NCDs strike people of all walks of life in every country. Prominent people are not excluded, and many have self-identified or told stories of their family’s challenges, often to bring attention to the need for cures. They include Bill Clinton and heart disease, Ronald Reagan and Alzheimer’s disease, Sheryl Crow and breast cancer, Halle Berry and diabetes, Jenny McCarthy’s and Drew Brees’s sons and autism, Michael J. Fox and Parkinson’s disease, Selena Gomez and lupus, Miley Cyrus and celiac disease, Phil Mickelson and psoriatic arthritis, Kim Kardashian and psoriasis, Montel Williams and multiple sclerosis, and Jillian Michaels and polycystic ovary syndrome (PCOS).
A scenario we see all too often in modern medicine starts with a group of women who learn that they are expecting babies that they have long hoped for. Through absolutely no fault of their own, the women happen to have NCDs. They may be overweight with diabetes and asthma or have high blood pressure and elevated risk of stroke, or heart disease, or arthritis, or thyroid disease, or celiac disease. These are common occurrences of NCDs. They seek out an OB-GYN to help manage the pregnancy and deliver a healthy baby. The NCD symptoms are managed during the pregnancy, but the diseases are not cured. The women carry microbiomes that are dysfunctional as they are aligned with one or more NCDs. Additionally, their own mammalian chromosomes or genes have epigenetic marks that can promote NCDs. Some of these were established thanks to the dysfunctional microbiomes. Working with the OB-GYN, many of the women will have elective cesarean deliveries. Since it’s a surgical procedure, antibiotics will be administered. This further compromises the microbiome. Even those who vaginally deliver will pass along the dysfunctional microbiomes linked with the mother’s NCDs. The babies are delivered and appear to be absolutely fine. Job well done. It is a wonderful outcome of modern medicine. Or is it?
The babies from this group of mothers are launched on their life trajectory. They either missed getting seeded with Mom’s gut microbes or were seeded with microbes connected to the NCDs. These babies are passed on to pediatricians. The frustrated pediatricians know all too well what is coming. They begin to diagnose NCDs in this group of children with seemingly little they can do to avoid it. Atopic dermatitis shows up in one at six months of age. By two years of age, several have food allergies to peanuts, dairy, eggs, or other foods. By four years of age, a few have asthma or have been diagnosed with autism. By six years of age, obesity is a concern for several and ADHD for others. At eight years of age, type 1 diabetes appears in some children and celiac disease in others. In their teens, respiratory allergies and depression are prevalent.
What do these children have in common as teenagers? They all have NCDs requiring prescription medications. In some cases multiple medications are needed. The diseases and medications are unlikely to go away. In many cases, quality of life is already impacted. What lies ahead? Current prognoses say heart disease, cancer, multiple sclerosis, lupus, inflammatory bowel disease, PCOS, and Alzheimer’s disease among others—and, of course, more medications to go with each disease. These diseases rarely go away. Instead, we collect them. Finally, all of these children carry incomplete or dysfunctional microbiomes. This is precisely what our current best efforts have brought us simply because we have been treating only the minority mammalian patient. To get really serious about NCDs and whole human health, we need to take a different focus, one placed squarely on our microbial co-partners.
Having discussed the inability of health and prevention measures taken so far to resolve the NCD epidemic, we now must look for solutions. We must allow the new biology to flow into a reenvisioned kind of medicine.
It doesn’t mean that every good thing we have been doing in medicine must be discarded. It does mean that everything—every medical procedure, every drug, every major therapy—needs to be scrutinized in light of the new things we have learned about basic human biology. We will benefit from blending the old with the new. There are many bright spots ahead on the path of whole human health, including more preventive care, personalized medicine, and broadened access to and sustainability of health services. The goal is reversing the NCD epidemic and allowing talented health care professionals to manage health instead of managing disease symptoms.
Precision medicine for the superorganism will treat you like an ecosystem. All of your body’s thousands of species on the skin and in the gut, mouth, nose, airways, and reproductive tract need to be included within your health management. This is the future of medicine. It is one of the reasons a June 2015 CNBC report on medicine called the microbiome “Medicine’s Next Frontier.” This change is not something to fear or dread. In fact, it is very exciting and full of remarkable promise, even if some questions remain.
We already have a pretty good idea what this new, more precise medicine will look like. There are different strategies and routes and specific microbes that can be involved in manipulating the microbiome toward being healthier. This is possible no matter the individual’s age and can help to prevent or treat NCDs.
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Here are twenty major shifts I see ahead involving the microbiome and NCDs.
How do we know the idea of superorganism medicine isn’t just some kind of fad? That was among the wide range of intriguing questions to greet me following my microbiome lecture before a record crowd of largely pharmaceutical company scientists at a recent drug discovery and safety meeting held in New Jersey’s rich “pharmaceutical alley.” Most of the largest drug companies in the world have corporate sites within a few miles of this meeting location, and several others call home to megacomplexes just a short distance across the border in Pennsylvania.
After all, I had just told a room full of the brightest pharma and biotech scientists (plus a few drug regulators, academics, and a former astronaut in attendance) that nothing would stay the same in medicine and human safety as major changes were coming. The old biology was out, and the human superorganism was here to stay. I told them that the basis for looking at drug efficacy and drug safety would change and that we would soon be working through, or at least in concert with, the microbiome. Much of safety testing had to be redone or reconsidered since the prior work had excluded consideration of the microbiome. Antibiotic administration would soon require complementary probiotic therapies or be considered a potential form of malpractice. The patient was not what they had always been told he or she was but instead was something quite different.
This was startling news for biomedical scientists, some of whom had years of personal blood, sweat, and tears invested in specific new drugs working their way toward final approval and/or the marketplace. They took the news very seriously. But before the attendees returned to work after the conference and immediately rewrote all of their job descriptions, it was reasonable to ask, is this just a fad? Is it the Hula-Hoop, pet rock, disco, twerking (yuck), karaoke (please tell me that is a fad), mobile phones—oh, wait, the last one is not really a fad either. The reason superorganism medicine is not a fad is that there is nothing temporary about our new biological understanding of you as a superorganism. The exact way we respond to it might be transitory, but not the fact that we have microbial co-partners, have had them for millennia, and know that they impact our health and well-being. We ignore them at our own peril.
Once I left the speaker’s podium in New Jersey and returned to my seat, my conference neighbor leaned over and commented to me, “I think this is a paradigm shift.” A half hour later I was on the phone with someone who had attended one of my lectures on the microbiome four days earlier and a continent apart (in California). He had almost exactly the same comment, “This seems like a paradigm shift.”
If you think about it, change in medicine is not really that problematic. It is only the matter of degree and speed of change that can challenge doctors and patients alike. Doctor visits, hospital and outpatient care, prescription and over-the-counter drugs, medical tests, and medical monitoring devices do change every few years. You may have noticed this. A comparatively recent change is that everything is now electronic. Doctors are never without their tablet appendage or a nearby laptop. Many drugs that used to be prescription are now available over the counter. More high-tech instruments are common in more and more doctors’ offices. Patient monitoring for blood sugar/insulin levels is very different from a decade ago. So change happens in medicine; nothing stays the same. But these examples have been a comparatively slow progression, comparatively narrow in scope, and mainly involve the doctor, monitoring, and drug-treatment end of things. Up until now the patient has stayed largely the same.
Medicine has no choice but to change in a major way because you as a superorganism are a very different patient. You are probably familiar with the preliminary data collected once you enter a doctor’s office or hospital. They usually take a medical history (or ask about updates) and get blood pressure and temperature measurements from you. They may even order blood tests and review those results. But did they check the status of your microbiome or whether there had been any change in it since the last visit? Wouldn’t it be useful if they had been tracking your microbiome status with each annual visit and change in health status? Wouldn’t it be useful if they had monitored changes in your microbiome after you had been on drug therapy and could make adjustments?
In your last doctor’s visit, did they prescribe a drug without knowing the status of your microbiome? Did they prescribe an antibiotic without a complementary plan to reinstall or repair your microbiome after it was damaged by the antibiotic? Or were you left much like a damaged coral reef?
The first step to applying superorganism medicine is an evaluation of the existing microbiome in a patient. That will be the benchmark for planning adjustments to the microbiome as well as considering therapeutic strategies (e.g., drug selection and dosing in light of the microbiome). Think of a patient’s microbiome fingerprint as a new version of the standard blood pressure readings, temperature measurements, and blood chemistry profiles all rolled into one thing. Microbiome analysis will become basic stuff that will tell the doctor if you are 100 percent complete or are missing a few critical microbial species you need to be healthy.
At present, there are three main ways to do the microbiome analysis. Samples of skin scrapings, nose, cheek, and urogenital swabs as well as feces can be used to measure the microbial species and their relative abundance based on species identification. This is known as a taxonomic approach. But sometimes subsets of the same species of microbes can carry slight but meaningful differences in genes. Therefore, an evaluation of the microbial genes that you carry and their abundance can be useful. This is called a metagenomics approach. The term refers to analysis of the genomes from a community, and that is exactly what is done when a sample of your microbiome is being analyzed in this way. Finally, the end information a doctor may need concerns the chemicals that your microbes are making. It is much like your blood chemistry profiles except that this is very detailed and shows a fingerprint of the metabolites produced by your microbiome. This is called a metabolomic analysis. All three are useful.
With this as a baseline, it is now possible to tailor treatments designed to adjust the microbiome. By having individual patient information on the microbes present, the treatments follow the push to have personalized medicine using precise adjustments. From there, treatments all have one goal in common—to adjust part or most of the microbiome depending upon the circumstances. These adjustments are called rebiosis. Basically, rebiosis involves installing a good balance of microbes in the gut or in other body locations (e.g., vagina, skin, mouth, airways) and feeding the ones you want to keep around. That means feeding them what they can best use as food to survive and thrive. It is a microbiome makeover. This will not replace or eliminate the medical options that exist. But in the end, it will make those medical therapies more effective and less dangerous.
Changing the mix of microbes in a given body site can change our metabolism, physiology, and immune status and break the stranglehold of certain NCDs and/or prevent the emergence of these diseases. The challenge is to match the right microbiome alteration with the disease and patient, and that is where a broadening knowledge of specific microbiome metabolism will be useful. In Part Three of this book, I will discuss the full range of microbiome-modification strategies, but the type of applications already being used or that appear promising include new strategies for disease prevention, complementary therapies to existing treatments, stand-alone new therapies, and major microbiome reconstruction.
Antibiotic administration may kill pathogenic bacteria, but treatment can also leave the patient vulnerable both to recurrent infections and NCDs connected to a depletion of the microbiome. Many people have had the experience of getting sick a few weeks after their primary infection was eliminated by antibiotics. By administering specific probiotics, often with their preferred food (prebiotics), some antibiotic regimes can be made more effective by reducing the risk of unintended microbial damage and later health complications. This was the finding in a study done in Italy that combined antibiotic therapy to treat prostatitis with a mix of probiotic microbes (called VSL#3). With the combined treatment of antibiotics and probiotics, patients had significantly fewer complications.
Another strategy is to administer specific microbiome components to produce particular types of infections and, in the process, shift the immune response and/or better control inflammation. One of the ways this has been used is to address allergies. Research MDs have investigated gut microbe modification through the use of parasites, specifically parasitic worms called helminths. The helminths make certain chemicals that alter our capacity to tolerate external environmental factors (including worms—unpleasant as they nevertheless are). The idea has been around for a while in treating allergic diseases, but the full understanding of exactly how it works has only recently emerged. Helminth worms don’t actually suppress the immune system. They simply modulate the part of our immune system that protects the helminths from aggressive immune attack. The worms are doing nothing more than protecting themselves. However, in doing so, they dampen down the exact type of responses and over-the-top inflammation that produce allergies. The treatment is not without some controversy. But it shows the power of microbiome manipulation in applying the new biology to medicine. Perhaps this knowledge will lead to a less controversial therapy.
You don’t have to have antibiotic therapy to enjoy health benefits from probiotics. Probiotic supplementation can be used as a stand-alone therapeutic strategy. One of the better-studied mixes of probiotics is named VSL#3. It was recently tested in several NCD clinical trials. In a study in India of patients with liver cirrhosis, VSL#3 was administered daily for six months. At the end of six months, the probiotic group had significant reduction in both hospitalization and liver disease scores compared with controls.
A research group at the University of Kentucky conducted a meta-analysis of five separate clinical trials examining the effects of VSL#3 on ulcerative colitis. Most of the patients had the probiotic along with conventional therapy versus controls who had the conventional therapy alone with no probiotic. Remission rates for the disease in the experimental group were almost double that of the conventional therapy alone (43.8 percent versus 24.8 percent). The probiotic mix significantly improved the treatment outcome for this autoimmune disease. In other clinical trials, VSL#3 produced useful changes in studies of heart disease, nonalcoholic liver disease in children, and irritable bowel syndrome. In the last case, it was suggested that VSL#3 increased melatonin levels, and that may have contributed to the improvement in symptoms.
In some cases, even a single strain of bacteria given at the right time of development appears able to shift important maturational processes going on in the immune system. One example concerns the gut bacterium Lactobacillus rhamnosus GG and risk of food allergy. This bacterium appears to tip the scales in favor of a healthier immune balance and oral tolerance to cow’s milk. It can prevent an overabundance of Th2-driven responses to food allergens by shifting the way the immune system interacts with foods. Additionally, this probiotic bacterium has been given in pediatric clinical trials in Australia along with oral immunotherapy for peanut allergy. The combined treatment with probiotics produced success in 82 percent of the treated children (compared with only 3.6 percent of controls). This shows the potential for treatment with even a single type of probiotic bacteria to counteract infant immune problems that promote NCDs. Maybe peanuts won’t be forever the bane of parents’ lives.
In another study, patients with rheumatoid arthritis were treated for eight weeks with probiotic supplements containing Lactobacillus casei versus controls. The probiotic-administered group not only had a significant reduction in traditional symptom scores for this disease but also had decreased levels of three pro-inflammatory immune hormones. The latter observation suggests that the bacterium was able to ramp down or resolve the inflammation that had been supporting the arthritis.
Key microbes can be used either as targets of new therapies or as biomarkers to measure the progress of existing therapies. One example of this is the previously mentioned bacterium Akkermansia muciniphila. It turns out that the prevalence of Akkermansia muciniphila bacteria in the gut is a useful indicator of dietary manipulations that were effective on overweight/obese adults. Researchers noted that if they saw no changes in Akkermansia muciniphila, the diets were not going to work. Of course this also suggests that simply changing the prevalence of Akkermansia muciniphila in the easiest possible way might be a useful weight-loss strategy.
When the microbiome requires major changes, complete reconstruction can be performed. Such was the case of Grant Fisher from Wisconsin. As an infant he was deathly ill, having developed bronchitis at ten months old. A standard course of antibiotics cleared his airways, but he soon developed disturbing GI tract symptoms. He lost weight and was not thriving due to a Clostridium difficile (C. diff) infection. The doctors gave him more antibiotics in combination but to no avail. The little boy was dying. By eighteen months, Grant was on his deathbed. Then the doctors tried a radical strategy.
Knowing that such huge, prolonged courses of antibiotics kill off friendly as well as harmful gut bacteria, they performed a fecal microbiota transplant (FMT). They took some of his mother’s stool and transplanted it into his gut. It worked like a miracle.
Within twenty-four hours, Grant’s symptoms had disappeared. Within a week, tests could no longer detect C. diff in his system. The transplant swamped out the pathogen and reestablished a healthy gut microbiome. Grant’s life was saved. Agriculture has been using similar strategies for more than forty years to protect against problematic microbes.
The FMT procedure itself has gotten technologically better during its brief history. Originally, the transplant was given via a type of colonoscopy procedure. The Mayo Clinic in Arizona has used the procedure for several years for recurrent C. diff and reports a more than 90 percent cure rate. Recently, FMT has been successfully performed with frozen capsules taken orally. It is a less risky procedure.
Is FMT usable to treat any other diseases? The answer appears to be yes, but the exact range of its utility is still debated. Of course one of the wild cards in the procedure is the donated poop. It really needs to be from a healthy person with a well-balanced microbiome. Otherwise, you might transplant a dysfunctional microbiome and set up the recipient for other diseases (just like in the case where the mice became obese after receiving a transplant of obesity-associated gut microbes).
FMT appears to be useful for other gastrointestinal disorders. In particular it has been successful in treating ulcerative colitis (UC), one of the inflammatory bowel diseases. While not the 90 percent cure seen in C. diff infection, FMT has been 25 percent successful in ulcerative colitis patients. That is still remarkable progress in attacking this disease compared with the previous alternatives, which mainly employed immunosuppression. The investigators suspect the success rate can be increased once key microbes that are needed in order to reverse UC can be selected for inclusion within the donated poop.
A question remains about FMT for treatment of NCDs outside the gut. More trials are needed, but the biology suggests that it should be useful if the right donor is employed. One of the areas of investigation is with metabolic syndrome. Insulin resistance is a prelude to diabetes, and some studies have looked at FMT and its effect on insulin responsiveness. Because researchers know what some of the missing microbial signals are that prevent the control of obesity and diabetes, it may well turn out that targeted transplants or specific probiotic mixes are all that are needed. One of the initiatives under way is to standardize donor microbiomes since this is a variable that changes significantly among various clinical studies.
Finally, there is reason to believe that microbiome-based treatment of some conditions may not even require live probiotic bacteria or FMT. Several research groups have isolated gut microbial chemicals that can modulate the immune system, resolve inflammation, and change other physiological systems. These fall into several different categories, including sugars, fatty acids, and lipids. For example, Harvard microbiologist Dennis Kasper had encouraging results using polysaccharide A, a component of the bacterium Bacteroides fragilis. This bacterial sugar can dampen the immune system in cases of autoimmune disease and holds promise for treating diseases such as multiple sclerosis. Changing the balance of short-chain fatty acids (SCFAs), which are a fermentation product of specific gut bacteria, can have profound effects on both the immune system and the brain. A number of clinical research groups are pursuing using these chemicals in corrective therapies of NCDs with a particular focus on neurodevelopmental and neurodegenerative conditions. It has been exciting to discover that sphingolipids produced by gut bacteria can improve brain function and prevent dementia. This is potentially another whole category of microbiome-based therapeutics.
The research and clinical findings to date clearly show the value of focusing on the microbiome, in particular regarding the prevention and treatment of NCDs. If modifications to the microbiome are made, and balance and completeness is obtained, and yet the disease still remains, then the same standard drug therapies for symptom management (e.g., statins, antidepressants) with their sometimes severe side effects are still available. But to administer these drugs first without ever addressing a dysfunctional microbiome dooms the patient to a high probability of more physiological dysfunction and additional NCDs later in life. Our best health care providers will not soon forget the lesson of digoxin and food emulsifiers when it comes to the importance of the microbiome. Nor will they forget what we now know to be the largest part of our biology.
But what are nonprofessionals doing as this new paradigm emerges? What can we ourselves do with this new knowledge? Let’s turn to Part Three.