Patient presenting with gastroenteritis and liver enzyme elevations: How do we approach this dog’s workup? Photo courtesy Dr. Laura B. Gaylord The gut-liver axis is defined by the bidirectional crosstalk between the gastrointestinal tract and the liver in health and disease. Signals continuously arise from dietary, genetic, and environmental factors. Key players in this conversation are the intestinal mucosal barrier, the gut microbiome, the portal vein, and the liver/biliary system. The immune system also interacts with each component of the gut-liver axis. Understanding each part of this axis and its role in gastrointestinal and liver disease may help direct therapies, including nutritional interventions, medications, and supplements that modulate and support the gut mucosal barrier, intestinal microbiota, and liver regeneration and repair. Gut-liver crosstalk How many cases of gastroenteritis do you see where elevations of liver enzymes are present, or perhaps mild cases of vomiting and/or diarrhea where you see an elevation of alanine transaminase (ALT) liver enzyme and no clinical signs are noted? For some cases, we can see this enzyme rise when signs of gastroenteritis occur and then resolve, but for others, it seems to persist over time. Questions arise: what is the cause of this liver enzyme elevation, and why is it persistent despite resolution of clinical signs? We must work through our differential list for all possible causes of ALT elevation (in dogs and cats, this includes hepatocellular injury or, less often, muscle damage and is related to cell damage, increased membrane permeability, blebbing or necrosis, which can be transient or permanent; half-life of ALT is 59 hours in dogs and 2.8-4.4 hours in cats).1,2 However, this rise in ALT may reflect the crosstalk within the gut-liver axis that is always happening. The Gut-Liver Axis Anatomy27 in the dog is composed of the intestinal mucosal barrier within the intestine, the portal vein, the liver/ gall bladder/ biliary system, and the gut microbiome. Source: Disorders of the Liver and Gallbladder in Dogs by Sharon A. Center The intestinal barrier Within the intestinal tract, specialized barriers exist to regulate what bacteria, bacterial products, nutrients, and metabolites may cross through and reach the liver. Anatomically, this includes the intestinal mucosa, the epithelium, and the immune system. The intestinal mucosal barrier serves as the interface between the inside of the body (interstitium or submucosa) and the outside (intestinal lumen, the external environment). A mucous layer exists on its surface, which may be affected adversely or even disappear during conditions of dysbiosis.3 Tight junctions are present between mucosal epithelial cells that work to prevent the translocation of bacteria and bacterial products from the intestinal lumen across the barrier to gain access to the body and its vascular system. Bacteria within the microbiome produce short-chain fatty acids (SCFAs), which provide energy for mucosal cells as well as ligands that seal and boost gut barrier function.4 Bile acids within the intestinal lumen also serve as metabolic regulators by influencing the gut bacterial composition in addition to assisting with fat digestion and absorption. They interact with specialized receptors on intestinal and immune cells.5 A specialized receptor called Farnesoid X receptor (FXR) serves as a sensor of bile acid synthesis and secretion along with enhancing mucosal epithelial barrier function and even repairing gut microvasculature.6 The Intestinal Mucosal Barrier in Health and Disease.28 On the left, the intestinal mucosal epithelium has a loosely adhered and tightly adhered mucous layer. The epithelial cells are aligned with normal anatomy, intact tight junctions and normal villi perform digestive and absorptive functions. On the right, the intestinal epithelial barrier is depicted in a compromised state such as that which occurs with patients with chronic enteropathies. A dysbiotic microbiome is present with less diversity and function, the mucous layer is disrupted and less attached, and the intestinal epithelial cells are shortened and will have less optimal digestive and absorptive function with loss of tight junctions that may allowpotential translocation of bacterial and bacterial by-products across the barrier stimulating an inflammatory response. Source: Suchodolski JS - Assessing and Managing the Gut Microbiome in Canine and Feline Practice. In “Purina Institute - Canine and Feline Clinical Nutrition Handbook, 2023 edition” Portal vein The portal vein functions to transport nutrient-rich blood from the gastrointestinal tract to the liver for processing, storage, or conversion to energy. Carbohydrates, fats, and proteins are all transported to the liver to participate in further metabolic pathways. Toxins and waste products from digestive organs are also transported to the liver and detoxified. Blood from the portal vein delivers antigens from the gut to the liver, where it interacts with the immune system and serves as the first line of defense from pathogens and toxins entering the body from the gastrointestinal system.7 When liver disease is present, portal hypertension can disrupt the intestinal barrier and cause vasodilation, elevated plasma volume, intestinal wall edema, and expansion of epithelial intercellular spaces leading to loss of tight junctions. This will increase intestinal permeability and cause “leaky gut,” which increases the risk of translocation of gut luminal contents across the gut barrier. Bacteria and their metabolites, including endotoxin (lipopolysaccharide), will activate the immune system triggering both pro-inflammatory and pro-fibrotic cascades. With a diseased liver, exaggerated or unregulated immune responses occur.8 This inflammation will cause increased oxidative stress and decreased antioxidant status leading to direct cellular damage and further degradation of the intestinal barrier. The gut microbiome The gut microbiome comprises bacteria, yeast, viruses, parasites, and archaea that live within and throughout the intestinal tract.9,10 Abnormal gut microbial balance, or dysbiosis, is thought to be a key stimulus of intestinal inflammation and intestinal barrier dysfunction.11 Dysbiosis is characterized by a loss in microbial diversity. Within the gut-liver axis, it may be impacted by impaired enterohepatic circulation, altered gut motility, or altered bile acid metabolism. With dysbiosis, the intestinal barrier becomes compromised, and bacterial translocation creates a cycle of increased inflammation, immune system activation, impaired bile acid metabolism, and reduced SCFA production. These contribute to worsening gut barrier function. Liver and biliary system Liver disease can include cholestasis or hepatic dysfunction, and decreases in bile acid metabolism are seen. This can alter intestinal motility and permeability, stimulating both hepatic and intestinal inflammation. Compounded with this is a reduction of bile acid-converting bacteria resulting from dysbiosis, which increases the level of primary hydrophobic toxic bile acids traveling through the intestinal tract and directly damaging intestinal and hepatic cell membranes. A decline in FXR signaling reduces intestinal barrier function, further decreasing primary bile acids. Nutrition and supplements What does this mean for the veterinary practitioner? For our patients with suspected disruption of the gut-liver axis, we need to consider interventions that support and restore normal gut balance at all components. For mildly affected patients, we can recommend a “multi-modal” treatment plan focused on nutrition, prebiotics, probiotics, postbiotics, and sometimes fecal microbial transplantation. More severely affected patients or those with persistent liver enzyme elevations will warrant further workup (bile acid testing, gastrointestinal panel (TLI, pLi, B12, folate), imaging (ultrasound), and liver biopsy). In some cases, we may need to consider antibiotics, anti-inflammatory or immune-suppressing medications, or even bile acid sequestrants. For many patients, however, using strategies with diet, supplements, and medications that address each area of the gut-liver axis can help improve our patient’s care. Nutrition is the foundation Diets recommended to manage acute gastroenteritis will be highly digestible, highly palatable, and contain a moderate protein level (not excessively high or low), moderate to lower fat, and include variable amounts of mixed fiber sources. A therapeutic commercial gastroenteric diet or a temporary home-prepared diet can be offered until appetite and stool quality improve. A therapeutic commercial diet or a complete and balanced home-prepared diet can be fed long term if the patient responds positively. For some patients, diet trials on different foods may be required to find the best nutrition plan. Examples of appropriate diets for managing dogs presenting with gastroenteritis are included in Table 1. Examples of highly digestible diets Home-prepared options (Note: for intermittent, supplemental use only; recipes are not balanced) 1 part cooked lean meat/protein + 2 parts cooked highly digestible, low-fiber carbohydrate ○ Lean meat/proteins (cooked): chicken breast, turkey breast, boiled pork tenderloin, boiled lean ground beef (<5 percent fat), whitefish (tilapia, cod), cottage cheese (1 percent or 2 percent) ○ Highly digestible, low-fiber carbohydrate (cooked): white rice, pasta noodles, rice noodles, tapioca pearls/starch, white bread Commercial veterinary therapeutic diet options (Note: fat and fiber content in products vary) ○ Rayne Nutrition TheraDiet Growth/Sensitive-GI (dry, chunky stew) ○ BLUE Natural Veterinary Diet GI Gastrointestinal Support or GI Gastrointestinal Support Low Fat (dry, canned) ○ Purina Pro Plan Veterinary Diet EN Gastroenteric, EN Gastroenteric Naturals, or EN Gastroenteric Low Fat Canine Formulas (dry, canned) ○ Royal Canin Veterinary Health Nutrition Gastrointestinal, Gastrointestinal Moderate Calorie, or Gastrointestinal Low Fat (dry, loaf) ○ Hill’s Prescription Diet i/d Dog Food or i/d Low Fat Dog Food or i/d Stress Dog Food (dry, stew, loaf) ○ JustFoodForDogs Vet Support Rx Balanced Remedy or Hepatic Support Low Fat (fresh food diet) ○ Nine and Line Therapeutic Diet Low Fat Digestive Care with Chicken or Kangaroo (fresh food diet) ○ Wynwood Dog Food Company Digestive Support: Turkey + Rice (fresh food diet) Prebiotics, probiotics, postbiotics, and fecal microbial transplantation Prebiotics and probiotics improve intestinal health primarily by interacting with the intestinal microbiota, increasing beneficial intestinal metabolites, enhancing mucosal barrier properties, and promoting cellular and humoral immunity.12 Prebiotics nourish the beneficial microbes and support microbiome balance and diversity and can be delivered by natural foods or supplements. Numerous fibers have been studied as inclusions in pet foods, and research is ongoing to understand how fibers can support various populations of gut microbes in positive ways. Trial and error may be required to find the best fiber type, level, or combination for an individual patient. Probiotics can interact with the existing patient microbiota and create competition for nutrients, antagonism, or secretion of bacteriocins and other antimicrobial factors inhibiting pathogens and supporting microbiota stability. Postbiotics have traditionally referred to the metabolites produced by probiotics; however, the definition now includes inactivated micro-organisms and their fragments, which can also provide positive benefits to the microbiome. Fecal microbial transplantation (FMT) is becoming an increasingly popular therapy for dogs with acute and chronic enteropathies. A few studies have noted improvements in clinical indices and a reduction in disease severity.10,13,14 Potential benefits of utilizing FMT could include restoration of secondary bile acids, increased proportion of SCFA-producing bacteria and SCFAs, and improvement or resolution of dysbiosis.15-17 These features can also help support the gut-liver axis. Antibiotic stewardship Prescribing antimicrobials for acute and chronic diarrheas has been common practice in veterinary medicine.18,19 However, empiric use in dogs and cats has little scientific support, . A recent study noted no improvement in outcomes of dogs receiving antimicrobials versus other supportive supplements.20 Use of antimicrobials has been shown to cause dysbiosis and a reduction in microbiota richness and composition.21,22 These changes may result in an unstable microbiome and relapses after treatment. In addition, exposure to antimicrobials has been identified as a risk factor for the development of inflammatory bowel disease.23,24 Other supplements For liver support, supplements can be added to provide antioxidant support, such as S-adenosylmethionine, silymarin/ silybin, and vitamin E. Curcumin, the active component in turmeric, has anti-inflammatory and anti-angiogenic properties and may improve circulation and reduce hepatic fibrosis.25 Immunomodulation with arginine and beta-glucans is often provided in supplements targeting gut support. L-glutamine may supply the preferred fuel source for enterocytes and support repair of the epithelial barrier; however, caution is warranted with significant liver dysfunction as supplementation may challenge ammonia tolerance.26 In more chronic cases, supplementing the omega-3 fatty acids to provide eicosapentaenoic acid (EPA) and docosahexaenoic acid may help reduce the production of inflammatory molecules. Additional supplementation of B vitamins (cobalamin, folate) may be considered for the provision of metabolic cofactors or correction of depletion caused by gut dysbiosis. Multi-modal therapy is key When making treatment plans for these patients, remember to consider all aspects of the gut-liver axis, as they have both gastrointestinal and hepatic involvement. Consider how you can support each component of this axis, how you can do so with nutrition and/or supplements, then reassess and adjust. For mildly affected patients, it may only be necessary to use nutritional changes, but the addition of select supplements may also hasten recovery. For those with more severe clinical signs or persistent liver enzyme elevations, it is warranted to pursue additional diagnostics as usual, and medications may be indicated along with nutritional and supplemental interventions. Laura B. Gaylord, DVM, DACVIM (Nutrition), is an independent consultant and the owner/founder of Whole Pet Provisions, PLLC, a nutrition consulting company established in 2016, which offers veterinary nutrition consulting to pet owners, veterinarians, the pet food industry, and pet supplement companies. Dr. Gaylord offers homemade diet recipe formulation and commercial diet consultations through her business for pet parents and their veterinary team.
