Researchers say that new insight into the microbiome will lead to new opportunities for treating a variety of medical conditions, both within and outside the gut.
But even as C. diff strains grow hardier and more toxic, mounting evidence suggests that more than 90% of recurrent infections can be cured with feces transplanted from healthy donorsâ€‘â€‘an increasingly popular procedure that may portend a new breed of probiotic treatments.
Dozens of recent studies have found strong correlations between various gut flora and a wide range of conditions, including asthma, diabetes, obesity, anxiety, and tooth decay. Some researchers now believe that the thousands of species that collectively form the human microbiome will prove more important to health and more susceptible to modification than the human genome. Others researchers find such predictions absurdly optimistic.
To date, the only probiotic treatment to demonstrate dramatic improvement over older alternatives is fecal microbial transplantation (FMT) for antibiotic-resistant strains of C. diff, an anaerobic, spore-forming rod that causes severe diarrhea, fever, abdominal pain, and, often, pseudomembranous colitis.
Common-but-unidentified gut flora prevent C. diff from infecting healthy people, but antibiotics eliminate that protection and set the stage for infections. Additional antibiotics cure more than 75% of patients, but the durability of some C. diff strains has long inspired experimental treatments.
New evidence for effectiveness of old therapy
Published reports of FMT date back to 1958, with nearly all of them claiming spectacular cure rates. It was only in January 2013, though, that the New England Journal of Medicine first published results from a controlled trial that compared FMT with conventional procedures for chronic C. diff infections.
A group of 16 patients took the antibiotic vancomycin for four days, underwent an intestinal wash and then receivedâ€‘â€‘via nasal tube threaded to the small intestineâ€‘â€‘an infusion of feces that had been blended with saline and strained. A second group of 13 patients took vancomycin for two weeks and received the intestinal wash, while a third group of 13 received nothing but two weeks of vancomycin.
15 people in the FMT group were cured after the first treatment, compared to three in the second group and four in the third. The 18 uncured control patients then received FMT, which cured 15 of them.
“Even if FMT proves unable to cure anything else, this still qualifies as a major advance. More Americans die each year from C. diff than from any other healthcare-acquired infection,” said Daniel A. Leffler, MD, MS, Director of Clinical Research for The Celiac Center at Beth Israel Deaconess Medical Center and Director of Quality Assurance for the hospital’s Division of Gastroenterology.
“We’re nowhere near the point where every practicing gastroenterologist should be doing FMT in the office, but all of them should be aware of the procedure and discuss it with appropriate patients.”
Looking beyond IBS
Some researchers believe that FMT, or similar treatments designed to optimize gut flora, may also cure other gastroenterological conditions such as irritable bowel syndrome (IBS) and certain variants of inflammatory bowel disease (IBD).
A few disease-specific detailsâ€‘â€‘like the six-fold increase in IBS vulnerability immediately after gastrointestinal infectionâ€‘â€‘suggest those diseases may relate, at least in part, to bacteria, as do a small number of published reports that correlate FMT with long-lasting and apparently complete cures for several IBD patients.
Many clinicians remain skeptical about the claims of widespread benefits.
“We already knew that antibiotics facilitate C. diff infection by killing the flora that normally protect us. It didn’t take a genius to figure out that restoring those flora might be a good idea,” said Ciaran P. Kelly, MD, Professor of Medicine at Harvard Medical School and Director Gastroenterology Fellowship Training at Beth Israel.
“But there’s no reason to expect fecal transplants to cure IBS or IBD. We don’t know what causes them. And we’ve already tried other types of probiotic therapy, with very limited success.”
Similar warnings apply when the topic turns to the stark and unexpected correlations that link a wide variety of conditions with the intestinal bacteria at the heart of gastroenterology.
Asthma: A National Health and Nutrition Examination Survey involving 3,327 children age 3—13 years showed in 2007 that those who carried Helicobacter pylori were 53% less likely to experience asthma than those who did not have the bacterium. A 2011 study at the University of Zurich exposed two groups of mice to allergens. Asthmatic inflammation developed in all of the mice that were exposed to H. pylori as adults but none that were exposed six days after birth.
Obesity: A 2011 meta-analysis of 19 studies with 1,801 participants showed significantly higher circulating concentrations of the appetite-stimulating hormone ghrelin in H. pylori-negative participants than in H pylori-positive participants [Effect estimate (95%CI) = -0.48 (-0.60, -0.36)]. A 2012 NYU study published in Nature found that mice given any of several common antibiotics in infancy have 15% more body fat than control mice fed the same diet.
Diabetes: Researchers from University College, London, performed Roux-En-Y gastric bypasses on mice to explore why the surgery usually cures type-2 diabetes and found major changes in gut flora. Altered mice had 52 times as much Enterobacter hormaechei as control mice but lower concentrations of Firmicutes (4.5-fold) and Bacteroidetes (two-fold).
Anxiety: Researchers at McMaster University transferred gut flora between two strains of mice, one known for aggression and the other for timidity. Flora from either type of mouse inserted into germ-free mice of the other type halved the behavioral gap. A study of human women published in Gastroenterology found that four weeks of fermented milk with added probiotics affected the brain regions that control central processing of emotion and sensation.
“The incredible variety and strength of the findings put me in the camp that expects this research into the microbiome will lead to new opportunities for treating a variety of medical conditions, both within and outside the gut.” said Stephen M Collins MBBS, FRCPC, Associate Dean of Research for the Health Sciences School at McMaster University in Canada.
The real question, however, is where patients will turn for those new treatments. Some observers believe that gastroenterologists will probably land some role in treating any condition that stems, at least in part, from bacteria in the digestive tract. Others believe that the specialists who already treat any given field will fight like tigers to keep gastroenterologists away from “their” patients.