Probiotics are live microorganisms that, when ingested in adequate amounts, confer a health benefit to the “host” (WHO definition). In contrast, prebiotics are substances (often carbohydrates, dietary fibres) that promote growth of probiotics. When probiotics and prebiotics are combined, the resulting product is called a synbiotic.

Unfortunately, few studies have demonstrated any health benefit of alleged probiotics in small animals at all (negating the definition of a probiotic) and no trial has evaluated their use in critically ill small animals. However, there have been trials in dogs with both acute and chronic gastrointestinal (GI) conditions, which might be useful for some dogs or cats seen by emergency services.

Inference of treatment recommendations from the use of probiotics in critically ill people to dogs or cats is problematic. The most commonly used probiotics are different (mostly Lactobacillus, Bifidobacterium, Streptococcus in people) to what is used in small animals (Enterococcus, Saccharomyces). Effects of probiotics have not only been demonstrated to be dose dependent, but crucially both strain and species specific. This makes sense, as probiotics are supposedly mimicking or strengthening the “friendly” microbiota already present in the gut, but the composition and abundance of this commensal microbiome is somewhat different in small animals, especially cats.

Broadly speaking, probiotics likely need to be characterised by the overall immunological response (mucosally or systemically) they induce. Immunostimulatory probiotics are characterised by the ability to promote activation of natural killer cells and the development of a T helper (Th)1 adaptive immune response, resulting in augmentation of the immune defense against infection. Immunoregulatory probiotics are characterised by the ability to induce development of regulatory T cells (Tregs) and control inflammatory responses, resulting in an increase in allergy, inflammatory bowel disease (IBD), and autoimmune disease (see figure 1). It is largely unknown which probiotics exert these or more flexible responses in small animals. The type of immune response elicited might also depend on the responding cell types and simultaneous stimuli (multifunctional probiotics), which explains how the same probiotic has been successfully used in different conditions in people.

Figure 1 Modes of action of immunostimulatory and immunoregulatory probiotics on the innate and adaptive immune system.

Most of the proposed benefits and mechanisms of action of probiotics are still directly or indirectly related to the GI tract, i.e., either through interaction or competition with less beneficial luminal or adherent microorganisms (competition for nutrients, binding of toxins, production of vitamins, antimicrobial peptide production, changes of the microenvironment), effects on intestinal epithelial cells (affecting barrier function, permeability, production of mucus and protective proteins, stimulation of innate immune receptors) or the mucosal immune system. The latter likely involves both modulating signaling pathways of innate immune cells (i.e., macrophages [MΦ], dendritic cells [DCs]) and maturation of adaptive immune cells (i.e., induction of a certain Th cell profile, class-switching of immunoglobulins [Ig] or strain-specific IgA production) (see figure 2). Through this, a systemic immune effect is also proposed.

Figure 2 Proposed mechanisms of action of probiotics on the intestinal epithelial cells and local mucosal immune system.

The probiotic most commonly used in small animals, Enterococcus (E.) faecium, has undergone some in vitro testing of its properties: it adheres to human as well as canine intestinal mucus, produces lactic acid, and survives sufficiently in 1% bile (up to 98%) and at a pH of 3 for 3 hours (87%). Results of testing of the effect of E. faecium on immune parameters in dogs and cats are limited. It increased total faecal and serum IgA levels (but not IgG) in healthy puppies, increased lymphocyte counts in kittens and might influence some parameters of routine biochemistry in healthy adult dogs, but results of these studies are of unknown value in ill animals. Conditions in which probiotics have been tested in dogs and cats are summarised in the table below.

Table. Selection of conditions in which probiotics have been assessed as treatment modality in dogs and cats (C)

But what about critically ill patients? In people, recent data shows that critically ill patients undergo dysbiosis (“unbalancing” of the composition and richness of the microbiota) at several organ sites including the skin, GI tract and the lungs, with loss of microbial diversity and a propensity for potential pathogens to dominate. This appears to contribute to nosocomial infections, sepsis, multiple organ dysfunction syndrome, and can even be predictive of poor outcomes. A role for probiotics in reducing the risk of infections in human ICU settings was initially described in 2012. Even before that, the use of probiotics has been advocated for antibiotic-induced diarrhoea or C. difficile colitis in people. Since then, most trials have focused on the role of reducing ventilator-associated pneumonia (VAP), where the role of probiotics remains controversial. A Cochrane review found a low quality of evidence that probiotic therapy is associated with reduction of VAP. However, two separate meta-analysis showed that probiotics continue to show a significant reduction in infections following critical illness. A trend toward a decrease in ICU length of stay was also observed. However, a wide range of probiotic species and doses was utilised, so no recommendations can be made for the dose or type, with the exception of Saccharomyces boulardii, which should not be used in human ICU patients.

The theoretical benefits from probiotics in the ICU (for both people and animals) are easy to see: protection from infection and sepsis through maintenance of epithelial barrier function, generation of nutritional support for the host epithelial cells, change of the metabolic transcriptional landscape, thereby editing of the local and systemic immune system, and inhibition of colonisation with harmful bacteria. The latter is mainly believed to be due to effects of short chain fatty acid fermentation, i.e., either through a boost of b-oxidation in colonocytes, which promotes a hypoxic environment, or through the production of lactic acid, which reduces luminal pH in the colon.

A landmark trial in the benefit of probiotic and symbiotic therapy against sepsis in infants was recently published. This randomised double-blind, placebo-controlled trial of an oral symbiotic (Lactobacillus plantarum plus fructooligosaccharide) demonstrated a significant reduction in the primary outcome (sepsis and death) in children in a developing country.

In addition to probiotic use, faecal microbiota transplantation (FMT) has shown a more than 90% effectiveness in curing C. difficile colitis in people. This treatment is now increasingly considered for other critically ill patients, and a case report of successful treatment of refractory severe sepsis and diarrhoea with an FMT has been published recently.

However, prior to widespread implementation and large clinical trials of “dysbiosis” therapy, in the form of probiotics, synbiotics or FMT, a greater understanding and characterisation of the microbiome changes in the ICU using culture-independent, amplicon and metagenomics-based sequencing techniques are needed in broader ICU populations, both in human and veterinary medicine.