Tuesday, October 6, 2015

Lyme and the microbiome

The effect of long-term antibiotics used for Lyme disease is an 800 pound gorilla in the living room that my blogs have left unaddressed. The microbiome is a virtual organ comprised of thousands of species of microbes, primarily bacteria with a few yeast, archaea and protozoans thrown into the mix. The microbiome interacts closely with the mucosa of the gut creating a virtual organ system. The gut-microbiome influences endocrine functions, include the HPA axis (hypothalamic pituitary) dysfunction of which leads to adrenal fatigue amongst many other issues. It is now known that the gut-microbiome plays a major role in regulating innate and acquired immune responses. The microbiome plays a key role in regulation of the autonomic nervous system. Elaborate microbiome connection to the overall immune system and the neuro-immune system are of critical importance. We know there is a gut-brain connection which plays a critical role in overall health. The human microbiome is an area of intensive, multidisciplinary research. Alterations in gut function have been closely connected with mood disorders including depression – and anxiety.  The news regarding antibiotics is not all bad. For example, minocycline has some antidepressant effects. One hypothesis relates to inhibition of glial cell activation and neuroprotection. An alternate hypothesis is that changes in the microbiome may be the predominant mode of action. It has been suggested that alterations in gut flora contribute to cognitive dysfunction. An altered microbiome may relate to small intestinal overgrowth syndrome, various forms of dysbiosis and leaky gut syndrome. The antibiotic rifaximin has been used to favorably alter the composition of the microbiome and has been demonstrated to have clinical efficacy. Doxycycline has long been known to be associated with a low risk of C. diff compared to other antibiotics. A study in a major hospital showed that the addition of doxycycline to Rocephin for the treatment of pneumonia significantly decrease rates of C. diff. The choice of antibiotics and the method of administration will lead to variable effects on the microbiome. Antibiotic use has been associated with increased expression of resistance genes amongst the gut flora. Interestingly, these genes have been around for thousands of years, long before the antibiotic era. Many gut bacteria produce natural antibiotic-like substances. We are told to worry that overuse of antibiotics leads to the creation of superbugs. This can only happen when pathogenic bacteria are exposed to antibiotics. The antibiotics we take primarily impact the good guy:  the creation of superbugs is not as common as one is led to believe. Dysfunction of the gut flora is associated with pro--inflammatory cytokines, a driving force in many disease states. In addition, the dysregulated microbiome leads to release of gram negative derived LPS, lipopolysaccharides, into the systemic blood stream, the likely source of toxins that many associate with Lyme disease. Lyme spirochetes lack these toxins altogether. Lyme leads to overall immune dysregulation which may indirectly drive the release of gut cytokines and toxins. I have long wondered why patients may relapse only days after antibiotics have been discontinued; perhaps the explanation is tied to gut cytokines and endotoxins rather than Lyme (in the short term). Lyme bacteria just don’t reproduce that fast. This may also explain the benefits of weaning off antibiotics rather than abruptly discontinuing them.

I have found research only on the effect of short courses of antibiotics on gut flora. Even after a short course of antibiotics shifts in the microbiome can lasts for months or up to a year. We can only imagine what the effects of long term antibiotics might be.  

Mast cell activation, my recent area of focus, has been shown to play an important role in gut inflammation. A mast cell stabilizer, disodium cromoglycate reversed visceral colonic hypersensitivity in an irritable syndrome model (in rats).

The gut produces tryptophan, a key precursor of serotonin, a key signally molecule in the gut brain axis. This process is dependent on the microbiome. Most of our serotonin is in the GI tract, not the brain.

The microbiome has been shown to directly detoxify drugs such as digitalis.

Areas of interest in microbiome dysfunction research include fecal transplantation and purposeful infection with parasites including whip worm and hook worm. Strange, but true.

It should be clear that probiotics are key and should always be incorporated alongside long term antibiotics. For a long time I and others have recommended Florastor or other brands of Sacchromyces boulardii (the good yeast). There is one study that suggested that Florastor may have reduce the incidence of C. diff in antibiotic treated patients. While C. diff is a horrific game changer there is an increasing spectrum of other considerations. A rationale for this agent is that it can be taken with the antibiotics and not be destroyed on the way down. But S. boulardii constitutes a trivial portion of the microbiome. Other studies have suggested that Bifidobacterium and acidophilus are very beneficial. Many other bacteria species and strains, too numerous to list, also have beneficial effects. Many of these beneficial bacteria survive the journey to the gut despite antibiotics. Perhaps enteric coated preparations have a better change.  How many bacteria is enough: five billion, fifty billion one hundred billion? The answer is the highest number you can find/afford. Billions are a drop in the bucket: there are an estimated 100 trillion bacteria living in our guts.

Diet likely plays an important role. Many patients worry about the wrong diet feeding their Lyme. This does not happen. But we want our diet to feed our microbiome. Low carb diets are not the way to go. The complex carbohydrates or sugars, like inulin, which our bodies do not use are adsorb are microbiome food. Prebiotics are supplements made of these polysaccharides and are frequently taken with or in addition to probiotics. Eating the right diet will have a greater impact.  

So we can’t ignore the 800 pound gorilla. When we takes lots of antibiotics the microbiomes shifts in ways we do not understand and many of our friendly residents become highly resistant to antibiotics. The microbiome and gut generally continue to function well.

Lyme is a devastating disease. As clinicians we always have to weigh the risk/benefit analysis of any treatment we propose. We need to appreciate the emerging importance of gut-microbiome organ system. As we know, Lyme is a multisystem disease and can negatively impact virtually every organ system in the body. We have previously shown that Lyme can live in the gut, likely disturbing the microbiome without any help from us.
As we learn more about treating Lyme, in the future we will likely consider positive and negative impacts on the microbiome with a greater awareness of its impact on: mood, the neuro-endocrine axis, the HPA axis, the immune system, antibody production, inflammation and pain, detoxification and toxin production and many more things not listed here and many others yet to be discovered


david fielding said...

Dr. Jaller,

In referring another to your blog for an 'alternative' perspective on chronic Lyme, I just read this post on gut health and microbiome. Over the last year or so, I've read many entries in your blog. Your experience and knowledge is very well presented... as valuable for the online community as it is for the patients you serve.

The apparent evolution of your thoughts with regards to the long-term antibiotics protocols is refreshing. For me, it was seemingly inconguous to holistic thinking, but not enough for me to discount the value of your experience and treatment methods. I'm anxious to read more as your protocols evolve to include methodologies in diet, gut health, supplementation, etc.

I'd encourage you also to look at integrating SNPs/genetics as part of your protocols. You've probably heard of Dr. Amy Yasko, a leader in the field of methylation and nutrigenomics. Her family of websites are linked from knowyourgenetics.com (a free service for interpreting 23andme genetic data). Specifically, the free e-book 'Genetic Bypass' was the one that brought it all together for me. Her forum ch3nutrigenomics.com (moderated by her team) is one of the deepest forums I've seen on any topic.

Thanks again for your blog.

David Fielding
Bethesda, MD

Caroline Green said...

Thanks for your sharing! This post is quite good!

lymie said...

I was under the impression the low carb diet was meant to prevent the development of yeast overgrowth rather than feeding the lyme. Falling off the low carb wagon certainly has that result.

Confused about the longterm effect of antibiotics on gut flora. I too understood it was longterm, but recently heard about a study that showed the gut flora recovered in a shorter time than expected. That, of course, presumes that the antibiotics stopped, which is not possible for some chronic lyme cases.

Unknown said...

Very well written entry on such a critical topic. I would suggest that with regards to probiotic replacement, one focuses more on number of strains as apposed to numbers of singular strains. A simple way to address this is to make your own Kambucha tea. It contains multiple strains of bacteria, yeasts and vitamins which restore the microbial balance quite cheaply.