Faecal Microbial Transplantation in Critically Ill Patients – Structured Review and Perspectives

The human gut microbiota consists of bacteria, archaea, fungi, and viruses. It is a dynamic ecosystem shaped by several factors, which play an essential role in both healthy and diseased states of humans. A disturbance of the gut microbiota, also termed “dysbiosis,” is associated with increased host susceptibility to a range of diseases. Because of splanchnic ischaemia, exposure to antibiotics, and/or underlying the disease critically ill patients loose 90% of the commensal organisms in their gut within hours after the insult. This is followed by a rapid overgrowth of potentially pathogenic and pro-inflammatory bacteria altering metabolic, immune, and even neurocognitive functions and turning the gut into the driver of systemic inflammation and multiorgan failure. Indeed, restoring healthy microbiota by means of faecal microbiota transplantation (FMT) in the critically ill is an attractive and plausible concept in intensive care. Yet, available data from controlled studies are limited to probiotics and FMT for severe C. difficile infection or severe inflammatory bowel disease. Case series and observational trials generate hypothesis that FMT might be feasible and safe in immunocompromised patients, refractory sepsis, or severe antibiotic-associated diarrhea in ICU. There is a burning need to test these hypotheses in randomized controlled trials powered for determination of patient-centered outcomes. metronidazole, FDX – fidaxomicin; SEX - F- female, M- men; Way of administration - Ug -upper GI, Lg-lower GI, Ngt nasogastric tube, Ngi-nasogastric infusion, Njt - nasojejunal tube, Ent - enteroscopy, C - colonoscopy, S- sigmoidoscopy, E-enema, Caps- capsule; IBD - inflammatory bowel disease - a- active, s-severe, ref-refractory


Introduction -Defining human gut microbiome
The term microbiota refers to a community of microorganisms (comprising of bacteria, archaea, fungi, protozoa, and viruses) that inhabit a particular environment. Growing attention is attributed to the microbial communities associated with various niches in human body. Their genomes (genes and plasmids) are referred to as microbiome. It is estimated that the microbiota of a healthy human consists of between 500 and 2000 species [1] (Rastelli et al., 2018). The density of microorganisms is highest in the colon and gross majority of bacteria are strict anaerobes [1]. Gut microbiota are indispensable for a range of aspects of the healthy human physiology. Most notably, microbiota influence gastrointestinal motility, regulate mucosal barrier function and epithelial cell turnover, influence immune responses, and suppress pathogen overgrowth. Indeed, they also play important role in the host metabolism, converting dietary fiber to short chain fatty acids (SCFA), which serve as energy substrate for colonocytes. Butyrate producers are also protective against mucosal inflammation and infection [2].

Intestinal microbiota diversity and relation to immunity and inflammation
Gut microbiota is a dynamic ecosystem shaped throughout human lifespan, from prenatal conditions (mothers health and fetus genetic factors), mode of birth (Caesarean section versus vaginal delivery), diet, BMI, weight, environment, antibiotic exposure, to hospitalizations during later life. Gut microbiota of the adults is dominated by taxa belonging to two phyla Bacteroidetes and Firmicutes, with their relative proportions differing among populations. The interindividual variability in microbial composition is remarkable, but most individuals can be categorized into three different enterotypes, probably linked to long-term dietary habits (Wen & Duffy, 2017). One of the most important functional characteristics of human microbiota is its diversity, i.e. species richness.
Dysbiosis, a state with low bacterial diversity, in which the homeostasis of the gut microbiome is disrupted, has been associated with a range of diseases [1,3].
Commensal bacteria, and bacteria in the gut in particular, are essential for the development and maturation of the human immune system. Germ-free mice have significantly reduced lymph nodes in gut-associated lymphoid tissues [4]. Microbiota composition can affect immune cells in the gut via microbial components (LPS) or products of microbial metabolism (i.e. SCFA) [4]. Bacteroidetes and other Gram-negative bacteria contain lipopolysaccharides (LPS) in their cell wall, strong immune response activators [2]. Worsening of intestinal barrier function leads to leakage of gut bacteria components or even whole bacteria into the circulation. On the contrary, SCFA reduce proinflammatory cytokines production in monocytes and T-cells, and strengthen the tight junctions of gut epithelia cells and butyrate-producing bacteria have beneficial immunometabolic effects [2].
These mechanisms may also explain the link between dysbiosis and autoimmune diseases [5,6].

Intestinal barrier function
Mucosal barrier is not only essential for the digestion and absorption of nutrients, but it also prevents the entry of diverse exterior antigens (food antigens, commensal bacteria, pathogens, and toxins). In the intestine, the front line of this barrier is only a single layer of specialized epithelial cells

Changes in gut microbiota in critically ill patients
Critical illness is an extreme alteration of homeostasis, which requires medical and instrumental life support in addition to the treatment of the underlying disease. As the human microbiome is a result of complicated interplay between the host and gut microbiota, it comes without surprise that critical illness is almost invariably associated with dysbiosis in a degree directly proportional with disease severity (Lamarche et al., 2018). Most prominent is the relative increase in pathogenic bacteria (such as the Proteobacteria, Enterobacter and Staphylococcus) and a reduction of SCFA-producing protective microorganisms (such as Firmicutes and Bacteroidetes) and antiinflammatory species as Faecalibacterium (Nakov et al., 2020;Zaborin et al., 2014). The dynamics of this microbiota alteration is astonishing. Ninety percent of the commensal organisms are lost within the first six hours of ICU stay (McClave et al., 2018). Factors contributing to the dysbiosis of the critically ill can be summarized as follows: 1. Artificial instrumentation of upper airways and upper GI tract (endotracheal intubation, nasogastric tube) which overcome natural immune barriers and lead to bacterial colonization of normally nearly sterile surfaces [8].
2. Host responses to critical illness leads to ischemia-reperfusion injury of the gastrointestinal tract. This, in addition to the above discussed barrier disruption, also reduces the production of gastric protective mucus and the secretion of microbial peptides and IgA and reduces partial pressure of oxygen within and near intestinal wall.
3. The lack of luminal nutrients in the gut cause catabolic starvation of bacteria, creating an additional selective pressure. 4. The effect of medication. Opioids and other drugs, which reduce intestinal motility, and proton pump inhibitors, which alter pH in the stomach, both have the potential to alter microbiota composition. Yet, by far the most disruptive factor is the exposure to antibiotics.
The US Centers for Disease Control found out 55% of all hospitalized patients received an antibiotic during their hospital stay. This proportion increases to 70% in the subgroup of patients in ICU (Wischmeyer et al., 2016), (Vincent et al., n.d.). Clinical manifestation of a profound microbiome alteration is antibiotic-associated diarrhea (AAD), which occurs in 5% to 35% of exposed subjects [12]. In addition, exposure to antibiotics increases Clostridium difficile (CD) or multi-drug resistant organisms (MDROs) colonization. Genes of antibiotic resistance then persist in microbiome of the gut. This creates the rationale for the restoration of physiological microbiota by means of FMT, as discussed below.
5. Environmental exposure to disinfectant agents and subtherapeutic concentrations of drugs plays likely a minor role as healthy hospital workers do not seem to have gut microbiota significantly altered (Johanson1969, n.d.).

The effect of dysbiosis on critically ill patients
It is likely that not only the milieu in the human body affects microbiota, but that this relationship also works in the opposite direction. Patients hospitalized with dysbiosis-associated diseases are at significantly increased risk of sepsis and septic shock (Prescott et al., 2015). Altered intestinal microbiota may lead to metabolic, immune, and even neurocognitive disturbances in the critically ill by one or more of the following mechanisms:

3.
Dysbiosis reduces specific microbial stimulatory signals for T-helper cells and dysregulates immune system, resulting in infectious complications (Nakov et al., 2020). These are made even more difficult to treat due to resistance genes preserved in the metagenome.
4. Indeed, dysbiosis and MDRO colonization alters bacterial ecology of ICUs and hospital floors, expanding its effect beyond the level of an individual patient.

Dysbiosis therapy in ICU
In light of these rich bidirectional relations between the critically ill and their gut passengers, microbiota is an attractive potential treatment target. Indeed, the very first step and probably the most important in protecting gut microbiota is a strict antibiotic stewardship. Antibiotic overuse has repeatedly been associated with increase morbidity (including but not limited to Clostridium difficile   66,67]. Repeated FMT was also used in the treatment of intestinal failure associated with drug-induced hypersensitivity syndrome [68] and severe antibioticassociated diarrhea (AAD) [69]. The data is summarized in Table 3. successfully used in three patients with severe refractory gastrointestinal acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation [72] FMT to eliminate colonization by multi/drug resistant organisms. Animal experiments showed that the restoration of microbiome following FMT was associated with an immense reduction in the density of intestinal MDRO, probably by restricting their growt [73]. Indeed, critically ill exposed to broad spectrum antibiotics are often colonized with MDRO and in theory, FMT could be a plausible alternative to selective bowel decontamination strategy by using antibiotics alone, offering an advantage of not threatening bacterial ecology of intensive care units. An uncontrolled study of 20 immune compromised haematologic patients demonstrated a total elimination of MDRO from the stool in 15 (75%) patients after FMT [74]. On the other hand, no effect of FMT was observed in RCT.

Use FMT in intensive care unit
Thirty-nine immune competent patients colonized with MDRO were randomized to receive no treatment or five-day course of nonabsorbable antibiotics followed by FMT. There was no significant difference in colonization rate in stool samples (MDRO eradication in 41% vs. 29% in controls) [75].
Unfortunately, large scale RCTs measuring patient-centred and ecological outcomes are still missing.

Conclusions
FMT is an established treatment method for recurrent CDI and this is also beneficial for patients who are critically ill or develop CDI as a consequence of IBD, immune deficiency or protracted ICU stay. At the current level of evidence, FMT should be considered as a salvage treatment for the sickest patients with most severe forms of CDI in whom colectomy would otherwise be the only alternative.
The biggest promise and burning need of RCTs is in the treatment of post-antibiotic diarrhoea as FMT not only seems to eliminate symptoms, but it also may reduce colonisation rate with MDRO and improve systemic inflammation and outcomes. Current data suggest acceptable safety profile of FMT administered into lower gastrointestinal tract to critically ill patients including those who are immune suppressed, but due to uncontrolled nature of most of the available trials, this warrants confirmation in large scale randomised controlled trials.