites, flavonoids, promote SCFA production, upregulate the abundance of probiotics, e.g., Lactobacillus, and downregulate pathogenic bacteria, e.g., S. aureus.
Synbiotics are probiotics stimulated by prebiotics with several beneficial effects on the host. They modulate the innate and adaptive immunity arms to decrease systemic inflammation and promote the function of other organs. Additionally, they lower the concentrations of adverse metabolites in the gut.
For critically ill patients suffering from nosocomial infections, synbiotics offer a safe method to reduce endotoxins and serum inflammatory markers and sepsis-related complications.
Prophylactic synbiotics (e.g., Yakult combined with Shiorta) increase 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 appropriate for use as food supplements in patients with gut microbiota dysbiosis.
Acetic, propionic, and butyric acids are the most important SCFAs for gut health. They regulate myocardial tissue repair and support the activity of innate lymphocytes and B & T cells, strengthening the functioning of the gut immune barrier to clear pathogens.
However, the currently available evidence of their therapeutic effectiveness in critically ill patients is small.
Moreover, studies have shown that their high levels might exert direct cytotoxic effects on pathogens and contribute to multiple organ dysfunction syndrome (MODS).
Conclusions
Further studies should continue to explore mechanisms by which gut microbiome-based therapeutics benefit critically ill patients and validate their toxicity and appropriate therapeutic doses in inappropriate human and mouse models.
Studies should also evaluate more types of critical illnesses, ascertain the appropriate composition of FMT grafts to ensure patient safety, and validate novel methodologies, such as engineered symbiotic bacteria.
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