HOLON, Israel — The children's gastroenterologist Arie Levine isn’t shy about calling himself a pioneer, at least when it comes to the origins of Crohn’s disease and how to cure it. He’s convinced that the genes kids are born with are not the reason so many of them in the developing world are getting Crohn's and other inflammatory bowel diseases, or IBDs. The real reason, he said, is all the animal fats, unmixable liquids known as emulsifiers and food additives they’re putting in their stomachs. Levine, a native of Rochester, N.Y., heads the Pediatric IBD Center at Wolfson Hospital in Holon, a suburb of Tel Aviv. A member of the D-ECCO Working Group of the European Crohn’s and Colitis Organisation, he’s seen an alarming rise in the incidence of Crohn’s. And it's not just among Ashkenazi Jews, whose well-documented genetic predisposition to Crohn’s has made it common in Israel. “Until five years ago, Crohn’s disease was perceived by the medical world as an autoimmune disorder, in which the immune system attacks the intestines. All the drugs developed by pharmaceutical companies are against the immune system,” Levine told IBD News Today at his clinic at Wolfson, where he’s worked since 1999. “But in 2007, I came up with a different concept. I thought this may be a defect in the immune system’s ability to prevent bacteria from sticking to the lining of the intestines, which then generates an appropriate counter-attack by the immune system.” Levine said IBD now afflicts half a percent of the Western world, including 1.2 million cases in the United States and 2.3 million in Europe. “A disease which was once rare and becomes so prevalent has to be environmental; it cannot be explained by genes,” he said. “Once seen primarily among Ashkenazi Jews, it’s now in India and China. Within a decade after the Berlin Wall fell, they had an epidemic of Crohn’s in the former East Germany, Poland, Hungary and other Eastern European countries.” Crohn’s Spreading Rapidly Through Developing World In fact, the prevalence of IBD has risen as much as 15 percent in newly industrialized countries since 2000, according to a report in December of 2017. The study, “Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies,” appeared in The Lancet. Other research has shown that 43 children and 214 adults per 100,000 Americans had Crohn’s in 2004-05, but the figures rose to 48 children and 236 in just four years. The cost of treating Crohn’s in the United States is about $3.6 billion a year — a hefty $8,265 per patient. “Imagine if you had people developing chronic lung disease before they knew smoking was causing the disease. Would they have been given drugs, or told to stop smoking? This is the same thing,” Levine said. “In the Western world, we’re being exposed to too many things like emulsifiers and artificial sweeteners. If don’t stop eating those things, you can take as many drugs as you like, but your disease will progress.” What Levine calls the worldwide epidemic of Crohn’s led him to suspect that poor nutrition — not genetics — was behind its spread. The problem, he said, isn’t that the immune system is overreacting to what's in the gut, but that the body isn’t properly clearing bacteria from the gastrointestinal tract. “Our GI tract has developed into a very smart defensive border against hundreds of billions of bacteria in every gram of stool,” Levine said. If the bacteria appear threatening, he said, the immune system can step in. "Crohn’s disease might be a disorder in which bacteria sticks to the lining of the epithelium [in the gut]," he said. "You can’t attack the bacteria without causing ulcers in the intestine." He thinks "we’re too focused on targeting the immune system instead of the bacteria which stimulates the immune system.” The more damage that's done to the intestine, Levine theorizes, the more Crohn’s can penetrate it. What began shifting the medical community’s opinion on this, he said, were studies suggesting that genetic susceptibility accounts for only 15 to 25 percent of Crohn’s cases. “We suspected not only a change of microbiome or gut bacteria, but also a change in the ability of the intestines to fend off those bacteria. So we started looking for what could be driving these changes, and that was very attractive to me as a hypothesis,” he said. Levine: ‘It’s The Diet, Dummy!’ The European Crohn’s and Colitis Organisation now recommends that children with Crohn’s consume only liquids as a first-line treatment before trying a drug. In 2010, Levine developed his own Crohn’s Disease Exclusion Diet based on whole foods. He said his eureka moment came on a day when a woman brought in her son, who had recently developed Crohn’s. “I wanted to put the kid on a liquid treatment but didn’t want to give steroids because at the time it wasn’t covered by insurance. But the mother and son were very much opposed to the liquid diet,” he said. “The kid got better in three weeks with just regular food — no drugs and no formula. That to me said everything: It’s the diet, dummy!” A second Crohn’s patient, a 21-year-old woman, had been put on an immune suppressive agent but was not doing well, Levine said. “She came to me for a second opinion. I told her that I believed diet was driving the disease. She went into complete remission without any drugs,” he recalled. “It blew my mind away. I’m removing the stimulus that’s triggering the immune system, and it’s triggering it through the bacteria. If you remove the agent, the intestines can heal by themselves.” As simple as that sounds, Levine said, “nobody believed my concept. I started with a hypothesis that went against everything in the medical community.” Nevertheless, in 2011 the processed foods giant Nestlé — which makes a liquid product for Crohn’s — invited Levine to Switzerland to meet with its scientists. The company awarded him a grant that allowed him to start his research. Levine Oversees 5 Crohn’s Dietary Studies Levine has received $1.5 million in funding toward seven IBD dietary studies — five in Crohn’s disease and two in ulcerative colitis. Four employees are helping him with clinical trials, which range anywhere from $150,000 to $600,000 each. Pursuing the research hasn't been easy, he said. “I’m working off of grants, since there was no industry developing this field of research, and we have to do all the regulatory stuff ourselves,” he said. “It’s very challenging to do clinical trials in multiple countries as an investigator.” The first of Levine’s five Crohn’s studies, “Partial Enteral Nutrition With a Unique Diet vs. Exclusive Enteral Nutrition for the Treatment of Pediatric Crohn’s Disease” (NCT01728870), is a randomized control trial in Israel and Canada. It is comparing his Crohn’s Disease Exclusion Diet with a liquid-formula diet that ECCO recommends. “We’re going head-to-head against the best therapy,” he said, adding that results of the 72-patient study should be available by the end of this year. The second study in children with Crohn’s, “Diet for Induction and Maintenance of Remission and Re-biosis in Crohn’s Disease” (NCT02843100), started Jan. 1 in Canada, Spain, Ireland and Israel. Levine plans to enroll 50 patients in it. The third trial, “Pilot Study of Partial Enteral Nutrition With a Unique Diet for the Treatment of Adult Patients With Crohn’s Disease” (NCT02231814), is a proof-of-concept study involving 40 adults. Levine is already enrolling patients in Israel. Praise for 'Pioneering' IBD Research. Levine declined to reveal exactly what's in the Crohn’s Disease Exclusion Diet, although he did say “it’s not an anti-inflammatory diet, or a diet that affects the immune system. All we’re doing is removing offending agents that will change the composition of bacteria in the intestine or weaken the intestinal barrier." Johan Van Limbergen, an associate professor of pediatrics at Canada’s Dalhousie University, praises Levine’s pioneering research. “The increasing number of children affected by inflammatory bowel disease around the world points to environmental factors playing an important role,” Van Limbergen said in an email from Halifax, Nova Scotia. “Diet has been shown to be one of the key factors. Professor Levine’s studies of dietary changes to alter the gut microbiome and help control inflammation are likely going to offer new treatment options for IBD patients in the near future.” Dr. James D. Lewis of the University of Pennsylvania's Perelman School of Medicine hailed Levine for "pushing the boundaries of using diet" as a primary and add-on therapy for IBD. "His approach is refreshing in the way he has drawn on existing biologic principles to develop diets that address multiple potentially important aspects of the underlying etiology of IBD and factors that contribute to perpetuating the inflammatory process," Lewis said. "His early clinical trial results are extremely promising for the field."