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              The microbiome may have an impact on susceptibility to autoimmune diseases

By David Dunaief, M.D.

Dr. David Dunaief

Every human carries in its body a microbiome, consisting of bacteria, viruses and single-cell eukaryotes. Our relationship to these organisms is complex, and much of it is still only loosely understood. What we do know, however, is that these trillions of microorganisms have key roles in our healthy functioning.

The microbiome is found throughout our bodies, including the skin, the eyes and the gut. Here, we’re going to focus on the gut, where the majority of our microbiome resides. The microbiome has been getting a lot of attention of late, because of its possible role in preventing and promoting diseases. Among these are obesity, diabetes, irritable bowel syndrome, autoimmune diseases, such as rheumatoid arthritis and Crohn’s, and infectious diseases, such as colitis.

The Human Microbiome Project

Like the Human Genome Project, which mapped our genes, the Human Microbiome Project, funded by the National Institutes of Health from 2007 to 2016, sought to map and sequence the composition and diversity of these gut organisms and to prompt future research. Already, there have been some enlightening preliminary studies.

What affects the microbiome?

Drugs, such as antibiotics, can wipe out microbial diversity, at least in the short term. Also, lifestyle modifications, such as diet, can have a positive or negative impact. Microbiome diversity also may be significantly different in distinct geographic locations throughout the world.

The microbiome and obesity

Many obese patients continually struggle to lose weight. Obese and overweight patients now outnumber malnourished individuals worldwide (1).

For a long time, the paradigm for weight loss had been to cut calories. However, extreme low-calorie diets were not having a long-term impact. It turns out that our guts, dominated by bacteria, may play important roles in obesity and weight loss, determining whether we gain or lose weight.

The results from a study involving human twins and mice are fascinating (2). In each pair of human twins, one was obese and the other was lean. Gut bacteria from obese twins was transplanted into thin mice. The result: the thin mice became obese. However, when the lean human twins’ gut bacteria were transplanted to thin mice, the mice remained thin.

By pairing sets of human twins, one obese and one thin in each set, with mice that were identical to each other and raised in a sterile setting, researchers limited the confounding effects of environment and genetics on weight.

The most intriguing part of the study compared the effects of diet and gut bacteria. When the mice who had received gut transplants from obese twins were provided gut bacteria from thin twins and given fruit- and vegetable-rich, low-fat diet tablets, they lost significant weight. Interestingly, they only lost weight when on a good diet. The authors believe this suggests that an effective diet may alter the microbiome of obese patients, helping them lose weight. These are exciting, but preliminary, results. It is not clear yet which bacteria may be contributing these effects.

This suggests that gut bacteria diversity may be a crucial piece of the weight-loss puzzle.

Rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease that can be disabling, with patients typically suffering from significant morning stiffness, joint soreness and joint breakdown. What if gut bacteria influenced RA risk? In a study, the gut bacteria in mice that were made susceptible to RA by deletion of certain genes (HLA-DR genes) were compared to those who were more resistant to developing RA (3). Researchers found that the RA-susceptible mice had a predominance of Clostridium bacteria and that those resistant to RA were dominated by bacteria such as bifidobacteria and Porphyromonadaceae species. The significance is that the bacteria in the RA-resistant mice are known for their anti-inflammatory effects.

Can you counteract antibiotics’ negative effects?

Many have gastrointestinal upset while taking antibiotics, because antibiotics don’t differentiate between good and bad bacteria when they go to work. 

One way to counteract these negative effects is to take a probiotic during and after your course of antibiotics. I recommend Renew Life’s 30-50 billion units once a day, two hours after an antibiotic dose and continuing once a day for 14 days after you have finished your prescription. If you really want to ratchet up the protection, you can take one dose of probiotics two hours after every antibiotic dose.

Although nobody can say what the ideal gut bacteria should consist of, we do know a few things that can help you. Diet and other lifestyle considerations, such as eating and sleeping patterns or their disruptions, seem to be important to the composition and diversity of gut bacteria (4). Studies have already demonstrated prebiotic effects of fiber and significant short-term changes to the microbiome when eating fruits, vegetables, and plant fiber. The research is continuing, but we’ve learned a lot already that may help us tackle obesity and autoimmune disorders.

References:

(1) “The Evolution of Obesity”; Johns Hopkins University Press; 2009. (2) Science. 2013;341:1241214. (3) PLoS One. 2012;7:e36095. (4) Nutrients. 2019 Dec;11(12):2862.

Dr. David Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, visit www.medicalcompassmd.com or consult your personal physician.

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Rheumatoid arthritis typically begins with stiffness in the joints of the hands.
RA medications may increase other risks

By David Dunaief, M.D.

Dr. David Dunaief

We know that inflammation is a critical part of many chronic diseases. Rheumatoid arthritis (RA) is no exception. With RA, inflammation is rampant throughout the body and contributes to painful joints, most commonly concentrating bilaterally in the smaller joints of the body, including the metacarpals and proximal interphalangeal joints of the hand, as well as the wrists and elbows. With time, this disease can greatly diminish our ability to function, interfering with our activities of daily living. The most basic of chores, such as opening a jar, can become a major hindrance.

In addition, RA can cause extra-articular, a fancy way of saying outside the joints, manifestations and complications. These can involve the skin, eyes, lungs, heart, kidneys, nervous system and blood vessels. This is where it gets a bit dicier. With increased complications comes an increased risk of premature mortality (1).

Four out of 10 RA patients will experience complications in at least one organ. Those who have more severe disease in their joints are also at greater risk for these extra-articular manifestations. Thus, those who are markedly seropositive for the disease, showing elevated biomarkers like rheumatoid factor (RF), are at greatest risk (2). They have an increased risk of cardiovascular disease events, such as heart attacks and pulmonary disease. Fatigue is also increased, but the cause is not well understood. We will look more closely at these complications.

Are there treatments that may increase or decrease these complications? It is a very good question because some of the very medications used to treat RA also may increase risk for extra-articular complications, while other drugs may reduce the risks of complications. We will try to sort this out, as well. The drugs used to treat RA are disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate; TNF (tumor necrosis factor) inhibitors, such as Enbrel (etanercept); oral corticosteroids; and NSAIDs (nonsteroidal anti-inflammatory drugs).

It is also important to note that there are modifiable risk factors. We will focus on two of these, weight and sugar. Let’s look at the evidence.

Cardiovascular disease burden

We know that cardiovascular disease is very common in this country for the population at large. However, the risk is even higher for RA patients; these patients are at a 50 percent higher risk of cardiovascular mortality than those without RA (3). The hypothesis is that the inflammation is responsible for the RA-cardiovascular disease connection (4). Thus, oxidative stress, cholesterol levels, endothelial dysfunction and high biomarkers for inflammation, such as ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein), play roles in fostering cardiovascular disease in RA patients (5).

The yin and yang of medications

Although drugs such as DMARDs (including methotrexate and TNF inhibitors, Enbrel, Remicade and Humira), NSAIDs (such as celecoxib) and corticosteroids are all used in the treatment of RA, some of these drugs increase cardiovascular events and others decrease them. In meta-analysis (a group of 28 studies), results showed that DMARDs reduced the risk of cardiovascular events by up to 30 percent, while NSAIDs and corticosteroids increased the risk (6).

The oral steroids had the highest risk of heart complications, approximately a 50 percent rise in risk. This may be one reason rheumatologists encourage their RA patients to discontinue oral steroid treatments as quickly as possible.

In an observational study, the results reaffirm that corticosteroids increased the risk of a heart attack in RA patients, this time by 68 percent (7). The study involved over 8,000 patients with a follow-up of nine years. Interestingly, there was a dose-response curve. In other words, the results also showed that for every 5 mg increase in dosage, there was a corresponding 14 percent increase in heart attack risk.

Baffling disease complication

Most complications seem to have a logical connection to the original disease. Well, it was a surprise to researchers when the results of the Nurses’ Health Study showed that those with RA were at increased risk of cardiovascular disease and of respiratory disease (8). In fact, the risk of dying from respiratory disease was 106 percent higher in the women with RA, compared to those without, and the risk was even higher in women who were seropositive (had elevated levels of rheumatoid factor). The authors surmise that seropositive patients have greater risk of death from respiratory disease because they have increased RA severity compared to seronegative patients. The study followed approximately 120,000 women for a 34-year duration.

Why am I so tired?

While we have tactics for treating joint inflammation, we have yet to figure out how to treat the fatigue associated with RA. In a Dutch study, results showed that while the inflammation improved significantly, fatigue only changed minimally (9). The consequences of fatigue can have a negative impact on both the mental and physical qualities of life. There were 626 patients involved in this study for eight years of follow-up data. This study involved two-thirds women, which is significant; women in this and in previous studies tended to score fatigue as more of a problem.

Lifestyles of the painful and more debilitating

We all want a piece of the American dream. To some that means eating like kings of past times. Well, it turns out that body mass index plays a role in the likelihood of developing RA. According to the Nurses’ Health Study, those who are overweight or obese and are ages 55 and younger have an increased risk of RA, 45 percent and 65 percent, respectively (10). There is higher risk with increased weight, because fat has pro-inflammatory factors, such as adipokines, that may contribute to the increased risk. Weight did not influence whether they became seropositive or seronegative RA patients.

With a vegetable-rich, plant-based diet you can reduce inflammation and thus reduce the risk of RA by 61 percent (11). In my clinical practice, I have seen numerous patients able to reduce their seropositive loads to normal or near-normal levels by following this type of diet.

Sugar, sugar!

At this point, we know that sugar is bad for us. But just how bad is it? When it comes to RA, results of the Nurses’ Health Study showed that sugary sodas increased the risk of developing seropositive disease by 63 percent (12). In subset data of those over age 55, the risk was even higher, 164 percent. This study involved over 100,000 women followed for 18 years.

The just plain weird – infection for the better?

Every so often we come across the surprising and the interesting. I would call it a Ripley’s Believe It or Not moment. In one study, those who had urinary tract infections, gastroenteritis or genital infections were less likely to develop RA than those who did not (13). The study did not indicate a time period or potential reasons for this decreased risk. However, I don’t think I want an infection to avoid another disease. When it comes to RA, prevention with diet is your best ally. Barring that, disease-modifying anti-rheumatic medications are important for keeping inflammation and its progression in check. However, oral steroids and NSAIDs should generally be reserved for short-term use. Before considering changing any medications, discuss it with your physician.

References: (1) J Rheumatol 2002;29(1):62. (2) uptodate.com. (3) Ann Rheum Dis 2010;69:325–331. (4) Rheumatology 2014;53(12):2143-2154. (5) Arthritis Res Ther 2011;13:R131. (6) Ann Rheum Dis 2015;74(3):480-489. (7) Rheumatology 2013;52:68-75. (8) ACR 2014: Abstract 818. (9) RMD Open 2015.  (10) Ann Rheum Dis. 2014;73(11):1914-1922. (11) Am J Clin Nutr 1999;70(6),1077–1082. (12) Am J Clin Nutr 2014;100(3):959-967. (13) Ann Rheum Dis 2015;74:904-907.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, visit www.medicalcompassmd.com or consult your personal physician.

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Consuming white fleshy fruits such as pears may decrease ischemic stroke risk by as much as 52 percent.

By David Dunaief, M.D.

Stroke remains one of the top five causes of mortality and morbidity in the United States (1). As a result, we have a wealth of studies that inform us on issues ranging from identifying chronic diseases that increase stroke risk to examining the roles of medications and lifestyle in managing risk.

Impact of chronic diseases

There are several studies that show chronic diseases — such as age-related macular degeneration, rheumatoid arthritis and migraine with aura — increase the risk for stroke. Therefore, patients with these diseases must be monitored.

In the ARIC study, stroke risk was approximately 50 percent greater in patients who had AMD compared to those who did not — 7.6 percent versus 4.9 percent, respectively (2). This increase was seen in both types of stroke: ischemic (complete blockage of blood flow in the brain) and hemorrhagic (bleeding in the brain). The risk was greater for hemorrhagic stroke than for ischemic, 2.64 vs. 1.42 times increased risk.

However, there was a smaller overall number of hemorrhagic strokes, which may have skewed the results. This was a 13-year observational study involving 591 patients, ages 45 to 64, who were diagnosed with AMD. Most patients had early AMD. If you have AMD, you should be followed closely by both an ophthalmologist and a primary care physician.

Rheumatoid arthritis (RA)

In an observational study, patients with RA had a 30 percent increased risk of stroke, and those under 50 years old with RA had a threefold elevated risk (3). This study involved 18,247 patients followed for a 13-year period. There was also a 40 percent increased risk of atrial fibrillation (AF), a type of arrhythmia or irregular heartbeat. Generally, AF causes increased stroke risk; however, the authors were not sure if AF contributed to the increased risk of stroke seen here. They suggested checking regularly for AF in RA patients, and they surmised that inflammation may be an underlying cause for the higher number of stroke events.

Migraine with aura

In the Women’s Health Study, an observational study, the risk of stroke increased twofold in women who had migraine with aura (4). Only about 20 percent of migraines include an aura, and the incidence of stroke in this population is still rather rare, so put this in context (5).

Medications with beneficial effects

Two medications have shown positive impacts on reducing stroke risk: statins and valsartan. Statins are used to lower cholesterol and inflammation, and valsartan is used to treat high blood pressure. Statins do have side effects, such as increased risks of diabetes, cognitive impairment and myopathy (muscle pain). However, used in the right setting, statins are very effective. In one study, there was reduced mortality from stroke in patients who were on statins at the time of the event (6). Patients who were on a statin to treat high cholesterol had an almost sixfold reduction in mortality, compared to those with high cholesterol who were not on therapy.

There was also significant mortality reduction in those on a statin without high cholesterol, but with diabetes or heart disease. The authors surmise that this result might be from an anti-inflammatory effect of the statins. Of course, if you have side effects, you should contact your physician immediately.

Valsartan is an angiotensin II receptor blocker that works on the kidney to reduce blood pressure. However, in the post-hoc analysis (looking back at a completed trial) of the Kyoto Heart Study data, valsartan used as an add-on to other blood pressure medications showed a significant reduction, 41 percent, in the risk of stroke and other cardiovascular events for patients who have coronary artery disease (7).

It is important to recognize that chronic disease increases stroke risk. High blood pressure and high cholesterol are two of the most significant risk factors. Fortunately, statins can reduce cholesterol, and valsartan may be a valuable add-on to prevent stroke in those patients with coronary artery disease.

Medication combination: negative impact

There are two anti-platelet medications that are sometimes given together in the hopes of reducing stroke recurrence — aspirin and Plavix (clopidogrel). The assumption is that these medications together will work better than either alone. However, in a randomized controlled trial, the gold standard of studies, this combination not only didn’t demonstrate efficacy improvement but significantly increased the risk of major bleed and death (8, 9).

Major bleeding risk was 2.1 percent with the combination versus 1.1 percent with aspirin alone, an almost twofold increase. In addition, there was a 50 percent increased risk of all-cause death with the combination, compared to aspirin alone. Patients were given 325 mg of aspirin and either a placebo or 75 mg of Plavix. The study was halted due to these deleterious effects. The American Heart Association recommends monotherapy for the prevention of recurrent stroke. If you are on this combination of drugs, please consult your physician.

Aspirin: low dose vs. high dose

Greater hemorrhagic (bleed) risk is also a concern with daily aspirin regimens greater than 81 mg, which is the equivalent of a single baby aspirin. Aspirin’s effects are cumulative; therefore, a lower dose is better over the long term. Even 100 mg taken every other day was shown to be effective in trials. There are about 50 million patients who take aspirin chronically in the United States. If these patients all took 325 mg of aspirin per day — an adult dose — it would result in 900,000 major bleeding events per year (10).

Lifestyle modifications

A prospective study of 20,000 participants showed that consuming white fleshy fruits — apples, pears, bananas, etc. — and vegetables — cauliflower, mushrooms, etc. — decreased ischemic stroke risk by 52 percent (11). Additionally, the Nurses’ Health Study showed that foods with flavanones, found mainly in citrus fruits, decreased the risk of ischemic stroke by 19 percent (12). The authors suggest that the reasons for the reduction may have to do with the ability of flavanones to reduce inflammation and/or improve blood vessel function. I mention both of these trials together because of the importance of fruits in prevention of ischemic (clot-based) stroke.

Fiber’s important role

Fiber also plays a key role in reducing the risk of a hemorrhagic stroke. In a study involving over 78,000 women, those who consumed the most fiber had a total stroke risk reduction of 34 percent and a 49 percent risk reduction in hemorrhagic stroke. The type of fiber used in this study was cereal fiber, or fiber from whole grains.

Refined grains, however, increased the risk of hemorrhagic stroke twofold (13). When eating grains, it is important to have whole grains. Read labels carefully, since some products that claim to have whole grains contain unbleached or bleached wheat flour, which is refined.

Fortunately, there are many options to help reduce the risk or the recurrence of a stroke. Ideally, the best option would involve lifestyle modifications. Some patients may need to take statins, even with lifestyle modifications. However, statins’ side effect profile is dose related. Therefore, if you need to take a statin, lifestyle changes may help lower your dose and avoid harsh side effects. Once you have had a stroke, it is likely that you will remain on at least one medication — low-dose aspirin — since the risk of a second stroke is high.

References: (1) cdc.gov. (2) Stroke online April 2012. (3) BMJ 2012; Mar 8;344:e1257. (4) Neurology 2008 Aug 12; 71:505. (5) Neurology. 2009;73(8):576. (6) AAN conference: April 2012. (7) Am J Cardiol 2012; 109(9):1308-1314. (8) ISC 2012; Abstract LB 9-4504; (9) www.clinicaltrials.gov NCT00059306. (10) JAMA 2007;297:2018-2024. (11) Stroke. 2011; 42: 3190-3195. (12) J. Nutr. 2011;141(8):1552-1558. (13) Am J Epidemiol. 2005 Jan 15;161(2):161-169.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, visit www.medicalcompassmd.com or consult your personal physician.

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