Letter from the Publisher

Probiotics Symposium

I had the pleasure to attend the October 2013 Probiotics Symposium in San Antonio, sponsored by Klaire Labs/ProThera. Like most integrative physicians, I had the notion that probiotic supplementation is an important part of the clinical prescription; all that I needed to know was that every patient needs to be using a probiotic supplement. After all, we know that most folks eat too much sugary, fatty fast food and that GI dysbiosis is a given for nearly everyone. From a nutritional viewpoint, the use of probiotics makes good sense – but what is the evidence base for its application in clinical medicine?

Michael Cabana, MD, MPH

Michael Cabana, MD, MPH, professor of pediatrics at UC San Francisco, is a principal investigator for the NIH/NCCAM study on Probiotic Outcomes on Enteric Microflora (POEM) and for the NIH Trial of Infant Probiotic Supplementation to Prevent Asthma. Cabana reviewed that the method of delivery plays a major role in the infant gut’s colonization: an infant delivered by C-section has gut flora that resembles the mother’s skin colonization; for example, Staphylococcus sp. In contrast, the infant delivered vaginally has a greater diversity of microbiota that more closely resembles the maternal vaginal and intestinal flora. Animal trials reveal that there is a “window of time” in perinatal development that plays an important role in the development of allergic disease. Epidemiologic data suggest that infants exposed to a rural, farm environment and to a broad range of organisms develop a more robust immune system compared with infants growing up in a more sterile, urban environment. The thinking then is that the administration of probiotics to infants may prevent development of allergic disease. A large number of diverse studies having varying populations and differing probiotic formulations have had either positive or negative outcomes in demonstrating probiotics prevention of allergic disorders. While there is insufficient evidence that prophylactic probiotic administration plays a role in the development of allergy, further studies are under way.

Maria Oliva-Hemker, MD

Studies undertaken by neonatologists of the role of probiotics in preventing necrotizing enterocolitis (NEC) in preterm low-birth-weight infants have more compelling evidence. Maria Oliva-Hemker, MD, chief of the Division of Pediatric Gastroenterology at Johns Hopkins University, reviewed trials supporting the use of probiotics in premature infants. Animal studies suggest that probiotic supplementation can protect against NEC. Human studies have demonstrated the role of breast-feeding in establishing diverse infant gut colonization as compared with formula feeding. The hypothesis is that probiotic supplementation in the neonate may play a role in preventing NEC. Clinical trials have demonstrated a consistent benefit in reducing NEC when the premature infant is supplemented with probiotics. There remain some concerns that there may be some adverse outcomes in the preterm infant population with probiotic supplementation.

Charalabos Pothoulakis, MD

The moderator of the event, Charalabos Pothoulakis, MD, officiated the Q&A, offering insightful scientific repartee flavored with his Greek accent from his 25 years of research of Saccharomyces boulardii. Pothoulakis is professor of medicine and director of the UCLA Inflammatory Bowel Disease Center. Pothoulakis’s lecture on the physiologic mechanisms by which S. boulardii controls Clostridium difficile infection was deserving of an honorarium. C. difficile is the primary cause of infectious disease associated diarrhea in the US. In its most extreme form it is capable of causing colitis, toxic megacolon, and death. Clostridia act by releasing toxins A and B. S. boulardii, originally discovered in 1920 and licensed in 1953, has been subject to more than 50 clinical trials and reported in more than 300 publications. The studies have established that S. boulardii effectively prevents and treats Clostridia-caused diarrhea. S. boulardii is very effectively colonized in the intestine while it is being administered therapeutically. S. boulardii reduces cytokine formation by Clostridia and inhibits intestinal fluid secretions induced by the toxins. More importantly, S. boulardii prevents the histopathologic damage to the intestinal cells. Intestinal cell barrier functions disrupted by Clostridia are preserved by S. boulardii.

S. boulardii acts as a trophic factor for the intestinal mucosa, preserving its integrity. Pothoulakis leaves little doubt that S. boulardii is vitally important in controlling C. difficile. Moreover, S. boulardii is an important probiotic yeast for the control of many other infections.

Stig Bengmark, MD, PhD

I was also delighted to hear and meet Stig Bengmark, MD, PhD, former chief of surgery at Lund University Hospital in Sweden and visiting professor at University College London. Bengmark is the author of more than 1000 scientific publications, of which 500 have been included on PubMed. He has pioneered the use of probiotics for chronic liver disease and for preoperative management and control of infections in patients undergoing abdominal surgery. His current work focuses on nutritional education for the pubic and health professionals: he teaches how to increase prebiotics and probiotics in a healthful diet. At 87 years of age, Bengmark and his wife live what he preaches. Bengmark reminds us that the gut microbiota based on the genome of 100 trillion bacteria is 150 times larger than the human genome. Hence a dysbiotic gut replete with bacteria and yeast that are pathologic will induce inflammation and disrupt our DNA processes. A diet high in sugar, processed foods, allergenic foods, chemicals, and preservatives will favor dysbiotic organisms. Such organisms will increase intestinal permeability and absorption of lipopolysaccharide endotoxins. Bengmark reminds us that high consumption of cooked meats and processed grains results in absorption of advanced glycated end products (AGEs), which favors dysbiosis. The only means to reverse this process is to emphasize a diet of greens, fruits, spices, nuts, with occasional meat, fish, and eggs. Even without allergy testing, individuals should avoid gluten, dairy, and sugar. Bengmark cites compelling literature to support the use of probiotics to treat abdominal inflammatory disease. He offers great patient education at his website: www.bengmark.com.

Russell Jaffe, MD, PhD

I was pleased to also meet Russell Jaffe, MD, PhD, at the symposium. Jaffe’s talk on predictive biomarkers is also the title of his and Jayashree Mani’s article in this issue of the Townsend Letter. I have had the pleasure of knowing Jaffe for years, as he has been a presenter at many conferences, including ACAM, ICIM, AAEM, and A4M. Jaffe is an internist, molecular biochemist, and clinical pathologist. Currently he is the lab director of ELISA/ACT Biotechnologies in Virginia. At the probiotics symposium, Jaffe reviewed laboratory biomarkers that enable one to assess the state of the human microbiome. Jaffe argues, with his coauthor, Mani, that these same biomarkers may be used to assess our overall health status and predict the relative risk for maintaining health or developing degenerative disease. The first three biomarkers, hemoglobin A1c (HgbA1c), high-sensitivity C-reactive protein (hs-CRP), and homocysteine, are well known to the conventional and integrative medical communities. Jaffe postulates that a very low HgbA1c, hs-CRP, and homocysteine would predict a greater than 99% likelihood that a person would be alive in 10 years; contrariwise he conjectures that high scores of these biomarkers would offer less than a 20% chance that a person would be alive in 10 years. Jaffe thinks that there is “power” in observing each of these biomarkers at the same time: if one biomarker is high and the others are low, then the risk is not nearly as bad as if one had only measured the high biomarker.

Jaffe and Mani state that elevated levels of HgbA1c, hs-CRP, and homocysteine are responsive to lifestyle changes including optimization of diet, nutritional supplementation, exercise, and stress reduction. Optimization of the diet requires more than a reduction of junk foods high in sugar and fat. Additionally, the authors argue that there needs to be a careful elimination of allergenic and sensitizing foods, through an “immunotolerant” diet. Further, the diet needs to focus on “super” foods having high levels of antioxidants, primarily by emphasizing more vegetables and fruits than starches and animal proteins. Getting the patient to implement these dietary changes requires considerable education and nutritional counseling (and medical coercion) as well as documentation of food allergies and sensitivities. Jaffe and Mani require that food allergies be tested; they propose that such testing include a measurement of reactive antibodies including IgA, IgM, and IgG as well as measurement of immune complexes and direct T-cell studies.

The idea that HgbA1c, hs-CRP, and homocysteine levels can be easily modified by adherence to a allergy-free “super food” diet is academically satisfying but may prove to be as unattainable as lowering an elevated cholesterol score without the use of a “statin.” Jaffe and Mani think that an ideal HgbA1c would be 5.0; I think that this would require not only a vigilantly policed low-glycemic diet but megadose nutrient supplementation to optimize pancreatic and liver functioning. Likewise, achieving a homocysteine score of 6.0 may require more than optimization of the methyl and sulfur pathways. While nutrient therapy with methylfolate, hydrocobolamin, and other nutritional sulfur factors is thought to optimize homocysteine, it has been my observation that lowering homocysteine levels poses a challenging therapeutic challenge. The reduction of an elevated CRP with an immunotolerant diet and nutritional anti-inflammatories would seem more readily achievable; however, patients having marked elevations of CRP and sedimentation rate who suffer with highly inflamed autoimmune disease may not be so fortunate to have reduction in their CRP scores by diet and supplementation alone.

Jaffe and Mani report on five other predictive biomarkers. They argue that the eight biomarkers taken as a whole offer a very comprehensive means to quantify the patient’s health status and ability to predict the risk for developing disease or maintaining health. The physical exam offered by primary doctors and internists typically includes a basic lab screening – the complete metabolic panel and a lipid panel. Although the lipid testing offers some insight into a patient’s health, the metabolic panel is generally normal. Thus patients are given “clean bills of health” at their physicals, but there are little laboratory data to support this diagnosis. The biomarkers discussed by Jaffe and Mani offer a much broader level of information capable of evaluating metabolic functioning, inflammation, glycemic control, food allergy reactivity, and antioxidant status. A patient tested for these biomarkers would truly be given a “bill of health.”

Jonathan Collin, MD