The gastrointestinal microbiome is a dynamic consortium of bacteria, archaea, fungi, protozoa, and viruses, implicated in a range of vital physiologic processes including energy homeostasis, metabolism, gut epithelial health, immunologic activity, and neurobehavioral development. The collective of microbes in a population is referred to as the microbiota and the genetic content as the microbiome. The real value of all this novel knowledge for the clinical care of patients in the intensive care unit (ICU) still has to be established.

The Microbiome

The recent advent of high-throughput DNA sequencing technologies, coupled with advances in bioinformatics, has revolutionized the field of microbiomics. To date, consistent data suggest that the microbiome is dynamic and subject to important changes during the life of the host in response to a variety of factors including diet, environment, medical interventions, and disease states (Wolff, Hugenholtz, Wiersinga 2018).

Before birth, all mammals are thought to be sterile with inoculation with microbes occurring at the time of birth (Barko et al. 2018). Recent studies in laboratory animals suggested that the intestinal microbiome directs the development of the immune system, gut epithelium, and brain, among other body systems. Although most studies in dogs and cats have focused on the characterization of the faecal microbiome, there are substantial differences in the composition of the microbiome in different segments of the gut in dogs and cats (Barko et al. 2018). Enterobacteriales had a higher relative abundance in the canine small intestine, and Clostridiales was the predominant order in the duodenum and jejunum (40% and 39%, respectively) (Barko et al. 2018). This contrasts with the ileum and colon in which Fusobacteriales and Bacteroidales were the predominant bacterial orders. In cats, Lactobacillales is also distributed along the length of the gut, particularly in the jejunum and colon (Hooda et al. 2012).

Role of Microbiome in Healthy States

The microbiome participates in vital physiologic and immunologic processes including energy homeostasis and metabolism, the synthesis of vitamins and other nutrients, endocrine signaling, prevention of enteropathogen colonization, regulation of immune function, and metabolism of xenobiotic compounds (Hooda et al. 2012). The microbiome in small intestinal crypts, for instance, regulates enterocyte proliferation by influencing DNA replication and gene expression, while the microbiome at the tips of the villi regulates the expression of genes involved in metabolic and immune function. Microbial fermentation of complex carbohydrates produces short-chain fatty acids (SCFA), which are essential in providing energy for colonocytes, maintaining the epithelial barrier by strengthening tight junctions, helping to regulate intestinal motility, and stimulating the production of anti-inflammatory compounds.

Role of Microbiome in Pathogenesis of Diseases

Despite the paucity of data, and lack of clarity regarding the microbiome’s role in the pathogenesis of small animal diseases, there are clear links between the intestinal microbiome and systemic health. Murine experiments have suggested that the gut microbiome plays a role in the acute kidney injury induced by ischaemia-reperfusion as well as in the pulmonary host defense against invading pathogens and acute respiratory distress syndrome (Andrade-Oliveira et al. 2015). The gut microbiota plays a protective role in the host defense against pneumococcal pneumonia (Dickson et al. 2016). To date, it is unclear whether the microbiome participates directly in the pathogenesis of these disease states or via modulation of the immune system. Nevertheless, virtually all patients in the ICU are continuously exposed to a wide range of endogenous modulators (e.g., increased production of catecholamines, altered glucose metabolism and gastrointestinal dysmotility) as well as clinical interventions (e.g., use of proton-pump inhibitors, opioids, nutritional support and most of all antibiotics) that have all been shown to affect gut microbial composition (Wolff et al. 2018). These insights into the composition of the microbiome during critical illness also fuel the ongoing debate on the optimal route of the administration of nutrition.

Therapeutic Manipulation of the Microbiome for ICU Conditions

The therapeutic targets of these interventions and their efficacy are not well established in veterinary medicine and have only recently been described in the human literature. These therapies are intended to shift microbial community steady states associated with dysbiosis to those associated with health (Barko et al. 2018) and can be categorized into three groups: faecal microbiota transplantation, probiotics and synbiotics.

Prebiotics

Prebiotics are fermented by colonic bacteria, generating end-products such as SCFAs that provide essential nutrients for the enteric epithelium. Although few studies exist, the potential benefits of prebiotic supplementation, especially by the addition of plant-derived polysaccharides, is a mainstay of treatment directed at modification of the intestinal microbiome.

Probiotics

Probiotics are formulations of live organisms that confer beneficial effects on the recipient when delivered in adequate amounts. Proposed mechanisms through which probiotics improve host health include reducing intestinal permeability by upregulation of tight junction proteins, increasing mucin secretion by goblet cells, increasing secretion of defensins which prevent pathogen colonization, production of SCFAs, stimulation of IgA secretion, decreasing luminal pH, and enhancing and directing immune cells to promote tolerance to commensals while maintaining protection against pathogens.

Antibiotic Administration

Recent studies have demonstrated that resistance patterns of enteric bacteria change in response to increased exposure to antibiotics (Guard et al. 2015). Given that on any one day, three-quarters of all human patients in the ICU are treated with antibiotics, it is easy to understand why the gastrointestinal tract is considered a major reservoir for the emergence and dissemination of antibiotic-resistant bacteria (Akrami, Sweeney 2018). The emergence of antibiotic-resistant bacteria is a phenomenon of concern to the clinician and the pharmaceutical industry, and a growing threat to public health in general, because it is a major cause of failure in the treatment of infectious diseases in humans as well as animals (Jones et al. 2008; Marshall et al. 2009). Moreover, transmission of resistant bacteria or resistance is likely to be enhanced because there is an overlap in classes of antimicrobial agents used in human medicine and in small animal practice, while domestic animals are commonly kept as pets living in close contact with humans, and as such, resistant bacteria might spread between animals and humans (Guardabassi, Schwarz, Lloyd 2004). Ideally antibiotics would treat an infection at one particular site with minimal impact on neighboring microbiomes. Beta-lactam antibiotics are known to dramatically alter the gut microbiome even when administered intravenously as these agents are excreted in the bile and reach the intestine as fully functional antibiotics. Monitoring the antibiotic susceptibility pattern of E. coli from fecal samples revealed that exposure to amoxicillin causes increased expression of antibiotic resistance against several unrelated drugs, while two weeks post exposure, the resistance patterns were returned to pre-exposure level in three of four dogs, demonstrating that withdrawal of amoxicillin decreased the prevalence of antibiotic-resistant fecal E. coli in this study (Grønvold et al. 2009). Even with judicial antibiotic usage, dysbiosis may be an unavoidable consequence of critically ill patients being treated for a life-threatening infection.

Faecal Microbiome Transplantation

Recent evidences in human patients, as well as in veterinary, suggests that faecal microbiotia transplantation may be associated with a more favourable outcome in some diseases (Pereira et al. 2018).

Conclusion

Patterns of dysbiosis within the various microbiomes of critically ill patients are becoming better understood and may be predictive of clinical outcomes. During a patient’s stay in ICU, their microbiota is influenced by both their illness and the care provided. These changes in the microbiota can, in turn, affect patient outcome and susceptibility to infection. The importance of these microbiotas is pushing us towards new types of treatments, in which we also start to treat the microbiota. Promising results in microbiome-based ICU therapies, however, must be tempered by the fact that there is potential harm with this approach. Nonetheless, growing appreciation of the critical illness microbiome has already impacted critical care by highlighting the need for judicious antibiotic usage and stewardship. In the future, critical illness may be treated with equal parts anti and probiotic therapy in an attempt to balance the dangers of infection and sepsis with the harm of dysbiosis.

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