By Brennen McKenzie, MA, MSc, VMD, cVMA

One of the most exciting aspects of science is the discovery and development of new ideas and insight that lead to new ways of understanding and manipulating the natural world. Theories that seem preposterous at first can turn out to revolutionize medicine and other science-based fields.

Sometimes, these theories are greeted with skepticism, but eventually prove themselves. The idea that living organisms too small to see exist and can cause disease took centuries to catch on and be empirically validated, but it has led to many of the most dramatic successes in medicine, such as immunization, antibiotics, and doctors washing their hands between patients. The concept that gastric ulcers could be caused by a bacterial infection was greeted with great skepticism in the 1980s, but the first proponents of the idea were awarded the Nobel Prize for their work in 2005.¹

Unfortunately, it also happens that some new ideas in medicine are adopted with great enthusiasm and put into practice only to be proven dangerously mistaken. The treatment of mental illness by deliberate surgical damage to the frontal lobe (a.k.a. lobotomy) also overcame initial skepticism and led to a Nobel Prize. The procedure became common and was performed on tens of thousands of patients. It is now widely recognized as one of the greatest clinical and ethical failures in modern medicine.²

It is impossible to know in advance which ideas in science will lead to great benefits and which will prove mistaken and result in equally great harm. Knowing this, a rational strategy would be to approach promising new hypotheses cautiously. A careful, stepwise evaluation from in vitro research through high-quality clinical studies and systematic reviews should be undertaken before we enthusiastically employ new ideas or methods in clinical patients.

Adopting such a cautious approach, unfortunately, often does not suit the human temperament or the psychological and economic incentives to turn hypotheses into therapies and products. In this column, I have written about promising veterinary treatments that have been embraced well in advance of reliable evidence for their benefits. Topics range from cannabis^3,4 to cold laser⁵ to probiotics⁶ to electromagnetic field therapies,⁷ and there are many others. Whether each of these will prove to be the next antibiotic or the next lobotomy remains to be seen, but the regulatory, economic, and cultural features of veterinary medicine seem to consistently encourage early adoption rather than than adopting a cautious, evidence-based approach.

Understanding the microbiome

The latest example of a promising idea that is being turned into clinical tests and therapies well before this is justified by scientific evidence is the concept of the microbiome.^8,9 The recognition that microorganisms can be beneficial, even necessary for a healthy organism is a legitimately revolutionary and exciting idea. While it is an exaggeration to say we each carry around more microbial than human cells,^10,11 there is no doubt we harbor a complex ecosystem of bacteria, viruses, and fungi that influence our health.⁹

The very complexity of this system is one of the major reasons simplistic concepts of "good bacteria" and "bad bacteria" or of "balancing" the system with diet changes or supplements is unlikely to be fruitful. We have only begun to even identify the myriad organisms humans and our animal companions carry on and within us, and we have little idea what they are up to. Even crude taxonomic assessments of the microbiome reveal tremendous variation with age, geographic population, diet, and innumerable individual factors. We have a lot of work to do just to understand the composition and activity of our microbiomes before we can hope to engineer them to prevent or treat disease.

Fecal microbiome testing

Despite this, there is currently a plethora of products in human and veterinary medicine purporting to do just that. Various companies^12,13 offer fecal microbiome testing for pets to "provide insight into their gut health,¹³ "improve your pets' gut and overall health,"¹³ and "to provide you with real insights on their unique needs [so] you can have the confidence you're making the best choices to provide them a happy, healthy life."¹² These companies, not surprisingly, offer supplements, diets, and even fecal microbiome transplantation purportedly guided by the analysis they conduct.

In reality, there is no reliable research evidence showing these tests provide accurate, actionable information about health or that they can be used to effectively guide dietary or health-care choices. We lack not only clinical studies validating these specific marketing claims, but even the basic understanding of the determinants of an individual's microbial ecology and the relationship of this to health and disease.

A few descriptive studies have provided information about the types of bacteria (other microbes are not routinely identified or studied) present in healthy dogs and cats.¹⁴ Other studies have compared the microbiota of individuals on different diets (e.g. cooked or raw, hydrolyzed)^15-17 or evaluated the bacterial ecology of individuals with specific health conditions (e.g. inflammatory bowel disease [IBD] and acute or chronic diarrhea, obesity, etc.).^18-21 A canine dysbiosis index (DI) has been developed to characterize differences in fecal microbial organisms between healthy dogs and those with chronic enteropathies.^22,23 Though this may eventually be clinically useful, the authors caution, "future studies will need to evaluate the clinical utility of the DI as an assessment tool for microbiota dysbiosis associated with chronic enteropathies (CEs) and the usefulness of tracking microbiota over time and in response to treatment… microbiota is just one of several factors in the pathogenesis of the disease [and there is] overlap in the DI seen between healthy and diseased dogs."²²

These are important preliminary steps toward a comprehensive and useful understanding of the microbiome, but they do not validate the claims often made for commercial fecal microbiome testing or treatment recommendations based on these tests.

The available research into the human microbiome is much more extensive than what is available for veterinary species. Here is what reviews of that evidence conclude:

• "The functionality of these microbial communities cannot be easily reduced to a simple summation of potential beneficial and harmful activities… While the premise behind individual microbiome testing is to inform personalized diagnosis and therapies, the current body of knowledge is not sufficient to allow for meaningful diagnoses… irrespective of what a company puts in their marketing material."²⁴
• "We are at the very beginning of understanding what one's microbiome profile means for their susceptibility to or progression of disease… There are far more unknowns than knowns regarding the role of the microbiome and human health."²⁴
• "Mechanistic links of specific changes in gut microbiome structure with function or markers of human health are not yet established; it is not established if dysbiosis is a cause, consequence, or both of changes in human gut epithelial function and disease."²⁵

Caveat emptor

While enthusiasm for new discoveries and hypotheses is a necessary part of scientific progress, the premature application of these to clinical patients can be harmful. Treatments based on fecal microbiome testing cannot be reliable when testing methods have been neither validated nor standardized, and the research showing clinical utility hasn't yet been done. Rolling the dice on promising, though unproven, new ideas sometimes works out well. However, the odds are greater we will fail to help or even harm our patients if we take shortcuts in the scientific road to understanding.

References

1. Marshall B. A Brief History of the Discovery of Helicobacter pylori. In: Suzuki H, Warren R, Marshall B, eds. A Brief History of the Discovery of Helicobacter Pylori. Tokyo: Springer; 2016.
2. Gallen M. A brief reflection on the not-so-brief history of the lobotomy | British Columbia Medical Journal. BC Med J. 2017;59(6):302-304. https://www.bcmj.org/mds-be/brief-reflection-not-so-brief-history-lobotomy. Accessed February 17, 2020.
3. McKenzie BA. Cannabis-based remebdies: No reliable clinical research evidence. Vet Pract News. August 2017:38.
4. McKenzie B. A conclusion on cannabis? Vet Pract News. July 2019:26-27.
5. McKenzie BA. Uses, Evidence, and Safety of Laser Therapy. Vet Pract News. August 2018:32-33.
6. McKenzie BA. Probiotics and today's pets. Vet Pract News. January 2018:30-31.
7. McKenzie B. Do pulsed electromagnetic field devices offer any benefit? Vet Pract News. January 2020:30-31.
8. Allaband C, McDonald D, Vázquez-Baeza Y, et al. Microbiome 101: Studying, Analyzing, and Interpreting Gut Microbiome Data for Clinicians. Clin Gastroenterol Hepatol. 2019;17(2):218-230. doi:10.1016/j.cgh.2018.09.017
9. Knight R, Callewaert C, Marotz C, et al. The Microbiome and Human Biology. Annu Rev Genomics Hum Genet. 2017;18:65-86. doi:10.1146/annurev-genom-083115-022438
10. Sender R, Fuchs S, Milo R. Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell. 2016;164(3):337-340. doi:10.1016/j.cell.2016.01.013
11. Sender R, Fuchs S, Milo R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLOS Biol. 2016;14(8):e1002533. doi:10.1371/journal.pbio.1002533
12. NomNomNow Microbiome - Everybody poops. https://www.nomnomnow.com/site/products/microbiome. Published 2018. Accessed February 17, 2020.
13. Microbiome Products Restore Pet Gut Health | AnimalBiome. https://www.animalbiome.com/how-it-works. Published 2019. Accessed February 17, 2020.
14. Deng P, Swanson KS. Gut microbiota of humans, dogs and cats: current knowledge and future opportunities and challenges. Br J Nutr. 2015;113 Suppl:S6-17. doi:10.1017/S0007114514002943
15. JS S, E O, JB H, et al. Effects of a hydrolyzed protein diet and metronidazole on the fecal microbiome and metabolome in healthy dogs. J Vet Intern Med. 2016;30(4):1455.
16. Schmidt M, Unterer S, Suchodolski JS, et al. The fecal microbiome and metabolome differs between dogs fed Bones and Raw Food (BARF) diets and dogs fed commercial diets. Loor JJ, ed. PLoS One. 2018;13(8):e0201279. doi:10.1371/journal.pone.0201279
17. Sandri M, Dal Monego S, Conte G, Sgorlon S, Stefanon B. Raw meat based diet influences faecal microbiome and end products of fermentation in healthy dogs. BMC Vet Res. 2016;13(1):65. doi:10.1186/s12917-017-0981-z
18. Handl S, German AJ, Holden SL, et al. Faecal microbiota in lean and obese dogs. FEMS Microbiol Ecol. 2013;84(2):332-343. doi:10.1111/1574-6941.12067
19. Minamoto Y, Otoni CC, Steelman SM, et al. Alteration of the fecal microbiota and serum metabolite profiles in dogs with idiopathic inflammatory bowel disease. Gut Microbes. 2015;6(1):33-47. doi:10.1080/19490976.2014.997612
20. Kalenyak K, Isaiah A, Heilmann RM, Suchodolski JS, Burgener IA. Comparison of the intestinal mucosal microbiota in dogs diagnosed with idiopathic inflammatory bowel disease and dogs with food-responsive diarrhea before and after treatment. FEMS Microbiol Ecol. 2018;94(2). doi:10.1093/femsec/fix173
21. Suchodolski JS, Markel ME, Garcia-Mazcorro JF, et al. The fecal microbiome in dogs with acute diarrhea and idiopathic inflammatory bowel disease. PLoS One. 2012;7(12):e51907. doi:10.1371/journal.pone.0051907
22. AlShawaqfeh MK, Wajid B, Minamoto Y, et al. A dysbiosis index to assess microbial changes in fecal samples of dogs with chronic inflammatory enteropathy. FEMS Microbiol Ecol. 2017;93(11). doi:10.1093/femsec/fix136
23. Suchodolski JS. Diagnosis and interpretation of intestinal dysbiosis in dogs and cats. Vet J. 2016;215:30-37. doi:10.1016/J.TVJL.2016.04.011
24. Staley C, Kaiser T, Khoruts A. Clinician Guide to Microbiome Testing. Dig Dis Sci. 2018;63(12):3167-3177. doi:10.1007/s10620-018-5299-6
25. McBurney MI, Davis C, Fraser CM, et al. Establishing What Constitutes a Healthy Human Gut Microbiome: State of the Science, Regulatory Considerations, and Future Directions. J Nutr. 2019;149(11):1882-1895. doi:10.1093/jn/nxz154

Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists' opinions do not necessarily reflect those of Veterinary Practice News.