Identification of Unique Gene Expression Profile in Children with Regressive Autism Spectrum Disorder (ASD) and Ileocolitis

Gastrointestinal symptoms are common in children with autism spectrum disorder (ASD) and are often associated with mucosal inflammatory infiltrates of the small and large intestine. Although distinct histologic and immunohistochemical properties of this inflammatory infiltrate have been previously described in this ASDGI group, molecular characterization of these lesions has not been reported. In this study we utilize transcriptome profiling of gastrointestinal mucosal biopsy tissue from ASDGI children and three non-ASD control groups (Crohn’s disease, ulcerative colitis, and histologically normal) in an effort to determine if there is a gene expression profile unique to the ASDGI group. Comparison of differentially expressed transcripts between the groups demonstrated that non-pathologic (normal) tissue segregated almost completely from inflamed tissue in all cases. Gene expression profiles in intestinal biopsy tissue from patients with Crohn’s disease, ulcerative colitis, and ASDGI, while having significant overlap with each other, also showed distinctive features for each group. Taken together, these results demonstrate that ASDGI children have a gastrointestinal mucosal molecular profile that overlaps significantly with known inflammatory bowel disease (IBD), yet has distinctive features that further supports the presence of an ASD-associated IBD variant, or, alternatively, a prodromal phase of typical inflammatory bowel disease. Although we report qPCR confirmation of representative differentially expressed transcripts determined initially by microarray, these findings may be considered preliminary to the extent that they require further confirmation in a validation cohort.

Figure 4 Overlapping unique ASDGI gene expression from TI and colon.

 

Overlapping unique ASDGI gene expression from TI and colon.

Learn more here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0058058#abstract0

For the first time, researchers isolate adult stem cells from human intestinal tissue

For the first time, researchers at the University of North Carolina at Chapel Hill have isolated adult stem cells from human intestinal tissue.

The accomplishment provides a much-needed resource for scientists eager to uncover the true mechanisms of human . It also enables them to explore new tactics to treat  or to ameliorate the side effects of chemotherapy and radiation, which often damage the gut.

“Not having these cells to study has been a significant roadblock to research,” said senior study author Scott T. Magness, PhD, assistant professor in the departments of medicine, biomedical engineering, and cell and  at UNC. “Until now, we have not had the technology to isolate and study these  – now we have to tools to start solving many of these problems”

The UNC study, published online April 4, 2013, in the journal Stem Cells, represents a leap forward for a field that for many years has had to resort to conducting experiments in cells from mice. While significant progress has been made using mouse models, differences in stem cell biology between mice and humans have kept researchers from investigating new therapeutics for human afflictions.

“While the information we get from mice is good foundational mechanistic data to explain how this  works, there are some opportunities that we might not be able to pursue until we do similar experiments with human tissue,” lead study co-author Adam D. Gracz, a graduate student in Magness’ lab. Megan K. Fuller, MD, was also co-lead author of the study.

The Magness lab was the first in the United States to isolate and grow single intestinal stem cells from mice, so they had a leg up when it came to pursuing similar techniques in human tissue. Plus the researchers were able to get sections of human small intestine for their experiments that otherwise would have been discarded after gastric bypass surgery at UNC.

To develop their technique, the researchers investigated whether the approach they had taken in mice would work in . They first looked to see if the same molecules they had found stuck on the surface of mouse stem cells were also present on human stem cells. The researchers established that these specific molecules – called CD24 and CD44—were indeed the same between the two species. They then attached fluorescent tags to these molecules and used a special machine called a fluorescence activated cell sorter to identify and isolate the stem cells from the  samples.

They found that not only could they isolate the human stem cells from human , but that they also could separate different types of intestinal stem cells from each other. These two types of stem cells – active and reserve – are a hot topic for stem cell researchers who are still trying to figure out how reserve stem cells cycle in to replenish active stem cells damaged by injury, chemotherapy or radiation.

“Now that we have been able to do this, the next step is to carefully characterize these populations to assess their potential,” said Magness. “Can we expand these cells outside of the body to potentially provide a cell source for therapy? Can we use these for tissue engineering? Or to take it to the extreme, can we genetically modify these cells to cure inborn genetic disorders or inflammatory bowel disease? Those are some questions that we are going to explore in the future.”

Digest this: Cure for cancer may live in our intestines

Digest this: Cure for cancer may live in our intestines

Treating a cancerous tumor is like watering a houseplant with a fire hose—too much water kills the plant, just as too much chemotherapy and radiation kills the patient before it kills the tumor.

However, if the patient’s gastrointestinal tract remains healthy and functioning, the patient’s chances of survival increase exponentially, said Jian-Guo Geng, associate professor at the University of Michigan School of Dentistry. Recently, Geng’s lab discovered a  that preserves the gastrointestinal tracts in mice who were delivered lethal doses of chemotherapy.

The findings, which will appear in the journal Nature, could revolutionize , Geng said.

“It’s our belief that this could eventually cure later-staged metastasized cancer. People will not die from cancer, if our prediction is true,” said Geng, who emphasized that the findings had not yet been proven in humans. “All tumors from different tissues and organs can be killed by high doses of chemotherapy and radiation, but the current challenge for treating the later-staged metastasized cancer is that you actually kill the patient before you kill the tumor.

“Now you have a way to make a patient tolerate to lethal doses of chemotherapy and . In this way, the later-staged, metastasized cancer can be eradicated by increased doses of chemotherapy and radiation.”

Geng’s lab found that when certain proteins bind with a specific molecule on intestinal stem cells, it revs intestinal stem cells into overdrive for intestinal regeneration and repair. Stem cells naturally heal damaged organs and tissues, but so-called “normal” amounts of stem cells in the  simply cannot keep up with the wreckage left behind by the lethal doses of chemotherapy and radiation required to successfully treat late-stage tumors.

However, the phalanx of extra stem cells protect the intestine and , which means the patient can ingest nutrients, the body can perform other critical functions and the bacterial toxins in the intestine are prevented from entering the blood circulation, Geng said.

These factors could give the patient just enough of an extra edge to survive the stronger doses of chemotherapy and radiation, until the tumor or tumors are eradicated.

In the study, 50-to-75 percent of the mice treated with the molecule survived otherwise lethal doses of chemotherapy. All of the mice that did not receive the molecule died, Geng said.

“If you can keep the gut going, you can keep the patient going longer,” Geng said. “Now we have found a way to protect the intestine. The next step is to aim for a 100-percent survival rate in mice who are injected with the molecules and receive lethal doses of chemotherapy and radiation.”

Geng’s lab has worked with these molecules, called R-spondin 1 and Slit2, for more than a decade. These molecules repair tissue in combination with intestinal residing in the adult intestine.