Introduction

Small intestinal dysbiosis is an alteration of the small intestinal microbiota in either composition or numbers. There are several different terms that describe similar clinical conditions: antibiotic-responsive diarrhea, tylosin-responsive diarrhea, small intestinal bacterial overgrowth (SIBO), and intestinal dysbiosis. At the current time it is unclear whether all 4 terms describe essentially the same condition or if one of these terms would be more appropriate than the other three is most or even all situations.

Antibiotic-responsive diarrhea is a case of diarrhea that responds to antibiotic therapy. Similarly, tylosin-responsive diarrhea describes a case of diarrhea responsive to tylosin treatment. This term was coined by a Finnish group after they had done several studies in dogs with chronic diarrhea. The dogs showed poor response to several different antibiotics, but all responded to tylosin. The reasons for these findings are unclear. One explanation is that tylosin has an optimal antibiotic spectrum against the intestinal bacteria that are responsible for the diarrhea. Another explanation is that tylosin has other properties in addition to its antibiotic properties. Small intestinal bacterial overgrowth refers to an expansion of unfavorable bacteria in the small intestinal tract. Finally, small intestinal dysbiosis refers to a qualitative and/or quantitative derangement of the small intestinal microbiota that leads to clinical signs of small bowel diarrhea. Again, it is unclear whether these conditions can really be separated, and for a lack of better understanding in the following text, the term small intestinal dysbiosis is used as an overarching term for all four conditions.

The intestinal microbiota is made up of a wide variety of microorganisms, including bacteria, viruses, and fungal organisms. Most attention has been given to the intestinal bacterial ecosystem, which is made up of a complex mixture of a wide variety of bacterial species. Traditional studies describing the intestinal bacterial ecosystem have employed traditional culture techniques. However, the true diversity of the intestinal bacterial ecosystem became evident only recently with the advent of new micromolecular techniques. These newer techniques have revealed a far greater diversity of the bacterial ecosystem in the intestinal tract than previously assumed and have also shown that fungal organisms, such as Pichia spp., Cryptococcus spp., Candida spp., and Trichosporon spp. are far more frequently present in the intestinal tract of healthy dogs than previously believed. Using these new methodologies, it has now been estimated that the intestinal bacterial ecosystem is made up of more than 1,000 different bacterial species.

Physiologic Importance of the Intestinal Bacterial Ecosystem

The intestinal bacterial ecosystem is initially established during birth and continues to develop during suckling. The impact of the intestinal microbiota and the bacterial ecosystem has been well established by studies in germ-free rodents. These rodents show a wide variety of morphological and physiological alterations that overall equate to a state of compromised intestinal function and immunity. In healthy animals, the physiologic microbiota, and most prominently the bacterial ecosystem, has several important functions. Firstly, it protects the host against pathogenic bacteria by competing for oxygen, luminal substrates, and space, but also by synthesizing and releasing substances that inhibit bacterial growth, so-called bacteriocins. Intestinal bacteria also produce short-chain fatty acids by metabolizing dietary components that are often non-digestible for the host. In turn, these short-chain fatty acids serve as an important energy source for the intestinal mucosa, leading to epithelial cell proliferation and mucosal growth. Members of the intestinal bacterial ecosystem also synthesize a variety of vitamins, including riboflavin (vitamin B2), biotin (vitamin B7), folic acid (vitamin B9), cobalamin (vitamin B12), and vitamin K. It is important to note, however, that physiologically, the synthesis of some of these vitamins, for example cobalamin, is not of significance to the host as the synthesis may occur distally to where the vitamin can be absorbed. Finally, intestinal bacteria also play a crucial role in the development of the intestinal immune system. They stimulate said intestinal immune system, which plays a crucial role in overall host defense throughout all stages of life.

It has long been known that some dogs and cats with acute or chronic diarrhea respond to antibiotic therapy. While some of these patients may be infected with a primary gastrointestinal pathogen, such as Salmonella spp. or some pathogenic Campylobacter strains, a specific causative organism can't be identified in most of these patients. A response to antibiotics would suggest that these patients are affected by an alteration of the intestinal bacterial ecosystem that leads to diarrhea and that modification of the intestinal bacterial ecosystem can lead to improvement of clinical signs.

Etiology

Small intestinal dysbiosis is caused by an abnormal proliferation of bacteria and/or the change in bacterial species present in the small intestinal lumen. However, dysbiosis should not be considered a primary disorder in most if not all patients with this disorder. There are several protective mechanisms that prevent a patient from dysbiosis. Gastric acid, intestinal motility and antibacterial activity of pancreatic juice all limit the bacterial numbers in the small intestine. Gastric acid directly destroys bacteria that are ingested with the diet and also decreases the pH of the ingesta, leading to a lower pH in the proximal small intestine. However, the lack of gastric acid secretion alone is not sufficient for dysbiosis to develop. Propulsive movements of the small intestine are probably the most important protective factor since there is no physical barrier between the large intestine and the small intestine that would prevent retrograde cultivation of the small intestine by the large intestinal microbiota. The antibacterial properties of pancreatic juice are not well understood. Pancreatic digestive enzymes may be partly responsible for the antibacterial action of pancreatic juice. Any disease process that affects one or more of the protective mechanisms discussed can ultimately lead to small intestinal dysbiosis.

Clinical Findings

Small intestinal dysbiosis in dogs and cats leads to chronic small bowel diarrhea that is often intermittent. Weight loss can be present in some cases. Other clinical signs may be due to the primary underlying disease process, such as partial obstruction, exocrine pancreatic insufficiency, or others.

Diagnosis

Part of the controversy about small intestinal dysbiosis is due to the fact that this disorder is difficult to diagnose. Traditionally, the gold standard for assessment of the small intestinal bacterial ecosystem is the culture of duodenal juice. However, not only is the collection of duodenal juice challenging, but also the culture of duodenal juice once collected is difficult, time-consuming, and expensive and requires a laboratory that has experience in this area. Also, bacterial culture methods grossly underestimate the bacterial diversity of the small intestinal bacterial ecosystem. Therefore, culture of duodenal juice is not suggested. It remains to be seen whether molecular-based methods allow for a better assessment of the small intestinal microbiota.

Noninvasive Diagnostic Tests

 Serum folate concentration - As pointed out previously folic acid is synthesized by enteric bacteria and is available for absorption. In dogs with small intestinal dysbiosis for a long period of time, serum folate concentration increases. While an increased serum folate concentration is fairly specific for small intestinal dysbiosis, it is not very sensitive. In one study, only 50% of all dogs with small intestinal dysbiosis had increased serum folate concentrations.

 Serum cobalamin concentration - Many species of bacteria utilize cobalamin and compete with the body for dietary supplies. Unlike an increased serum folate concentration, a decreased serum cobalamin concentration is not specific for small intestinal dysbiosis. Any severe small intestinal disease involving the ileum can lead to cobalamin deficiency. Also, a lack of intrinsic factor and digestive proteases in dogs with exocrine pancreatic insufficiency can cause cobalamin deficiency. A decreased serum cobalamin concentration is rather insensitive for small intestinal dysbiosis and in one study, only 25% of dogs with small intestinal dysbiosis had decreased serum cobalamin concentration. A combination of a decreased serum cobalamin and an increased serum folate concentration is highly specific for small intestinal dysbiosis but rather insensitive. These two parameters are, to date, the most practical diagnostic tools for the diagnosis of small intestinal dysbiosis.

Other noninvasive diagnostic tests, previously evaluated for the diagnosis of small intestinal dysbiosis, such as unconjugated bile acid concentration in serum, breath hydrogen concentration, ¹³C-xylose, and ¹³C-bile acid tests have not shown to be consistently useful for the diagnosis of this condition.

Treatment

The therapeutic goal in dogs with small intestinal dysbiosis is the identification and treatment of the inciting cause. For example, serum TLI concentration should be evaluated. Dogs with EPI and secondary small intestinal dysbiosis usually do not require specific therapy for small intestinal dysbiosis once they are treated with enzyme supplementation. If a primary cause cannot be identified, one of several therapeutic strategies or a combination thereof should be employed.

Prebiotics

Prebiotics are substances that preferentially support the resident bacterial ecosystem of the intestine. Basically, prebiotics are nondigestible food components (dietary fiber) that are being fermented by intestinal bacteria. This can lead to normalization of the intestinal microbiota. In a recent study, the use of fructooligosaccharides (FOS) in the diet showed a lasting advantageous effect. While this has not been evaluated as of yet, other prebiotics, such as inulin or beet-pulp, may also prove to be beneficial.

In one study, dogs with dysbiosis diagnosed based on clinical signs and serum folate and cobalamin concentrations were divided into two groups. One group was treated with an antibiotic for 6 weeks and the other group was switched to a diet containing FOS. Both groups of dogs responded equally with normalization of fecal quality among improvement of other parameters, but many of the dogs treated with the antibiotic showed a relapse after the antibiotic therapy was stopped, while the beneficial effect of the diet was maintained.

Probiotics

Probiotics have garnered a lot of interest in both human and veterinary medicine. Initially, probiotics were mostly embraced by holistic physicians and veterinarians and the expectations for probiotics were dramatic, with probiotics being hypothesized to be of benefit in disorders ranging from stress to gastrointestinal health, weight management, and even the prevention of cancer. These unrealistic expectations have been replaced with well-defined requirements for probiotics and controlled studies of their beneficial effects.

The three key requirements for a probiotic for use in dogs or cats are: 1) the probiotic must be safe; 2) the probiotic must be stable; and 3) the probiotic must be efficacious. In an older study, 8 veterinary and 5 human probiotics were evaluated, and only 2 of the 13 products contained the strains and concentrations of those strains were indicated on the label. Several of the products contained bacterial species that could potentially act as enteropathogens. One may suspect that these issues were related to start-up issues when probiotics first entered the marketplace. However, a recent study showed that of 22 veterinary products evaluated only 2 contained in it what the label stated. Part of the problem may be that many of the products offered are manufactured by small companies that may not have the technological capabilities to manufacture a stable product. The probiotic also must be stable throughout transport and storage until the product is being administered by the pet-owner. Finally, a probiotic must be efficacious. In order to be efficacious, the bacteria must reach the intestinal lumen. This requires that the bacterial species being used in the formulation are both acid resistant and bile acid resistant. Also, the bacterial species of the probiotic preparation should adhere to the intestinal mucosa to prolong the time of interaction. Finally, the presence of the probiotic species must have beneficial effects for the host. Several studies have been conducted in dogs that show that certain probiotics carry health benefits in dogs with gastrointestinal disorders. Scenarios for which there is good evidence of a beneficial effect of probiotics are the prevention of stress-related diarrhea, treatment of stress-related diarrhea, and acute nonspecific diarrhea. The effects of probiotics in dogs and cats with idiopathic inflammatory disease or dysbiosis have not been sufficiently studied, though a beneficial effect in patients with small intestinal dysbiosis would seem logical.

Synbiotics

Synbiotics are combinations of prebiotics and probiotics. There are three different approaches to synbiotic use. Some boutique pet foods are fortified with a prebiotic and are sprayed with a probiotic. Even though most of these pet foods use bacterial spores that show much greater resilience to environmental factors, this mode is likely unrealistic, as the bacterial load is small and the bacterial spores may not be stable enough to reach the patient. Another approach is to use a pet food fortified with a prebiotic and also use a probiotic nutraceutical concurrently. This is likely the most realistic synbiotic approach. The use of a nutraceutical that contains both the pre- and the probiotic may be realistic in cats and small dogs, but in large dogs the amount of prebiotic in the supplement is likely not sufficient to show any prebiotic effect.

Fecal Transplantation

In humans with chronic intestinal disease, there has been some experience with fecal transplantation. While in patients with chronic colitis application of the transplant by enema may be efficacious, in patients with small intestinal dysbiosis the transplant would need to be used through some oral route. Experience in dogs and cats with small intestinal dysbiosis is limited, and great care would need to be taken to transplant enteropathogens, especially in donors that are subclinically infected.

Antibiotics

Oxytetracycline used to be the therapy of choice for small intestinal dysbiosis, but oxytetracycline for oral use has become largely unavailable. Tylosin (25 mg/kg q12h for 6 weeks) is the new antibiotic agent of choice. Tylosin is extremely safe and is not used in humans for the most part - thus, creating resistant bacterial strains is not a big concern. In one study, a group of dogs was treated with 400 mg/kg daily for a period of 2 years and none of them developed any side-effects. The superb efficacy of tylosin has been well-demonstrated in studies from Finland. Some of those newer studies would suggest that smaller dosages may also be beneficial, but these findings will need to be verified. Other antibiotics, such as metronidazole, can also be used. Some patients respond to therapy rapidly and do not have a recurrence. However, other patients do not respond to antibiotic therapy alone. If there is no marked improvement after 2 weeks of appropriate antibiotic therapy, further work-up is necessary. Some patients may respond to therapy with a complete resolution of clinical signs but may have a recurrence of clinical signs as soon as antibiotic therapy is discontinued. These patients require further diagnostic work-up. In some of these patients, a specific underlying cause of the dysbiosis can be identified and treated accordingly. However, in some patients no specific cause can be identified; and prolonged, maybe even life-long, antimicrobial therapy is required.

Ancillary Therapy

If serum cobalamin concentration is decreased below the lower limit of the reference range or if cobalamin is in the very low end of the reference range, cobalamin should be supplemented.