Therapeutic Potential of the Gut Microbiota in the Management of Sepsis

Matteo Bassetti; Alessandra Bandera; Andrea Gori

Disclosures

Crit Care. 2020;24(105) 

In This Article

Modulation of the Microbiota as Potential Therapeutic Immunonutrition

Probiotics are considered as living microorganisms, which, in adequate amounts, can induce health benefits to the human host. Among them, the genera Lactobacillus and Bifidobacterium are the most widely used. Probiotics have been increasingly applied and studied in different clinical applications. Probiotics have been hypothesized to reduce the risk of disease through competition for binding locus and nutrients with pathogens, producing bacteriocins to kill pathogens, synthesizing IgA to support immune responses and reducing inflammation. Prebiotics are defined as a non-digestible food ingredient that beneficially impacts the host by stimulating the growth and/or activity of a limited number of bacterial species in the gut. Synbiotics are composed of probiotics and prebiotics.

In the context of sepsis models and ICU patients, probiotics have been studied and evaluated in terms of sepsis evolution and subsequent outcome. A study by Chen and coauthors reported that prophylactic administration of a probiotic bacterial species in a septic mouse model effectively reduced mortality.[22] More recently, a study conducted on a model of septic mice specifically demonstrated that after the onset of sepsis, there was an appearance of opportunistic gut pathogens such as Staphylococcaceae and Enterococcaceae and a disappearance of beneficial Prevotellaceae.[23] Relative abundance of potentially pathogenic commensals was associated with more severe immune responses during sepsis, demonstrated by higher peripheral pro-inflammatory cytokine levels, gut epithelial cell apoptosis, and disruption of tight junctions. Interestingly, in animals pre-treated with Lactobacillus rhamnosus GG, opportunistic pathogens decreased or even disappeared, while beneficial bacteria, such as Verrucomicrobiaceae, increased, promoting inhibition of gut epithelial cell apoptosis and tight junction formation. Moreover, in a novel in vitro gut model to study Candida pathogenicity, the introduction of a microbiota of antagonistic lactobacilli emerged as a significant factor for protection against C. albicans-induced necrotic damage, with a time-, dose-, and species-dependent protective effect of probiotics against C. albicans-induced cytotoxicity.[24]

Use of prebiotics/probiotics/synbiotics in clinical ICU studies has been evaluated in many small studies in different populations (summarized in Table 1): (1) to prevent infections, especially in the context of postoperative and mechanically ventilated patients; (2) to improve outcome of sepsis; (3) to restore gut commensals after sepsis to reduce late infections and subsequent mortality.

Administration of probiotics and synbiotics had been demonstrated to reduce infectious complications, and meta-analyses suggest that probiotics are safe and effective at preventing infection in both postoperative and mechanically ventilated patients.[25,26] However, various concerns have been raised regarding the type and optimal dose of probiotic therapy, as well as the small size of the individual studies. Morrow et al., in the most rigorous study, reported that the incidence of ventilator-associated pneumonia (VAP) in patients treated with L. rhamnosus GG was significantly lower than in controls (19.1% vs. 40.0%) in 138 ICU patients. Moreover, probiotic administration significantly reduced oropharyngeal and gastric colonization by pathogenic species.[27] However, other clinical reports showed no significant difference in the occurrence of VAP in the ICU.[28] In a recent randomized controlled study, the effect of prophylactic synbiotics on gut microbiota and on the incidence of infectious complications including enteritis, VAP, and bacteremia was evaluated in mechanically ventilated patients with sepsis. Seventy-two patients completed the trial, of whom 35 patients received synbiotics and 37 patients did not. In the synbiotics group, the incidence of enteritis and the incidence of VAP were significantly lower compared to controls. The incidence of bacteremia and mortality, however, did not differ significantly between the two groups.[29] Currently, we are waiting for the results of a large randomized placebo-controlled study[30] aimed to determine the effect of L. rhamnosus GG on the incidence of VAP and other clinically important outcomes (C. difficile infection, secondary infections, diarrhea) in critically ill mechanically ventilated patients (Clinicaltrials.gov Identifier: NCT02462590).

Several studies have assessed the role of probiotics in other populations, such as pre-term and underweight children, finding no differences in sepsis incidence and mortality, indicating that the potential effects of microbiota restoration are not uniformly conserved across populations and settings.[31,32] Interestingly, a recent randomized, double-blind, placebo-controlled trial testing an oral synbiotic preparation (Lactobacillus plantarum plus a fructooligosaccharide) in healthy, termneonates in India was interrupted early because of a reduction of 40% in death and sepsis in the treatment arm.[33]

The last frontier in the context of immunonutrition is the development of next-generation probiotics able to selectively inhibit specific pathogens, such as C. difficile and MDR bacteria, in order to administrate a target population that would support colonization resistance and prevent infections and sepsis.[34]

Fecal Microbiota Transplantation

Fecal microbiota transplantation (FMT) consists of administering fecal material from a healthy donor into the intestinal tract of a patient with an altered gut microbiota to restore its functions. Clinician interest in this treatment was renewed in 2013 with publication of the results of a randomized controlled trial showing the substantial superiority of FMT over standard care in the treatment of recurrent C. difficile infections.[35] Based on the absolute number of introduced bacteria, FMT is thought to be the most powerful immunomodulatory tool. In animal models, FMT alone is capable of restoring bacterial communities in cecal crypts, which act as a reservoir of commensal bacteria to restore the intestinal epithelium. Crypts are also crucial in protecting intestinal stem cells and in preservation of immunological pathways by enhancing the expression of nod-like and Toll-like receptors. Depletion of commensal organisms in crypts enhances pathogen proliferation, which can result in severe inflammation and disruption of homeostasis. Another potential advantage of FMT is that, along with the transfer of bacterial communities, other products (short-chain fatty acids, bile acids, eukaryotic, and prokaryotic viruses) are introduced to the intestinal ecosystem, leading to a complete restoration of homeostasis.[36]

The rationale for use of FMT in critical illness is fascinating and promising. However, its application in clinical practice among ICU patients is unexplored. We believe that FMT can have a potential role in critical patients in two directions: (1) restoration of ICU-associated dysbiosis and (2) implementation of gut decolonization of MDR organisms. In fact, the introduction of a high burden of commensal bacteria may reverse resistant pathobiont dominance and even decrease the antibiotic resistance genes present in the microbiome (resistome).[37] However, only five cases have been described in which FMT has been employed to address disruption of the microbiota in the ICU. All these cases showed that treatment with FMT led to a successful reversal of dysbiosis, with subsequent improvement in outcome. In addition, some cases noted a steep decrease in inflammatory mediators and normalized Th1/Th2 and Th1/Th17 ratios following FMT. Apart from difficulties with extrapolating the data derived from these case reports to the general ICU population, we are far from obtaining conclusive evidence that restoration of dysbiosis by FMT in critical illness is beneficial. However, given the promising results of FMT learned from C. difficile treatment experience, clinical trials are needed to implement a microbiota-targeted approach.

Colonization with MDR bacteria is a leading cause of sepsis complications especially among vulnerable ICU patients.[38] The use of FMT for this purpose has been evaluated in different case series, retrospective and prospective studies, highlighting that this approach can be feasible safe and effective.[39] Results cannot be easily analyzed because of the high risk of bias in smaller studies, but in a recent review that considered only studies with low and moderate risk of bias, an eradication rate between 37.5% and 87.5% was described.[40] However, results of different studies cannot be conclusive because of different patient populations (with the most commonly organisms isolated pre-FMT being carbapenem-resistant Enterobacteriaceae [CRE], vancomycin-resistant Enterococci [VRE], and extended-spectrum β-lactamase [ESBL]-producing bacteria, and also Pseudomonas, methicillin-resistant S. aureus [MRSA], and Acinetobacter, and differences in route of administration, choice of donors, and length of follow-up.[39] Recently, a randomized controlled trial has been completed showing that patients given nonabsorbable oral antibiotics followed by FMT had a slight decrease in ESBL and CRE colonization compared with control patients, although without reaching statistical significance. The unfavorable results are potentially due to the study design (two different routes of FMT in the interventional group and contemporary antibiotic administration may have influenced carriage in the interventional group) and early trial termination.[41] However, it is important to note that so far none of the published studies has been conducted in ICU patients. Until now, only one pilot study is ongoing among ICU patients with a prevision of enrollment of 10 mechanically ventilated patients with MDR colonization (Clinicaltrials.gov Identifier: NCT03350178).

Various concerns specific to ICU patients have been raised in addition to other unanswered questions regarding FMT itself (e.g., transmission of pathogens, dose, route, and long-term safety), as well as several practical aspects that need to be investigated. First, we do not know which candidate population of septic patients is best and what the correct timing of FMT administration is in relation to antibiotic use because of the risk of nullifying the effects of transplantation.

A microbiota suspension as a fecal filtrate transfer (FFT) seems to maintain the ability to stimulate host responses via pattern recognition receptors enabling ecologic niches to be modified for outgrowth of existing beneficial bacteria or even successful novel colonization.[42] This characteristic, together with a possibility to create a capsule, can increase the chances of successful FMT application even during antibiotic treatment, reducing also the potential risk of instillation of large bacterial burdens among immunocompromised patients.

Furthermore, more experience is crucial to evaluate what is the best route of administration (colonoscopy or enema vs nasogastric tract) and use of autologous vs heterologous transplantation. Colonoscopy or enema are the most commonly used methods of stool delivery. A randomized study found that FMT using the nasogastric tract was less effective than colonoscopy.[43] Expert opinion tends to favor colonoscopy because of its ability to visualize the entire colon and to deliver larger amounts of stool near the affected pathological segment of the bowel.[44] Moreover, non-inferiority of capsule use over colonoscopy was demonstrated in a randomized study.[45]

Finally, the use of autologous vs heterologous FMT needs to be clarified because autologous FMT can have a higher potential application in the ICU setting among patients receiving solid or hematopoietic transplant in an attempt to prevent infections after a period of dysbiosis.

In conclusion, we believe that the potential benefits from FMT (regarding the control of MDR bacteria and C. difficile infection) justify the investigation of this promising approach in ICU patients.

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