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Abdominal pain, irritable bowel in children reflected in microbial signatures

For a significant percentage of children, stomach pain is not "belly-aching." It is deep and visceral and can keep them from going to school or enjoying pleasurable activities.

In a first step toward identifying and ultimately treating this problem that can affect as many as 20 percent of school-age children, researchers at Baylor College of Medicine, Texas Children's Hospital, and the USDA/ARS Children's Nutrition Research Center at BCM and Texas Children's have identified specific bacterial signatures that include several unusual organisms in children with recurrent abdominal pain and irritable bowel syndrome. Youngsters with irritable bowel syndrome have stomach pain that is associated with changes in their bowel movements – either constipation or diarrhea. A report on their findings appears in the current issue of the journal Gastroenterology.

It is the first major report by the Texas Children's Microbiome Center and Baylor's Alkek Center for Metagenomics and Microbiome Research, which have been federally funded to understand the links between children's gastrointestinal diseases and their microbiomes. The microbiome refers to the billions of bacteria, viruses and fungi that inhabit the skin, intestines, genitourinary tract and other parts of the human body. The organisms in the microbiome outnumber human cells by a factor of 10 to 1, and the genes in the microbiome outnumber the genes in the human genome by a factor o f100 to 1. As scientists and physicians understand the microbiome and the genetic sequences of the bacteria involved, they may be able to intervene in a host of disorders.

Chronic belly pain

"It is a mystery as to what triggers the chronic belly pain of some children," said Dr. James Versalovic, professor of pathology & immunology at BCM and director of the Texas Children's Microbiome Center. "Why do some kids have frequent bouts of pain and why can it be associated with constipation or diarrhea?"

Versalovic is corresponding author of the study and also a professor of pediatrics, molecular and human genetics and molecular virology and microbiology as well as the programs in cell and molecular biology and translational biology & molecular medicine at BCM. He is also head of the department of pathology at Texas Children's Hospital.

To understand the mysteries of abdominal pain better, Versalovic and his colleagues assembled a profile of the bacteria in the intestines of children with irritable bowel syndrome and compared it to a profile of the bacteria of children who did not suffer from the disorder.

Dr. Robert Shulman, professor of pediatrics – gastroenterology at BCM and Texas Children's Hospital and a member of the Children's Nutrition Research Center and his colleagues have long attempted to understand the source of chronic belly pain in children. Shulman is also part of the Texas Children's Microbiome Center.

Pain, frequency associated with bacteria type "When we characterized the bacteria in the intestines of children with irritable bowel syndrome, we found it was different from what we found in healthy children," said Shulman. "We also found that the severity of their pain and how frequently it occurred was associated with certain types of bacteria. That does not mean necessarily that the bacteria cause the pain, but these children had certain species of bacteria that were less likely to be found in the intestines of healthy children." Shulman is also a senior author of the report.

A total of 44 children completed the study. Half of the children had irritable bowel syndrome and half were healthy. Children kept diaries of their abdominal pain and bowel function for two weeks. They also gave a stool sample for microbiome analyses. Some children gave several stool samples as part of a sub-study.

Researchers extracted DNA from the samples and determined what types of bacteria were present in the samples. While the total amount of bacteria did not differ between the two groups, the researchers did find differences in the kinds of bacteria. Children with irritable bowel syndrome had more Gammaproteobacteria than the healthy ones. Gammaproteobacteria encompass a wide range of bacteria – some benign and others associated with disease. In particular, the study found a greater proportion of Haemophilus parainfluenzae, Veillonella and Alistipes bacteria in the children with irritable bowel syndrome than those who were healthy. They also found a novel organism related to a genus of bacteria called Ruminococcus that was more common in the intestines of children with irritable bowel syndrome.

First study to use sequencing

"This is the first study of children with recurrent abdominal pain and irritable bowel syndrome, using comprehensive next generation sequencing approaches of human microbiome research," said Versalovic. "The next step is to see if there is causation and whether we can use this information to devise new treatments that change gut bacterial composition, including probiotics, antibiotics or specific diets."

Shulman said the findings make many important contributions. With more studies, the scientists will be able to figure out how these bacteria might influence the severity of pain or changes in bowel habits.

"It allows us to look at children more objectively. Instead of just relying on children's or parent's reports of their symptoms, we can characterize them by the bacteria in their guts," he said.

Shulman and Versalovic hope to expand the study, encompassing a wider group of children with chronic belly pain. In the future, being able to determine what kind of belly pain a child has by the character of the bacteria in the gut may make treatments easier.

Study provides foundation

"Two children who appear to have the same type of chronic belly pain may actually need two different treatments," said Shulman.

"This study provides a foundation," said Versalovic. "It tells us there are differences. Now we need to explore these differences in gut bacteria further in a larger patient population. That will give us the information we need to develop new strategies for treatment."

Those who wish to enroll in the expanded study should call 713-798-0381.

Others who took part in this research include Delphine M. Saulnier, Kevin Riehle, Toni-Ann Mistretta, Maria-Alejandra Diaz, Sabeen Raza, Erica M. Weidler, Xiang Qin, Cristian Coarfa, Aleksandar Milosavljevic, Joseph F. Petrosino, Sarah Highlander, Richard Gibbs, all of BCM, and Debasmita Mandal and Susan V. Lynch of the University of California San Francisco. Saulnier is now with NIZO, Ede, The Netherlands. Many of the BCM researchers are also affiliated with Texas Children's Hospital. Petrosino is director of the Alkek Center for Metagenomics and Microbiome Research at BCM.

Funding for this work came from the National Institute of Diabetes, Digestive and Kidney Diseases , the National Human Genome Research Institute, , the National Institute of Nursing Research, the Daffy's Foundation, and the Rainin Foundation.

Versalovic is the Milton J. Finegold Professor of Pathology & Immunology at BCM.

Shulman holds the Texas Children's Hospital Foundation Chair in Pediatric Gastroenterology.