A previous article discussed the growing interest in the gastrointestinal microbiota and its many and varied roles in pet health and disease. Four key ways have been identified to manipulate the gastrointestinal microbiota therapeutically: antibiotics, faecal matter transplants, prebiotics and probiotics. This article will focus on current and future applications of probiotics.
Probiotics – properties and proposed mechanisms of action
This report listed the ideal properties of a probiotic as being non-pathogenic, stable during shelf-life and resistant to temperature, resistant to gastric and intestinal digestion by acid, bile and enzymes, able to adhere to intestinal epithelium, able to interact with gastrointestinal flora in a positive way and capable of influencing host immune responses.
Proposed mechanisms of actions for some probiotics include: reducing intestinal pH allowing beneficial bacteria which generally thrive in acidic environments to survive; destroying pathogenic bacteria and toxins; competing for essential nutrients or receptor sites required by pathogens; binding of pathogenic bacteria; or producing inhibitory antimicrobial substances such as bacteriocins and peroxides.
Although the mechanism of action of probiotics is not completely understood, they are likely to exert an effect on the resident intestinal microbiota of the host and may also affect the intestinal and systemic immune system (Hart et al., 2012).
Probiotics in gastrointestinal disease
Some of the primary applications for probiotics in companion animals are acute and chronic gastrointestinal disturbances, and evidence for use of them in this context is generally strongest (Bybee et al., 2011; Lappin, 2018). In cats, Enterococcus faecium SF68 has been shown to reduce the duration of acute diarrhoea in cats housed in shelters in a double-blinded, placebo-controlled study (Bybee et al., 2011). This was a short-term study, suggesting the beneficial effect was likely from probiotic influences on intestinal microflora, rather than systemic immunomodulation. E. faecium SF68 has also been shown to have benefits in acute diarrhoea in kittens (Czarnecki-Maulden et al., 2007). A multi-strain synbiotic administered to cats with chronic diarrhoea resulted in improvements in mean faecal score based on a standardised faecal scoring system, and 72 percent of owners perceived an improvement in their cat’s diarrhoea after a 21-day course of synbiotic supplementation (Hart et al., 2012) although there was no control group in this study.
In dogs, E. faecium SF68 has been shown to have benefits for canine stress-related diarrhoea (Gore and Reynolds, 2012). E. faecium 4b1707 has also been associated with a better clinical outcome compared to a placebo in dogs with acute, uncomplicated diarrhoea, where dogs in the treatment group receiving the probiotic had on average a 15-hour shorter duration of diarrhoea (Nixon et al., 2019). Although this was concluded to be of limited clinical relevance, fewer dogs in the treatment group required additional medical intervention for non-improvement or worsening. This is potentially of more clinical relevance, since it suggests probiotics could have the potential to decrease the use of antimicrobials – one of the main medical interventions which might otherwise be considered.
In canine inflammatory bowel disease (IBD), use of a multi-strain probiotic VSL#3, containing four strains of Lactobacillus, three strains of Bifidobacterium and one strain of Streptococcus thermophilus, appeared to confer some protective effects to dogs, with a significant decrease in clinical and histological scores and a decrease in CD3+ T-cell infiltration (Rossi et al., 2014). Protection was associated with an enhancement of regulatory T-cell markers in dogs receiving the probiotic, and this was not seen in dogs receiving a combination therapy of prednisolone and metronidazole. A normalisation of dysbiosis after long-term therapy was also observed in the probiotic group. This study indicated the potential immunomodulatory effects of probiotics.
Probiotics may also have potential benefits in constipation. A pilot study with a multi-strain probiotic containing Lactobacillus spp. and Bifidobacterium spp. was conducted in cats with chronic constipation refractory to traditional therapy (Rossi et al., 2018). Treated cats showed significant clinical improvement and biopsies of the colonic mucosa showed improvements in the feline chronic enteropathy activity index and mucosal histology scores, suggesting a potential anti-inflammatory effect of the probiotic.
A final application for probiotics impacting gastrointestinal clinical signs in companion animals is their potential role to help ameliorate the negative impacts that some antibiotics – given for gastrointestinal disease or other reasons – may have on the microbiome. E. faecium SF68 has been shown to both offer benefits to companion animals with diarrhoea in the presence of concurrent antibiotic administration (Fenimore et al., 2017) and potentially ameliorate adverse side-effects of a commonly administered antibiotic in cats (Torres-Henderson et al., 2017).
Applications of probiotics beyond the gastrointestinal tract
There is also evidence that some probiotics may induce immune-modulating effects with potential benefits reaching beyond the gastrointestinal tract, including helpful roles in the management of atopy and infectious diseases with systemic involvement in companion animals including feline herpesvirus-1 (FHV-1). In one placebo-controlled study of cats with chronic FHV-1, cats were administered either the probiotic E. faecium SF68 or a palatability enhancer as a placebo. When mild stress was induced, cats supplemented with the probiotic had significantly fewer episodes of conjunctivitis compared to the placebo group, suggesting the probiotic lessened morbidity associated with chronic FHV-1 infection (Lappin et al., 2009). The test group also demonstrated a more stable faecal microbiome. In chronic kidney disease (CKD), increased concentrations of uraemic toxins may contribute to intestinal dysbiosis. The probiotic VSL#3 has demonstrated benefits in, for example, increasing glomerular filtration rate and degree of proteinuria in dogs with CKD, although there was no improvement in the degree of azotaemia (Lippi et al., 2017). In azotaemic cats with CKD, serum urea nitrogen and creatinine concentrations decreased after administration of a probiotic for 60 days (Palmquist, 2006). However, concurrent treatments varied and the relationship to quality of life and survival time was unclear. The potential application of probiotics to aid treatment in chronic kidney disease is a particularly interesting area that warrants more research before any clear recommendations can be made.
Probiotics have also been looked at when considering anxiety in dogs. In one placebo-controlled, crossover study conducted with anxious Labrador Retrievers, administration of the probiotic Bifidobacterium longum BL999 appeared to reduce anxious behaviours including barking, jumping, spinning and pacing and reactivity to strangers (McGowan, 2016). Physiological changes including lower cortisol responses to stresses were also noted.
How can veterinarians increase the likelihood that a particular probiotic may have benefits in individual patients?
Whilst the above discussion has focused on studies where probiotics appear to have been found to have beneficial effects, in the context of gastrointestinal health or extraintestinal diseases, it is important to highlight that not all studies have found this (Jensen and Bjørnvad, 2019). There are a number of challenges associated with interpretation of the efficacy of a particular probiotic, both in the research setting and in clinical practice. Variability in the species, strains and dose rates of probiotics can lead to differing results, especially since each probiotic strain will have specific properties which may make it useful for a particular phenotype. When considering use in gastrointestinal disturbances, diarrhoea – whether acute or chronic – can have multiple causes so it can be difficult to apply a single product to a whole range of different diseases. The initial variability in test animals’ microbiomes may also impact on study findings. As with the use of probiotics in humans with gastrointestinal diseases, the effectiveness of supplementation in veterinary patients is likely to depend on the combination of appropriate cases with specific probiotic strains (Hart et al., 2012), and it would be potentially useful to identify clinical criteria that would predict perceived therapeutic success, or failure, prior to initiation of supplementation. Unfortunately, there is still a relative lack of research in this area. Within a clinical context, probiotics are often used as part of a multimodal approach where it is difficult for clinicians to determine their individual impact on any improvement in the animal.
Are all probiotics created equal?
Unfortunately, there is great variability in the quality and potential efficacy of different probiotic products available within the veterinary profession, and the focus for the authorisation of most probiotics is based only on provision of nutritional support for animals in good health. Clinicians should critically assess the evidence for the particular strain and preparation of probiotic being marketed, since some probiotics have strong evidence for efficacy, whilst for others, the evidence is scant. Only a small number of veterinary-authorised probiotic products have shown efficacy in controlled studies and this should be a key factor in selection (Lappin, 2018). Probiotics should be purchased from a reputable company with excellent quality control and that supports research of their product efficacy. One study of commercially available products demonstrated that many probiotic labels were inaccurate: only 4 out of 15 products that had specific claims of viable organisms met or exceeded their label claim, and only two of these also had an acceptable label which accurately described the contents (Weese and Martin, 2011). Thus, deficiencies in veterinary probiotic quality remain. Where possible, a probiotic product should be selected that has been tested and shown success in the same species in providing the right nutritional support for the condition it is being used in. It is not enough to know the species of bacteria in the probiotic product: the specific bacterial strain is very important, as different strains can have very different effects.
Nutritional support in the form of supplements such as probiotics show great potential and may have roles in both acute and chronic diarrhoea, ameliorating the adverse side-effects encountered with some antibiotics, decreasing anxiety and modulating the immune system. Probiotics may offer many potential therapeutic applications and is an exciting and rapidly developing area of research; however, many questions remain unanswered. It is not yet known if multi-strain probiotics are more effective than single-strain probiotics, since different bacteria may have counteractive effects, and we still do not know which particular probiotic may be of most benefit for pets presenting with different disease conditions. The optimum dose of probiotics has also not been identified. More, larger scale and preferably multicentre controlled studies are needed (Jensen and Bjørnvad, 2019). It is important to remember that the types and amounts of microbes in products differ greatly, the quality of products varies and veterinarians cannot extrapolate from one product to another – just as they cannot extrapolate the impacts different antibiotics may have. Not all probiotics are created equally and there should be critical appraisal of the evidence for efficacy before products are selected.