Summary: I’ve wondered literally for years now, ever since I first learned of the microbiome, do microbiomes on drugs look healthy? I call it the “drugged microbiome,” and I (foolishly perhaps) expect the drugged microbiome to look like a “healthy microbiome” since this is where 80 to 85% of our immune status resides. We already know that ~60 drugs are known to be affected by the microbiome though researchers suspect the real number is much higher. My question turns this on it’s head and asks,
“What’s your drug doing to your microbiome?”
Though this question applies to any and all drugs, this post looks at immunosuppressants/biologics and proton pump inhibitor (PPIs) mainly since there is a lot of published insights into what the drugged physiology and microbiome looks like as well as user health status. Also, a lot of folks use these drugs or they are a top in sales. From April 2014 through March 2015, PPIs esomeprazole (Nexium, AstraZeneca) ranked third in number of prescriptions written having ~18.2 million and biologics Humira (adalimumab) was the number 1 top sales drug at $8.2 billion with Remicade (infliximab) ranked tenth in sales at $4.6 billion.
You can investigate your particular medication microbiome impact by goggling your disease’s name, microbiome, and diet. Pay attention to PubMed and journal results. Tease apart the study cohort to learn the reference microbiome. If the microbiome diversity is increased using diet, the drug likely is not nudging the microbiome to health. Use the same logic as the meds examined herein.
Spoiler alert: It seems immunosuppressant and biologic microbiomes are not ‘healthy looking’ as altering such with diet increases it’s diversity, nudging it towards more healthy, and can even result in reduction and/or elimination of the meds. The PPI microbiome is not healthy, and it is wrought with devastating health risks. Many use PPIs without indication based evidence including nearly half of nursing home patients.
Clearly, modern medicine is not tracking modern science
I don’t want pharma hate mail but it’s time all drug users question and know what the drug is doing to their microbiome. If the host’s microbiome remains in dysbiosis, that is strong evidence (putting on my attorney and mechanical engineer hat) that the drug is acting on only symptom suppression and not restoring microbiome health and immune status. Immunity is still compromised opening doors for disease relapse or pulling the trigger for other chronic disease(s). Sooner or later, that inflammation is going to get you.
Ironically, symptom resolution instead of microbiome health may be what Pharma wants
Pharma now appreciates that their product feeds the microbiome playing a huge role in drug metabolism, activation and reactivation. This paper notes that specific enzyme targets in the microbiota can be potently and selectively disrupted to achieve clinical outcomes… components of the microbiome should be considered “druggable targets.”
This paper, The Gastrointestinal Microbiota as a Site for the Biotransformation of Drugs, clarifies with a cautionary note:
The microbiota secrete a diverse array of enzymes (primarily for carbohydrate and protein fermentation) giving them substantial metabolic potential which can have major implications for drug stability. At least thirty drugs which are, or have been, available commercially, were subsequently shown to be substrates for these bacterial enzymes, and with increasing numbers of new and existing drugs having the potential for contact with the distal gut (through modified release systems or poor solubility/permeability), many more are expected to be discovered. The major concern with bacterial drug degradation is the behaviour of the metabolite; is it more or less active than the parent compound, or has toxicity resulted? For example, there were eighteen deaths in 1993 due to a drug interaction in which a toxic drug metabolite was produced by bacterial fermentation.
Thinking the big picture
You’d think we’d have a decent handle on what the drugged microbiome looks like given how cheap 16S rRNA sequencing now is. What is most concerning is that this affects a lot of people since there’s a lot of drug users. The CDC published the percent of persons using prescription drugs in the past 30 days (2009-2012), read the full report here, as:
- One prescription drug: 48.7%,
- Three or more prescription drugs: 21.8%, and
- Five or more prescription drugs: 10.7%.
Even more surprising… there is no consensus on what the definition of remission (goal of drug therapy) is for many therapies. For example — the IBD community has debated for years if it should be mucosal healing or symptom reduction. Given what we now know about the microbiome, the answer is obvious, and I believe patients would expect nothing short of a microbiome health based definition. See this paper, Mucosal healing and deep remission: What does it mean?
Ask your doctor what the definition is for remission for your disease. Is it microbiome health based?
But there is hope. “There is a transformation that is happening across our society where we do have this recognition about the gut being really the mother of the body and that we need to nurture it and take care of it very well,”
–Gerard Mullin, MD, Johns Hopkins Gastroenterology, Food MD excerpt from below Evolution of Health Functional Forum, Microbiome Maximized Medicine
So don’t be afraid to ask your doc the next time they want to prescribe a drug what the drugged microbiome will look like and if that’s a healthy resilient microbiome having strong immunity. Equally important, ask if the microbiome ever returns to the pre-drug microbiome. Your docs response will give you insight into their awareness of the microbiome. If it’s a gastroenterologist and they blow you off, understand that they’ve missed even realizing the existence of trillions of microbes in their organ of choice.
If your doc has some microbiome awareness, they’ll likely not be able to answer your question. As far as the antibiotic microbiome… that answer you already know — they’ll carpet bomb nuke your microbiome and likely will not restore to the pre-antibiotic state, ever for some, and it’ll take months for others. That’s the impetus for the push for judicious use of antibiotics and prescribing such only for situations that are clearly necessary. Those in the know say that in the future, broad spectrum antibiotics will become restricted drugs and used only as a last resort. – Dr. Emma Allen-Vercoe who presented at the “1st International Symposium on the Microbiome in Health and Disease with a Special Focus on Autism” on live fermentation of the gut microbiome. “The ICU Book” – the best-selling health textbook in critical care – has this to say about antibiotics:
“The first rule of antibiotics is try not to use them, and the second rule is try not to use too many of them.” -Alexandra Carmichael, Ubiome
Do microbiomes on drugs look healthy? Why focus on the PPI & Immunosuppressive microbiomes…
I’ve given the spoiler alert that these drugged microbiomes don’t resemble a “healthy microbiome” so the drugs are not targeting root cause; they are only targeting symptom suppression, if that even, and opening doors for disease relapse or trigger of other disease(s). Biologic and PPI medications are consistently in the top 10 meds prescribed and sales lists (see full list of top 100 here). How many are on these meds????
About 50 million Americans suffer from autoimmune disease. The NIH estimates this number much lower (23.5 million Americans ) since they only include the 24 diseases for which good epidemiology studies are available. Researchers have identified 80-100 different autoimmune diseases and suspect at least 40 additional diseases of having an autoimmune basis. Autoimmune drugs inhibit inflammatory pathways or reduce the activity of immune cells.
Immunosuppressive therapy with steroids, thiopurines, or biologic anti-TNF (infliximab, etc) is the conventional next step for many diseases including: rheumatoid arthritis (RA), psoriatic arthritis, juvenile arthritis, inflammatory bowel disease (Crohn’s and ulcerative colitis), lupus, ankylosing spondylitis, psoriasis, and more.
Surely, you’d think we’d know about the drugged microbiome for those using these medications given the billions in sales they rake in.
The biologic and immunosuppressive microbiome
I had the occasion to have my question asked and answered by Gerard Mullin, MD, Integrative Gastroenterologist out of Johns Hopkins at the Evolution of Health Functional Forum, called Microbiome Maximized Medicine, held in NY on October 5, 2015. Fast forward the below YouTube to time 1:13:37 to hear his response, or read my transcripted version:
1:13:37 “Do anti-TNF meds, for autoimmunes, change the microbiome to be more healthy, or not?”
Gerry said: “I don’t think there’s studies on that.” [NOTE: Dr. Mullin is sort of wrong here… as pictured below, we now have 16S rRNA findings for IBD that the immunosuppressant microbiome (Imuran) and/or biologic microbome (Remicad) is not diverse and that diet (SCD in particular) actually increases it’s diversity.] “But I can’t imagine how they’d be a help (audience laughter and some clapping) since they are, if you want to use the word poisoning, and really disarming our immune system to a large extent. They are really dampening the response to the microbes and certainly not rebuilding, certainly the gut immunity or the gut itself where the microbes are therein.”
“They are kind of preventing more casualties of war. But they aren’t really rebuilding the infrastructure. They are used unfortunately with what they call top down therapies which is a way that medicine tries to get… it is very good marketing that we kind of kill everybody or overload everybody with these medications that are overkill. Literally to shut down a response no matter what the spectrum is and not reserve them for emergencies or the worst case scenario. So you’re given to practically everybody and the marketing spin is called top down therapy. And of course it is going to work in the vast majority of the people since you are overwhelming the immune system and you are shutting it down. But in the meantime, the microbes themselves are not really correcting the underlying problem or root cause.”
I’d say not a good drugged microbiome and yet, a lot of risk of side effects.
At time 1:05:45 you can hear Dr. Mullin’s insights for managing IBD using anti-inflammatory medications or by microbiome, or read my transcripted version:
1:05:45 James Maskell asks: How is JHU, which is so esteemed, dealing with massive understanding about the dealings of microbes? Dr. Mullin: …We are taking a functional approach…
1:06:23 Dr. Corteza asks “… how would you treat [acute severe] UC… sectioning or as a microbiome? “ Dr. Mullin: Severe UC requires anti-inflammatory medications… that would be managed acutely… but long term we’re talking more about preventative medicine or long term approaches that would certainly include the microbiome…. probiotics do maintain UC in remission even treats acute UC that is moderately active… Listen in entirety but I especially want you to hear this conversation following Dr. Mullins answer:
1:07:25 Dr. Corteza said, under her breath, “YOU CAN REVERSE IT.”
James said, “YOU CAN REVERSE IT… under your breath… You had the mic… so everyone heard that at home.”
What is most amazing is that for many, moving onto a whole foods diet and lifestyle approach can reduce the need for these drugs.
Novel alternative therapies that do not suppress the immune system are welcomed.
Inflammatory diseases successfully using dietary anti-inflammatory, nutrient dense, low toxin regimens include autism, IBD, MS, RA, Lupus, depression and other neurological disorders, and more… That’s the point of my blog, to post the science showing that diet and lifestyle, be it healing diets such as SCD or another similar version thereof such as GAPS, PALEO, WAHLS, or AIP, can achieve remission from inflammatory microbiome, induce mucosal healing and nudge the microbiome towards health. I mostly write about SCD since even the IBD community, who forever told patients “diet has nothing to do with it,” are now incredibly seeing healing indices, see this post for details. SCD studies show increase in the diversity of the “drugged microbiome” meaning the reference “drugged microbiome” had reduced diversity. And we already know different diseases have skewed microbiome not just at time of diagnosis, but also at time coincident with medications, thus establishing what the “drugged microbiome” looks like.
Having a microbiome that looks ‘healthy’ is essential. The microbiota are essential for many arenas of human health [2,3], including nutrition  along with microbiota’s production of essential vitamins, including B3, B5, B6, B12, K, biotin, and tetrahydrofolate, and in the absorption of iron from the intestinal lumen , neurobiology , cancer , immunology , cardiovascular disease , biliary function , irritable bowel disorders , pregnancy , and metabolic diseases like obesity  and diabetes . –The Human Microbiome is a Source of Therapeutic Drug Targets. Consider too reading the post, SCIENCE BEHIND FOOD, DISEASE, MICROBIOME.
Dr. Mullin explains the microbiome import as: The gut is the controlling influencer of the body with axis between gut and brain, gut and liver, gut and kidney, and gut and other body systems such as circulation, cardiovascular… the gut is really one of the key players and drivers of the body’s health. That research has really exploded in the last 5 years with linkage to diabetes and autoimmune diseases, even pre-diabetes, brain disorders, behavior disorders, seems like you name it, it all starts in the gut. So the gut has to be integral with our ways of dealing with health.
The below slides show the many studies now published (focus is on IBD since this is so widely studied) which find SCD increases the microbiome diversity not only from the time at diagnosis, but also the drugged microbiome be it immunosuppressants such as Imuran and/or biologics such as Remicade. The studies find mucosal healing and reduced disease indices with the end result that SCD can maintain and/or induce remission allowing patients to reduce and even eliminate meds.
I want to be totally clear; I am not pharma bashing these drugs.
Some need them to achieve remission, at least at disease diagnosis. But the buck doesn’t stop there. Impact on microbiome needs known and addressed. Period. For IBD, about 75% with Crohn’s and 23-45% with UC eventually need surgery. The immune system outsmarts the anti-TNF meds a lot of times — 30 to 80% of the time for IBD. Isn’t that a crazy broad failure range? What this drugged microbiome scenario suggests is that instead of fixing the root cause of the inflammatory cascade, the meds are trying to stop the immune cytokine reaction, and not very effectively it seems:
These authors found for IBD, in April, 2015, that the death of important immune defense cells named Paneth cells, previously known to characterize Crohn’s, is actually a consequence of inflammation triggering, since it occurs after ileitis development, and not its cause, as previously suggested. So inflammation first, then death to the Paneth cells. The authors highlight that their findings show how imbalances in microbiome intestinal composition can trigger intestine inflammation, typical of Crohn’s exacerbated by follow-up failure of Paneth cell function. Logic would say: best to get rid of the inflammation, the root cause. That is what the healing diets do; IBD studies show that SCD reduces inflammation allowing many to achieve/maintain remission and even reduce/eliminate the meds. Without a healing diet:
The body continues to put gasoline on the fire while trying to douse it with a cup of water in the other hand.
The head GI surgeon at a major teaching hospital point blank asked me, “What do I do with non-medication responding IBD patients?” I suggested after CDiff is ruled out, to add healing diet tenets. I was told his patients can not read implying such would not be practical. I don’t see the connection there but it seems real as this 2015 RUSH University Medical Center study found out of the 50 patients using SCD to manage IBD and maintain remission, all but one had college or graduate degrees. That’s totally unacceptable; everyone has a right to know about healing diet tenets as they are not just relevant for disease management but for disease prevention too.
Defining the medications
Biologic medications are molecularly-engineered antibodies against key components of the human intestinal inflammatory cascade. Different diseases have different inflammatory cascades. The IBD pro-inflammatory cytokines include TNF-alpha, IL-1, IL-6, etc. The RA network of cytokines includes:TNF-alpha, IL-1 , IL-6 and IFN-gamma, GM-CSF and LIF, IL-7, IL-15, IL-17, IL-18, IL-21, MIP-1, etc. You can google your disease to see your list. Now you see… anti-TNF medications are used to downregulate the pro-inflammatory TNF-alpha cytokine. Drug names for biologics include: infliximab, adalimumab, certolizumab, natalizumab, vedolizumab, etc.
Since these meds fail (30 to 80% of the time for IBD) so often, new treatments are being sought that address the role of other anticytokine agents including antibodies against interleukin (IL)-6R, IL-13, and IL-12/IL-23 as well as new anti-inflammatory concepts (regulatory T cell therapy, Smad7 antisense, Jak inhibition, Toll-like receptor 9 stimulation, worm eggs). In addition, blockade of T-cell homing via the integrins α4β7 and the addressin mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1.)
Steroids include prednisone or budesonide.
Immunosuppressive or immunomodulator agents include azathioprine (Imuran), methotrexate, cyclophosphamide, etc.
More drugged microbiome findings for anti-TNF & EN:
The study, P-214 Gut Microbial Response to Anti-Tnf Therapy in IBD – ResearchGate, looked at the drugged anti-TNF microbiome at 0, 2, and 6 weeks for biologic-naive IBD patients being treated with either infliximab or adalimumab. Note: Prior antibiotic or other history that pre-skews microbiome is unfortunately not provided.
Findings: Relative abundance of Eubacterium spp. prior to anti-TNF exposure and a relative abundance of Ruminococcus spp. at 6 weeks post-treatment. All 5 patients reported clinical improvement or sustained clinical control following initiation of anti-TNF therapy, though certain patients still had continued disease activity. The preliminary data of this ongoing study indicate that microbial communities are indeed altered in a characteristic fashion following anti-TNF therapy, though it is currently unclear whether these changes reflect the effects of anti-TNF medications or differences in disease activity.
Anti-TNF and enteral nutrition (EN) microbiome. EN can induce remission for Crohn’s in ~80% of patients equaling the potential of steroids. This study noted that EN down regulates mucosal concentrations of pro-inflammatory cytokines, as well as improves mucosal integrity which is vital to the proper functioning of the intestines and yet the study confirmed that both the anti-TNF and enteral feeding microbiomes aren’t healthy looking. Multiple hypotheses for why enteral feeding works included: reduction in antigen exposure, overall nutritional repletion, improvement in intestinal barrier function, provision of micronutrients and reduction in dietary fat or carbohydrate, leading to reduced byproducts producing inflammation
PPI physiology & consequent health ramifications due to improper digestion — upstream/downstream ramifications
Proton pump inhibitors (PPIs) interfere with the digestive function of the stomach and train wreck the gut microbiome. Some names for PPIs are: Famotidine (Quamatel), Ranitidine (Zantac or Pylorid), or Omeprazole (Losec),
How PPIs wreck your gut microbiome: PPIs increase stomach pH to above 5.0 (within 5 days for omeprazole). However, protein digestion requires pH of 1.8-3.2 for the activation of pepsinogens. The stomach’s gate keeping protective function to mitigate bacterial infection is almost totally abolished due to the reduced stomach acid. Normal breakdown of food antigens is inhibited; intact food proteins persist in the small intestine increasing food allergy mucosal permeability occurs, vitamin/mineral deficiencies occur, and microbiome is skewed increasing risk of CDiff, which is epidemic.
“C. diff is very much the poster child for how we’ve messed things up by interfering with the microbiota. And it is just the most obvious problem [antibiotic resistance].”
-Dr. Emma Allen-Vercoe, Modern life versus microbes: Our obsession with clean living is harming us **** Scientists are concerned the microbiota is becoming more impoverished with each successive generation.
The PPI microbiome actually increases risk for a CDiff infection
That alone should require patient consent given the epidemic antibiotic resistance now associated with CDiff and other antibiotic resistant infections. A great PPI synopsis can be read at: Proton Pump Inhibitors – A Risky Experiment? Health ramifications of PPI stomach acid suppression include:
- Decreased diversity of microbiome gut bacteria at both low and high dosages of omeprazole, after both 1 week and 1 month, increasing risk for infections like CDiff and pneumonia:
These researchers found that at the end of the 28-day treatment period, the observed OTU counts were similar to those from patients with a first CDiff infection episode indicating the potential for PPIs to negatively influence the robustness of the host microbial ecology and increase the susceptibility to CDiff infection. The microbiome skew was only partly reversed after a 1 month recovery period. The authors suggest that with the elimination of nutrient competitors, PPI use may directly affect gene expression across metabolic pathways in favor of CDiff growth. –Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility and Proton pump inhibitors decrease diversity in gut microbiome, increase risk for complications
- Food allergy of common foods: 10% had a boost of pre-existing IgE antibodies and 15% had de novo IgE formation to milk, potato, celery, carrots, apple, orange, and wheat and rye flour. –Anti-ulcer drugs promote IgE formation toward dietary antigens in adult patients and Adverse Effects of Proton Pump Inhibitor Drugs: Clues and Conclusions
- Vitamin and mineral deficiencies including 44% increased risk of hip fracture. B12 (since stomach acid cannot separate vitamin from the protein it is attached), C, calcium, iron, magnesium. B12 deficiency risk is 65% for PPI and 25% for Histamine users. NIH estimates up to 15% of US population has a B12 deficiency. B12 is your body’s master anti-oxidant. –Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications and Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B12 Deficiency
- 16 to 21% increased risk of heart attack, see Common heartburn medications linked to greater risk of heart attack
- Also note, it is hard to wean off PPI due to rebound effect.
In conclusion: Ask for information on what the drugged microbiome will look like for any drug you are prescribed. You will likely decide it isn’t worth it and either try healing diet and lifestyle modifications alone or in concert with the medication to increase microbiome diversity.
On a side note: Thinking long term, try getting a reasonably priced long term care insurance plan with an autoimmune. I have an autoimmune but remain in remission med-free using healing diet tenets; I was offered a preferred reduced rate plan. My neighbor, on the autoimmune biologic roller coaster, not using healing diet tenets, was flat out denied coverage.
Last updated: February 15, 2017 at 15:56 pm for SEO optimization.
In health through awareness,