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Beyond Gut Instinct: New Technologies Help Revolutionize Thinking About Health

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Molecular biological tools developed in the last few decades have opened a window into the great world of intestinal microbiota, according to Frederic Gaschen, DVM, DACVIM, DECVIM-CA, professor at Louisiana State University (LSU).

Those tools allow the analysis of the 16S ribosomal RNA (rRNA), which is highly conserved between different species of bacteria, he explained.

“High throughput analysis of 16S rRNA has made it possible to document the presence of a vast number of bacterial rRNA sequences in the intestine. In addition, it has made it possible to predict the function of rRNA segments and, by extension, to understand the impact of the microbiome on multiple metabolic processes occurring in the gut. These new approaches have revolutionized our understanding about gut function and metabolism. The intestinal microbiome can now be considered like an essential organ for the health and wellbeing of animals and humans alike.

“As a profession, we are currently developing a better understanding of the central importance of the gut microbiome in the health of our canine and feline patients,” said Gaschen.

The Gut’s Complex Residents

The “gut,” or gastrointestinal tract, has been understood to be where the body takes in food, absorbs nutrients, and eliminates waste. But its function—or, more specifically, that of its residents—is turning out to be more complex.

The residents of the gut microbiome are microbiota: bacteria, viruses, fungi, and more. They live interdependently with their host and, research is discovering, play many roles in physical and chemical processes.

Studies in human and animal medicine are just starting to suggest some of that interplay, noting associations between changes in the diversity and composition of the microbiome and certain conditions or diseases.

“The gut microbiome has a great impact on the host metabolism because the microbiota produce myriad metabolites, and these metabolites may influence metabolic processes taking place in other organs,” said Gaschen. Those impacts may include metabolic diseases and even some neurological diseases.

“There’s probably good reason and good hypotheses that microbial factors may even contribute to anxiety and behavior disturbances, including dementia and cognitive disorders in dogs,” said Albert E. Jergens, DVM, PhD, DACVIM, of Iowa State University.

He noted one study by Nicholas Jeffery, BVSc, PhD, at Texas A&M University that found evidence that alterations in gut bacteria in dogs can modulate gut inflammation and are associated with inflammatory central nervous system disease, including meningoencephalitis of undefined origin.

“But the bottom line is,” Jergens admitted, “we don’t know.”

Besides what the gut microbiome affects, research is also looking at what affects the microbiome.

Genes, the environment, and diet have significant impact on the microbiome, said M. Katherine Tolbert, DVM, PhD, DACVIM, of Texas A&M University. Other factors also can affect it, such as:

  • external stressors, especially those that occur early in life;
  • exposure to xenobiotics, such as antibiotics or immunosuppressants;
  • the presence of disease;
  • the response of the body to disease
    or infection; and
  • treatments of those diseases and whether they occurred early or late in life.

The Chicken or the Egg?

But is it an unhealthy gut that precipitates a disease or disorder, or is it the start of a disease or disorder that alters the gut?

“Is it the chicken or the egg? It seems like there is evidence for things to go both ways,” said Gaschen. “In health, the gut microbiome contributes to the protection of the intestinal barrier and prevents activation of the immune system and inflammation. These beneficial effects may be seriously compromised if severe changes in the composition of the intestinal microbiota occur.

“At the same time, intestinal inflammation may also cause changes in the gut microbiome through an abnormal intestinal mucosal microenvironment. To date, it remains unknown if microbiome changes are primarily responsible for the diseases they have been associated with.”

Jergens offered the example of wheaten terriers, German shepherd dogs, and boxers—canine breeds that are genetically predisposed toward gastrointestinal problems.

“It’s obvious that microbial imbalances accompany the gastrointestinal diseases in these animals. But are the imbalances the cause or a consequence of chronic intestinal inflammation?” he asked.

“We believe that a healthy gut has diverse microbiota,” said Tolbert. “In research with dogs and cats with intestinal diseases, one consistent theme is that biodiversity of the microbiota is decreased. So, in a way, having a wide diversity of microbiota is one key to gut health, but it’s really hard to pinpoint the exact role of altered microbiota in the induction of disease. Usually all we can say is there appears to be an association.”

Tolbert gave the example of a study that might find that obese dogs have predominantly XYZ microbiota. When fed a diet low in fat, they lose weight and their microbiome changes from XYZ to predominantly ABC microbiota.

“Some might conclude that the change in microbiota led to their ability to lose weight—that is, a causative effect. Others might say that their microbiota changed as a result of the new diet, and the microbiota [are] merely associated with the diet change and weight loss,” she explained.

“We are really at the infancy of this research,” said Tolbert. “I think practitioners largely recognize the importance of gut health in their patients. The more we think about how we as practitioners might inadvertently induce dysbiosis through the inappropriate use of drugs, such as antibiotic therapy or long-term proton pump therapy, the better off our patients will be.”

Manipulation Options

While researchers seek answers, options available to influence the gut microbiome include prebiotics, probiotics, and fecal microbiota transplantation (FMT).

Prebiotics

First coined about 20 years ago, the term “prebiotic” has been redefined recently because of the developments that suggest more complex interactions than previously thought.

According to the International Scientific Association for Probiotics and Prebiotics (ISAPP, isappscience.org), a prebiotic is a substrate that is selectively utilized by host microorganisms conferring a health benefit. According to the ISAPP, the definition “expands the concept of prebiotics to possibly include noncarbohydrate substances, applications to body sites other than the gastrointestinal tract, and diverse categories other than food.”

While Jergens noted that prebiotics have not been extensively evaluated for dogs and cats, Gaschen suggested that they could have benefits since they provide the host with important metabolites, such as short-chain fatty acids.

Probiotics

Probiotics are beneficial live microorganisms intended to convey gastrointestinal health benefits when consumed. But as ubiquitous as probiotics have become, there is little evidence-based veterinary literature about their use, said Jergens.

“Both single-strain and multistrain probiotics in dogs with chronic enteropathies have been evaluated, and in general, the results have been equivocal. In other studies, single-strain probiotics have been shown to be beneficial in mitigating acute diarrhea,” he noted.

“However, with chronic enteropathies in dogs, probiotics have not necessarily been shown to be beneficial as compared to standard therapies for treating chronic gut inflammation. That said, probiotics have been shown to significantly enhance type junction protein expression in these dogs, which may translate into improved intestinal barrier function.”

Jergens said while there are little data about the use of probiotics in cats, he was aware of one Colorado State University study using a single-strain supplement for diarrhea in shelter cats that found a positive effect versus a placebo.

“Veterinarians in general would observe ‘do no harm,’ but the bottom line is that there are good indications and not-so-good indications for probiotics,” said Jergens, noting, too, that neither prebiotics nor probiotics are regulated by the US Food and Drug Administration.

Adverse effects associated with probiotics in cats and dogs appear to be sparse, he explained. The main concerns include a leaky intestinal tract (where the organisms could translocate to the bloodstream) and profound immunosuppression.

But whether it’s prebiotics or probiotics, there may not be a one-size-fits-all situation, suggested Tolbert.

“Just because one prebiotic or probiotic works for one disease state or one individual does not mean that these products will be globally effective for all individuals,” she said. “And just because one choice for prebiotics or probiotics failed does not mean that an alternative choice or a higher dose would not work.”

Fecal Microbiota Transplantation

Fecal microbiota transplantation or “repopulation,” as Gaschen called it, is the latest up-and-comer to be considered for influencing the microbiome. It is a technique during which feces from a healthy donor are transplanted to a sick patient, helping reestablish a normal microbiome for the recipient.

The technique has gained popularity in human medicine as a successful treatment for people with Clostridium difficile colitis, but, said Gaschen, Clostridium difficile colitis does not occur in cats and dogs.

Despite many anecdotal reports, there is still no scientific evidence regarding indications for the use of FMT or the best protocol for performing it, said Gaschen, although clinically useful data will hopefully be available soon.

“FMT is not a priori exempt of potential side effects,” he said. “There are risks of transmitting diseases from the donor to the recipient that can be prevented through screening for intestinal parasites and/or broad-spectrum anthelmintics. The various scientific abstracts presented at congresses mostly report use of FMT in refractory cases of inflammatory bowel disease in dogs and cats, with success in some cases [and] failure in others. This has also been our experience at LSU.”

Peer-reviewed literature supporting the use of FMT in the treatment of acute or chronic diarrhea is sparse, said Jergens, partly because randomized controlled clinical trials have yet to be performed.

“The specifics of FMT—donor selection, quantity of stool to deliver, dilution techniques—and how FMT is administered to the recipient—as a capsule, as an enema, through endoscopic procedures—have not been fully addressed and are quite variable from one instance to the next,” he explained.

While prebiotics, probiotics, and FMT all represent attractive targets for therapy in animals with gastrointestinal disease, said Tolbert, they are unlikely to fix the underlying problem when used as a sole therapy. But, she said, they are likely beneficial as adjunctive therapies in certain disease states.

Clinical Trials Needed

As researchers more thoroughly explore the microbiome, Jergens said, he expects to see well-designed clinical trials validating or refuting certain interventions, particularly FTM; randomized control trials versus standard therapies; exploratory studies of the role of microbiota imbalance; and the gut-brain-microbiota axis as it relates to neurologic disorders in dogs and cats.

He encouraged veterinarians to inform their clients about ongoing clinical trials, noting that it’s difficult to get clients to enroll pets because “there is a perception that their animals are being experimented on, although that is not the case.”

Veterinarians can find clinical trials by searching the websites of individual colleges of veterinary medicine or checking the American Veterinary Medical Association’s Animal Health Studies Database.

Maureen Blaney Flietner is an award-winning writer living in Wisconsin.

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Gut Instincts in
Daily Practice

“It’s always a changing scene in what is available to treat different species for gastrointestinal health,” said Sally MacLane, DVM, of Appalachian Animal Hospital in Piney Flats, Tennessee.

She said the new studies have changed the way she considers gut health. For example, she now prescribes different dosages of H2 inhibitors for dogs and much less often for cats and incorporates prebiotics into diets to help with issues such as constipation.

For cats with chronic constipation who often develop megacolon, she said that instead of using enemas, stool softeners, medications, or even surgery, she has managed many with a diet containing prebiotics and probiotics.

While MacLane said she has not yet used fecal microbiota transplantation, she is open to trying it as it becomes more available commercially.

At AAHA-accredited Tiara Rado Animal Hospital in Grand Junction, Colorado, Troy Everson, DVM, CVA, CVCT, said probiotic therapy is regularly recommended for patients.

“Although we primarily think about probiotic therapy for patients with gastrointestinal disease, there is mounting evidence that individuals that have been on recurring or prolonged antibiotic therapy would also benefit. We also use probiotics for dysbiosis, chronic inflammatory intestinal issues, and opportunistic parasitic infections.”

Everson said he encourages food therapy for gastrointestinal disease, especially those prescription formulas fortified with fructooligosaccharides, to help nurture intestinal flora.

“I feel that incorporating these supplements has helped my patients improve faster or reduced the use of medications for the more chronic conditions,” he explained.

He admitted that probiotics are frequently part of multimodal therapy, and it can be difficult to remain objective about their benefits. But, he said, he believes that as a monotherapy in patients with recurring dysbiosis, it has helped many.

“I feel we still have a lot to learn about the impact that imbalances to the intestinal flora can have on an individual’s health—beyond the gut,” said Everson.

Fast Facts

  • Using donor poop to provide health benefits to another is nothing new. According to the US Department of Veterans Affairs, more than 1,700 years ago, a Chinese physician wrote down the recipe for yellow soup, a treatment for diarrhea. The soup, made using dried or fermented stool from a healthy person, was eaten by the sick patient, who apparently was then cured. In World War II, German soldiers sick with bacterial dysentery were returned to health when Bedouin camel herders shared their traditional treatment for diarrhea: eating the dung of healthy camels.
  • On January 20, 2018, the American Gastroenterological Association (AGA) Fecal Microbiota Transplantation National Registry enrolled its first of 4,000 human patients it hopes to track for 10 years after their FMT procedure. Administered by the AGA Center for Gut Microbiome Research and Education, the study will obtain data about the procedure’s short- and long-term effects for modern purposes.
  • The American Gut Project (americangut.org) is the world’s largest crowd-sourced microbiome research project. Part of the Knight Lab out of the University of California, San Diego School of Medicine, the project was started to provide a means to collect a large set of data surrounding the microbiome in and on the human body.
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