The gut microbiome in GI diseases: how and when to manipulate it?
The gut microbiome in GI diseases: how and when to manipulate it?
Dr Caroline Mansfield BSc BVMS PhD DECVIM-CA
Melbourne Veterinary School, University of Melbourne
250 Princes Highway, Werribee, Victoria 3030 Australia firstname.lastname@example.org
It is estimated that the mammalian gastrointestinal tract harbors at least 1012-1014 organisms, in the same order as the number of mammalian cells in the body. Various host factors such as genetic background, age, sex, initial environmental exposure, diet and antibiotic usage contribute to the development and maintenance of the intestinal microbiota. For these reasons, the gut microbiota varies from individual to individual, over time and even between mucosa, luminal contents and faeces.
The role of microbes associated with intestinal inflammation is gaining increased attention in people and in animals, with recent research concentrated on bacteria using culture-independent methods of next generation sequencing. Molecular studies have been conducted in dogs and cats to unravel specific organisms or dysbiosis that occur in chronic enteropathy (inflammatory bowel disease); however, results are mixed depending on the method used and population studied. Importantly, although the microbiome may be stable over time in healthy individuals, in inflammatory states there are often rapid changes, and it is uncertain whether the dysbiosis drives the inflammation or the inflammation causes the dysbiosis. Acute intestinal inflammation, either infectious or associated with stress/antimicrobial usage, is also associated with profound dysbiosis. In people following acute infectious diarrhea, the microbiome may take weeks to months to return to a baseline level.
Techniques used to characterise the GI microbiome include DNA sequencing and analysis (sequencing of the 16S ribosomal genes to identify bacterial species), metagenomics (the total genetic coding in the population), metatranscriptomics (RNA or function of the bacteria) and metabolomics (metabolites are produced by the bacteria or host). Full sequencing of individual animals presenting to a clinic is currently beyond the scope of possibility in veterinary medicine.
The canine dysbiosis index (CDI) measures the abundance of 8 bacterial groups using a faecal qPCR panel and is an alternative method for evaluating the microbiome in dogs. The results are summarised into a single number, with a CDI < 0 indicating normal faecal microbiota, and a CDI ≥ 0 indicating dysbiosis. In other words, CDI is negatively correlated with phylogenetic diversity. A CDI of 0 had 84% sensitivity and 86% specificity for differentiation of dysbiosis from eubiosis. Further studies have shown that the CDI may stay increased for several months, despite reduction in CIBDAI due to residual inflammation. An increased CDI has been reported in dogs with chronic enteropathies, exocrine pancreatic insufficiency and antibiotic-induced dysbiosis. There may also be geographical variation, and 15% of normal dogs have a CDI in the equivocal range (0-2).
There are three main ways to modify the microbiome: antibiotics, prebiotics/probiotics and faecal microbial transplantation (FMT). Prebiotics and probiotics affect the host microbiome by increasing diversity of species, decreasing pathogens and improving enterocyte health. Antibiotics eliminate pathogens and increase beneficial bacteria and concurrently decrease microbial diversity, whereas faecal transplantation attempts to replace the disrupted native flora and other constituents of faeces that may be beneficial.
Antibiotics are frequently used in the treatment of chronic enteropathy/IBD in dogs and cats, particularly metronidazole, oxytetracycline and tylosin. This paradigm is now being challenged, particularly in dogs for several reasons. Firstly, studies from multiple centres show that dogs with enteropathy treated with antibiotics (even with concurrent dietary therapy) do maintain long-term remission times and/or require intermittent, long term antimicrobial treatment to remain in complete or partial remission. Secondly, the metabolic effects on the host of drugs like metronidazole are being recently recognized. These effects seem to persist long after cessation of the antimicrobials and do not appear to be simply due to bactericidal effects. Finally, the requirement for prevention of antimicrobial resistance in veterinary practice should make use of antimicrobials in this clinical situation questionable.
In cats with chronic enteropathy, if there is concurrent infectious cholangitis and/or cholecystitis then antibiotics should be administered for those identifiable problems. Targeted and judicious antimicrobials should be used (based on culture results from bile or liver aspirates), rather than broad-spectrum in all cats with chronic gastrointestinal disease though.
Acute causes of diarrhea are usually viral or dietary induced, and as such seldom require antibiotic administration unless there is a concern for bacterial translocation. In fact, studies of dogs with acute hemorrhagic diarrhea syndrome suggest that there is no benefit in giving broad-spectrum drugs like amoxicillin-clavulonate.
Prebiotics are compounds that selectively stimulate the function or proliferation of beneficial bacteria in the colon. Prebiotics are often plant-derived carbohydrate compunds contained in the diet and include fructans (fructooligosaccharides [FOS] and inulin) and galactans.
Many diets designed for intestinal disease in dogs and cats already contain prebiotics, and likely confer this advantage. Likewise, many commercial products also combine probiotics with prebiotics. Dietary fiber supplements such as psyllium have historically been laxatives only, as they increase faecal water content and increase motility. However, recent research would suggest that psyllium does selectively and beneficially to a small degree alter the microorganisms in the colon. Research assessing prebiotics in clinical cases are difficult to evaluate, as it is seldom that they are used in isolation (i.e. usually in diet with other potential benefits, or in combinations with a probiotic). Regardless, as prebiotics are not harmful to the host it is likely that supplementation will be beneficial in most cases.
Probiotics are defined as live microorganisms that confer a health benefit on the host when administered in adequate amounts. In addition, probiotics should survive gastric acid and bile to reach and adhere to the intestine, be able to proliferate and colonize the colon, modulate the intestinal immune system, be active against pathogenic microorganisms and have no carcinogenic, toxic, pathogenic or mutagenic effects. The most common types of bacteria contained in probiotics that are used in veterinary medicine include Bifidobacterium, Lactobacillus, Enterococcus faecium and the yeast Saccharomyces boulardii.
In clinical trials in dogs with CE, the results have also been varied, as have the study populations and probiotics used. To date, there have been one two reported studies where there has been a modest benefit (faster time to resolution, improved inflammatory markers), but there is no substantial clinical benefit that has been shown. There have been no studies in cats with documented IBD and probiotics, but in one study of 22 cats with chronic diarrhea, 72% of owners reported and improvement in their cats’ clinical signs.
In studies of probiotic administration in animals at shelters there appears to be a moderate benefit in reducing duration of diarrhea, particularly in cats. Likewise, studies have also shown a reduction in duration of clinical signs in dogs with acute (not parvo) gastroenteritis, including acute hemorrhagic diarrhea syndrome.
In summary, although the use of probiotics is gaining in popularity, there is still plenty unknown about this area of veterinary medicine. There may be some benefit in shelter animals (used prophylactically) and in some animals with acute (not parvoviral) enteritis. Care should be taken whenever administering probiotics to acutely ill animals, as it has been shown in people with severe pancreatitis that probiotics worsen prognosis substantively.
For chronic intestinal disease in dogs, the use of probiotics is probably is in its infancy. Ideally, we will reach a point where every individual animal, the individual GI microbiome (and its metabolic function) can be determined, and then matched to a specific probiotic (with specific strains). As the quality of probiotics on the market varies greatly, we can’t know what strain is required, and even if the strains remain viable, at this stage probiotic administration for CE in dogs is not recommended.
Fecal microbial transplantation
Faecal microbial transplantation has been effectively used in people for treatment of C difficile infection. The benefits of FMT are probably not limited to the actual bacteria that are transplanted, but also to the bacteriophages and bile acids that are present in faeces. Despite dogs being coprophagic in nature, some individual studies suggest FMT may be useful in dogs. FMT is even less explored in cats, and so cannot be recommended at this stage. There are no studies to determine the exact protocol or donor requirements, but there are few extrapolations from human medicine that are used.
FMT should be considered when dogs have failed a dietary trial, at the stage where typically would be considering antimicrobial administration. This is not a procedure that should be done in a severely unwell animal, as medical therapy should be administered first, and then FMT considered following clinical improvement.
It is important that recruitment of the donor considers the body condition score (must be lean so as not to pass on an ‘obese’ enterotype), have no history of gastrointestinal, metabolic or infectious disease and ideally no behavioural abnormalities. We also recommend that the animal is fully vaccinated and wormed, fed a regular commercial diet without additives and has not been administered antibiotics or gastric protectants in the previous 3 months. Ideally, the donor should have a normal CDI.
Options for administration of FMT include rectally or via a catheter through an endoscope to the duodenum. At our institution, we administer into the colon, and to date have had good success with no side effects from this method. The frequency and volume of FMT is mainly extrapolated now, and highly variable between veterinary centres. It is hoped that in the next few months publications and consensus on treatment guidelines will be reached.
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