Every year, about half a million patients are infected by Clostridium difficile, an otherwise harmless bacterium that can multiply out of control when the use of antibiotics upsets the balance of microorganisms in the gut. In 2011, about 15,000 deaths were directly attributable to the infection, according to a recent study by the federal Centers for Disease Control and Prevention (CDC).
Current probiotic treatments, which promote the growth of helpful bacteria, have been ineffective against the infection, also known as C. diff.
But work being done at U.Va.’s Division of Infectious Diseases and International Health could lead to a new treatment by the end of the calendar year, according to Dr. Bill Petri, chief of the division. That’s an unusually optimistic estimate in medical research, where scientific breakthroughs predate new treatments by several years.
“Some of these advanced probiotics are actually being tested today in the clinic for their role,” Petri said. “We’re actually participating in advanced clinical trials at U.Va.”
Immunologist Erica L. Buonomo was the driving force behind the new discovery, Petri said, which has to do with the role of white blood cells in protecting against C. diff.
Buonomo found that a particular type of white blood cells, called eosinophils, act as a barrier against the infection, which breaks down the lining of the gut. These eosinophils are recruited by a protein called IL-25. A serious C. diff infection kills eosinophils, allowing the bacteria to enter the gut.
The researchers found that gut bacteria stimulate the production of IL-25, so the right probiotic could help with the production of protective eosinophils.
“We identified a pathway in the immune response that reduces the severity of an infection,” Buonomo said. “When we activate this pathway, we find mice are a lot less sick.”
The discovery would be especially helpful for elderly patients, who are most at risk. It also could have larger implications in the world of microbiology.
Eosinophils are best known for their role in allergic reactions and asthma attacks, when a high number of eosinophils cause inflammation.
The function of these cells was not entirely clear before Buonomo’s discovery. She believes this knowledge could help doctors fight other types of gastrointestinal disorders, such as irritable bowel syndrome.
Pick a disease or disorder, and somebody, somewhere, has said that a probiotic supplement—an over-the-counter, unregulated pill usually filled with a single strain of friendly gut bacteria—might cure it, whether it’s cancer, obsessive-compulsive disorder, or a yeast infection.
But there’s very little evidence that probiotic supplements do any good. “There’s a lot of promise here but not a lot of proof yet,” said Cliff McDonald, associate director for science at the Centers for Disease Control and Prevention’s Division of Healthcare Quality Promotion.
Half a million people a year are infected with C. diff in the U.S., the CDC estimates, with 29,000 annual deaths related to the diarrheic bacterium. More than 65 percent of C. diff infections involve exposure in a health-care facility, according to a 2015 study, creating more than $4.8 billion in excess health-care costs at acute-care facilities alone.
C. diff. Treatments On The Horizon:
To Learn More About ALL C. diff. Clinical Trials In Progress Click On The Following Link:
Seres Therapeutics, a microbiome-based biopharmaceutical company in Cambridge, Mass., is developing a pill, subject to a rigorous approval process under the Food and Drug Administration, to tackle recurrent Clostridium difficile. (The digestive system’s microbiome is the community of healthy gut bacteria that normally reside in the body.)
Seres aims to put the science behind a proven treatment of recurrent C. diff, fecal transplants, in a pill, which wouldn’t require a colonoscopy. Like probiotic supplements, it’s a gut bacteria product. Unlike the supplements, by the time it’s available it will have gone through the FDA wringer. It will contain about 50 strains of bacteria proven effective in treating C. diff and will require a doctor’s prescription.
Recurrent C. diff is an obvious entry point for Seres, said Chief Executive Officer Roger Pomerantz. “We asked, what is the lowest-hanging fruit?” But it’s hardly the end. The company has built a microbiome library of 14,000 strains of human bacteria it hopes will help it treat a range of diseases, eventually without needing feces at all. Seres has embarked on the research with some pretty lofty goals, including finding treatments for obesity, liver disease, and cancer. It has partnerships with Massachusetts General Hospital, the Mayo Clinic, Memorial Sloan Kettering Cancer Center, and other respected medical institutions. “We will figure out exactly what’s wrong with the microbiome, design a drug, and then pull the organisms out with our library, never touching a human donation,” Pomerantz said. Seres’s lead product candidate, SER-109, will treat recurrent C. diff with four capsules taken orally instead of with transplants. While fecal matter is the raw material for the pills, the final product consists only of the spores necessary to treat the infection, which will have been extracted and purified. SER-109 is expected to become the first oral microbiome therapy approved by the FDA, though Seres declined to predict exactly when it will arrive. Results from the latest trials are due by midyear, and Phase 3 trials are scheduled to follow later in the year. Seres hopes to follow up quickly with SER-287, a drug to treat ulcerative colitis, which could be the first microbiome drug to treat a chronic disease, and SER-262, to treat primary C. diff before it turns into the recurrent kind.
Other companies are racing to collect enough data for FDA approval, but right now Seres, which is publicly traded, looks to be the one to beat. “Seres is probably going to be the first one that’s going to knock at the FDA’s door,” said Mohan Iyer, chief business officer at Second Genome, a microbiome company studying how to treat disease with the compounds produced by gut bacteria instead of the gut bacteria themselves.
“SER-109 is poised to be first-in-class among fecal microbiota transplant-derived drugs,” Joseph Schwartz, an analyst at Leerink Partners, wrote in a May report. The report says the latest trial results “wowed the Street” but warns that the company could still be held back by “disappointing clinical data” and obstacles in the regulatory process.
Another top contender is Rebiotix. Its RBX2660 is also designed to treat recurrent C. diff but, unlike SER-109, is administered with an enema; an oral version is in development. The treatment also differs significantly from Seres’s in formulation, including thousands of kinds of microbes from the donor’s stool, compared with SER-109’s 50 or so, as many as could be preserved and some of which haven’t even been identified.
“We make sure we have a minimum concentration of certain kinds that we know the patients lack,” CEO Lee Jones said. “But we don’t identify all of them. There’s no way to do that.” A recent study estimated that 1014 bacteria are in the human gut, most of which have never been isolated. Jones said the drug could hit the market by 2018.
The medications have been shown to be similarly effective—with no C. diff-associated diarrhea for 29 of 30 of Seres’s patients and 27 of 31 of Rebiotix’s, in the companies’ latest results—and equally safe. Adverse reactions for both are limited to such problems as moderate diarrhea and abdominal cramping, which could be from the C. diff itself. Both have been designated as “breakthrough therapies” by the FDA, allowing for an expedited approval process, and both are likely soon to provide an at-home alternative to fecal transplants.
Point Of View:
“I don’t know who is going to make it across the line first,” said Gail Hecht, director of gastroenterology and nutrition at Loyola University Medical Center and chairwoman of the American Gastroenterological Association for Gut Microbiome Research & Education. Hecht has attended a Seres advisory board meeting but doesn’t have a financial interest in the company. “It is indeed a race,” she said.
Seres does have at least one distinct market advantage. “Patients have different preferences,” Hecht observes, but “in general, people don’t particularly like enemas.”
Human Fecal Transplants:
For nearly two thousand years, doctors have looked to this unlikeliest of places for medicine. One of the earliest documented applications is from the fourth-century Chinese medical doctor Ge Hong, whose “yellow soup” recipe to treat diarrhea included a healthy person’s dried or fermented feces. Sixteen hundred years later, in 1958, patients infected with C. diff received the first known human fecal transplants.
Stool Bank Information:
Today the effectiveness of fecal transplants (formally known as fecal microbiota transplants) to treat recurrent C. diff is supported by a long list of studies, with researchers attributing the results to the restoration of the microbiome. OpenBiome, a nonprofit stool bank, shipped 1,828 treatments in 2014, a number that ballooned to 7,140 treatments in 2015 and looks to be eclipsed this year, with 4,323 treatments shipped to its clinical partners through May 31. And these numbers don’t take into account the transplants performed through directed fecal donations.
This article uncovers three major aspects in lifestyles that can directly impact the Microbiome.
The Gut Microbiome is a topic of great interest and with each new research comes a new discovery which opens a new window to possible medical influences in healthcare.
It’s a game changer and creating new avenues in science and medicine.
Dr. David Johnson, MD discusses Dietary Considerations focused in pre-biotics and pro-biotics and a new look at — —- A more recent study revealed that species of Faecalibacterium, Akkermansia, and other less well studied members may also be enriched.
The negative sides and new discoveries of “artificial sweeteners.”
Dr. Johnson shares great information regarding “Sleep.” ……. circadian rhythms regulate a number of gastrointestinal functions, ranging from gastric acid production to small intestinal nutrient absorption to colonic motility. These rhythms are also strong regulators of immunologic processes and the gut microbiome (abundance, speciation, and function), which fluctuates in accordance with their influence.
Along with “exercise” ….. the microbiota has an established role in the development and homeostasis of the gastrointestinal tract, the potential impact of exercise and fitness on the gut microbiota has attracted recent attention. However, more research is required to quantify the anti-inflammatory and metabolic effects of moderate exercise and to weigh these against the potential hazards of excessive exercise.
This is quite an interesting and informational article — one that will shine new light on a topic of interest in both the science and medical communities.
The gut microbiome, a dynamic feature of the gastrointestinal system, has the potential to dramatically influence health outcomes. Through complex interactions with the host immune system and signaling pathways, the gut microbiome can significantly influence the pathogenesis of disease states such as cancer, metabolic syndrome, inflammatory bowel disease, and nonalcoholic fatty liver disease.
Recent technological advances have vastly improved not only our understanding of the gut microbiome but also potential mechanisms through which we may confer health benefits by altering it. As what one eats partially determines the gut flora, there are very likely significant dietary effects on the gut microbiome and a likely interaction across a broad spectrum of systemic diseases. Furthermore, emerging data on factors such as sleep and exercise underline their potential role in affecting the microbiome. This review summarizes our current understanding of how microbiome health may be affected by these lifestyle factors.
A wide range of dietary carbohydrates, including prebiotic food ingredients, fermentable fibers, and milk oligosaccharides, have been shown to produce significant changes in the intestinal microbiota. These shifts in the microbial community are often characterized by increased levels of bifidobacteria and lactobacilli. A more recent study revealed that species of Faecalibacterium, Akkermansia, and other less well studied members may also be enriched.
Investigations of clinical outcomes associated with dietary modification of the gut microbiota have shown systemic as well as specific health benefits. Both prebiotic oligosaccharides comprised of a linear arrangement of simple sugars as well as fiber-rich foods containing complex carbohydrates have been clinically studied with variable benefit. However, inconsistency of response across study participants can make the outcome of dietary interventions less predictable and limit the value of making specific recommendations to individual patients.
Nondigestible food ingredients, prebiotics can beneficially affect the host by selectively stimulating the growth and/or activity of one or more bacteria in the colon. They do so via selectively fermented ingredients that can change the composition and/or activity in the gastrointestinal microflora. In order for a food to be classified as a prebiotic, it must resist gastric acidity, hydrolysis by mammalian enzymes, and absorption in the upper gastrointestinal tract, so that it is able to be fermented by the gut microbiota into short-chain fatty acids (including acetate, propionate, and butyrate) that can be used for energy. Thus, prebiotics not only can cause shifts in the microbiota by supporting growth of a particular intestinal microbiome but also serve as substrates for production of biologically active metabolites. The primary prebiotics are the inulin-type fructans oligofructose and fructo-oligosaccharides, yet there are a number of others, including the galactan galacto-oligosaccharide. Fermentation of prebiotic carbohydrates yields butyrate and other short-chain fatty acids as well as other end products that lower the local pH, stimulate mucin production by colonocytes, and induce immunomodulatory cytokines, all of which may have potential disease modulation effects.
Prebiotic fibers are often natural constituents of a variety of foods, especially whole grains, fruits, root vegetables, and legumes. Although some foods contain appreciable concentrations of these prebiotics, they are probably found too infrequently in most Western diets to contribute much fermentable fiber to the colon. Prebiotic fiber products such as psyllium have been commonly used to supplement where needed. As a practical strategy, consumption of fermentable fiber or combinations of prebiotics may enrich for a larger and more diverse population of gut microbes and should be a standard recommendation for most disease states.
In order for a live micro-organism to be classified as a probiotic, it must satisfy the following criteria: (1) exert a beneficial effect on the host; (2) be nonpathogenic and nontoxic; (3) contain a large number of viable cells; (4) be capable of survival and metabolism within the gut; (5) remain viable during storage and use; (6) have good sensory properties; and (7) be isolated from the same species as the intended host.
Probiotics have long been used as therapeutic agents for improving gastrointestinal health. Although several microbial taxa or genera have been suggested as being beneficial to the host, there is still no actual definition of what constitutes a healthy gut microbiome to a specific patient. Most available information concerns Bifidobacterium and Lactobacillus spp; consequently, most commercially available products generally contain bacteria from one or both of these species.
Probiotics have been shown to provide a number of health benefits and can potentially be used to alter the gut microbiome and thereby treat certain gastrointestinal conditions. Within the gastrointestinal tract, probiotics play a number of functional roles, including maintaining the intestinal barrier integrity, regulating mucin secretion, controlling immunoglobulin A secretion, and producing antimicrobial peptides, which influence cytokine production. In clinical trials, probiotics have shown beneficial effects in nonalcoholic fatty liver disease and ulcerative colitis, but a favorable effect has not been consistently demonstrated to date. The combined physiologic and clinical data strongly support the continued research of probiotics as a potential therapy for manipulating the gut microbiome.
Introduced over a century ago, artificial sweeteners were designed to enhance taste without the effects of caloric intake, theoretically benefiting health by weight reduction and enhanced glycemic control. These agents are commonly used in a broad array of foods, beverages, and candy designed for diabetics and those actively dieting. However, recent information shows that these formulations drive the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota, which in fact promote glucose intolerance. These agents may therefore have directly contributed to enhancing the very obesity epidemic they were intended to combat.
Similar to other organ systems, the gastrointestinal tract operates on a 24-hour circadian schedule that anticipates and prepares for changes in the physical environment associated with day and night. These circadian rhythms regulate a number of gastrointestinal functions, ranging from gastric acid production to small intestinal nutrient absorption to colonic motility. These rhythms are also strong regulators of immunologic processes and the gut microbiome (abundance, speciation, and function), which fluctuates in accordance with their influence. This occurs via bidirectional communication between the central nervous system and an immune system and is mediated by shared signals (neurotransmitters, hormones, and cytokines [the brain-gut axis]) and direct innervations of the immune system by the autonomic nervous system.
Prolonged sleep curtailment and the accompanying stress response invoke a persistent unspecific production of proinflammatory cytokines, which results in a low-grade chronic inflammatory state. Epidemiologic studies have established the best amount of sleep to target as approximately 7 hours. This is the range that best correlates with lower prevalence of cardiovascular disease.
Recent attention has also focused on the sleep disruption-related upregulation of provocative cytokines, such as tumor necrosis factor alpha in patients with inflammatory bowel disease, which can increase the risk of inducing a disease flare or perpetuating disease activity.
There has long been a connection between exercise and gut symptomatology. Exercise and fitness modulate vagal tone, which is an integral component of the brain-gut microbiome axis. With exercise contraction of skeletal muscle, there is an innate immunity enhancement created by the release of muscle-related anti-inflammatory cytokines or myokines. Additionally, there is an associated reduction of toll-like receptors (involved in many inflammatory and cancer pathways) on monocytes and macrophages. Exercise and the gut microbiome share many immunometabolic and physiologic processes that are well established in cardiovascular health and other areas beyond the gut.
Although there is an intuitive role for exercise in the prevention and treatment of gastrointestinal conditions such as irritable bowel syndrome, nonalcoholic fatty liver disease, and obesity, among others, the recommendation to include exercise and fitness is not yet standard for specific disease state management.
As the microbiota has an established role in the development and homeostasis of the gastrointestinal tract, the potential impact of exercise and fitness on the gut microbiota has attracted recent attention. However, more research is required to quantify the anti-inflammatory and metabolic effects of moderate exercise and to weigh these against the potential hazards of excessive exercise.
The effects of prebiotics, probiotics, and even antibiotics on the gut microbiome will continue to remain a mainstay of investigation and will hopefully advance our knowledge of the intricacies of the gut microbiome while improving clinical outcomes. Supplemental focus on exercise and sleep function will likely have an added beneficial effect. My prediction is that enhancing our disease management protocols will require us soon to all be in the “gut microbiome business.” This will likely be directed toward “dysbiosis” management using multiple approaches, often in combination.
Exciting work from the Weizmann Institute in Israel highlights the need to develop new nutritional strategies tailored to the individual patient, whereby unique diet and exercise protocols are used to correct the microbiome. In taking such an approach, we may no longer rely on empiricism or published clinical trial data but instead more accurately address each patient’s needs in order to restore microbiome balance.
Krumbeck JA, Maldonado-Gomez MX, Ramer-Tait AE, Hutkins RW. Prebiotics and synbiotics: dietary strategies for improving gut health. Curr Opin Gastroenterol. 2016;32:110-119. Abstract
Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;514:181-186. Abstract
Rosselot AE, Hong CI, Moore SR. Rhythm and bugs: circadian clocks, gut microbiota, and enteric infections. Curr Opin Gastroenterol. 2016;32:7-11. Abstract
Cronin O, Molloy MG, Shanahan F. Exercise, fitness, and the gut. Curr Opin Gastroenterol. 2016;32:67-73. Abstract
Zeevi D, Korem T, Zmora N, et al. Personalized nutrition by prediction of glycemic responses. Cell. 2015;163:1079-1094. Abstract
With the warmer weather season upon us…..a cup of refreshing homemade frozen yogurt is not only enjoyable but is beneficial.
Natural probiotics should be ingested at the end of a meal; on a full stomach. This is due to the Ph balance of the G.I. system making it a desirable time for the live cultures to survive and be the most beneficial to the gastrointestinal system.
* Note: When taking Antibiotics it is best to wait two hours after ingesting probiotics to obtain the maximum benefits of the probiotics. Frozen YogurtRecipe : 6 ounces fresh or frozen berries stirred into 16 ounces vanilla yogurt then placed into a container recommended for freezing and enjoy. For extra caloric value: Add a 5 ounce package of shortbread cookies crushed well and then stir into the mixture before freezing.
C Diff Foundation, Sponsor, with Founder Nancy C. Caralla, Executive Director and Dr. Chandrabali Ghose, Chairperson of the Research and Development Community will be broadcasting live on Tuesdays delivering the most up-to-date information pertaining to a leading super-bug/ Healthcare Associated Infection (HAI), C. difficile, with additional HAI’s, and a variety of related healthcare topics.
Topic experts will be joining your hosts to discuss prevention, treatments, clinical trials, and environmental safety products on a global level.