Gastrointestinal research provides food for thought

May 17, 2011, 3:04 a.m.

A paper published in PLoS One last week by researchers from the School of Medicine reveals that short-term digestive problems early in life may increase one’s risk for depression and other psychological problems. Standing counter to previously held medical assumptions, the new findings suggest that human psychological conditions may be the consequence — not the cause — of gastrointestinal disorders.

Medicine professor Pankaj Pasricha, chief of gastroenterology and hepatology, spearheaded the study. In collaboration with research associate Liansheng Liu and other colleagues at Stanford, UC-San Francisco and the University of Kansas, Pasricha began tracing the psychological symptoms of gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia.

“A characteristic feature of disorders such as irritable bowel syndrome or functional dyspepsia is their association with psychological problems such as anxiety or depression,” Pasricha wrote in an email to The Daily. “The current thinking generally is that the latter cause or exacerbate gastrointestinal symptoms.

“We sought an alternative explanation, namely that gastrointestinal problems cause depression and anxiety. Thus, both long-lasting pain and psychological problems can result from a single cause, gastric irritation, if it occurs in vulnerable individuals.”

According to Pasricha, the gut has its own nervous system — one that is connected to the brain by nerves such as the vagus nerve but operates “relatively independently.” It is this complex communication system that is responsible for changes in the gut getting sent directly to the brain.

Using developmental models of gastrointestinal illness, products of more than a decade’s worth of construction, Pasricha and his colleagues unearthed the time connection between age and intestinal vulnerability. The long-term impact of the digestive irritation is largely dependent on not only the genetic makeup of the patient but also its early onset during development, when the internal organs are especially sensitive.

“As an example, we have produced a model of irritable bowel syndrome in adult rats that results from neonatal irritation of the colon as well,” Pasricha said. “So there is something vulnerable in the nervous system during this period of life that renders the animal susceptible to other insults and causes long-lasting changes.”

In this particular study, researchers followed a procedure in which they subjected 10-day-old Sprague-Dawley rats to mild gastric irritation via oral doses of 0.1-percent idoacetamide, an alkylating agent. Such treatment resulted in temporary inflammation as well as a brief period of hypersensitivity after the inflammation healed.

Some eight to 10 weeks later, the rats were tested with sucrose preference. Forced swimming tests were used to examine depression-like behavior. Elevated plus maze (EPM), open field and light-dark box tests were used to assess anxiety behaviors.

The results were striking. The rats that experienced early gastric problems were much more likely than the control rats to exhibit depressed and anxious behaviors. These behaviors manifested themselves in decreased consumption of sugar water, less active swimming in warm water and a tendency to stay in the dark areas during the maze test.

The treated rats also exhibited higher than normal levels of the stress hormones corticosterone and corticotrophin as well as an increased resting level of corticotrophin-releasing factor (CRF), a hormone linked with depression in humans and other animals. According to Pasricha, the treatment interferes with the development of the central nervous system. The signaling from the gut to the brain permanently changes its function to induce anxiety and depression in the animals.

Moreover, blocking the rats’ sense of perception with the addition of a drug did not cause any significant change in their behavior. This indicates that the treated rats were not responding to any current pain. However, inhibiting the release of CRF dramatically reduced depression- and anxiety-like behavior, even in the rats that had initially experienced gastric irritation.

Having found the causal link in the vagus nerve between the gut and the nervous system, Pasricha is now investigating the specific mechanisms that govern this phenomenon.

“We are now exploring the molecules that are involved in signaling between the gut and the brain and the role of nerves such as the vagus that may be mediating these changes,” Pasricha said. “There are lots of questions to be asked, and we hope that this research will open up some new perspectives on depression and anxiety and the relationship to gastrointestinal disorders. There has been a lot of speculation linking autism to gastrointestinal disease.”

Research regarding the link between the nervous and gastrointestinal systems has opened up new realms of possibilities for novel treatments and approaches. Electrical modulation of the vagus nerve, a method patented by Cyberonics, has been approved by the Food and Drug Administration to treat stimulation for several years.

Pasricha alluded to other scientists who have proposed theories on this linkage.

“Others have espoused theories around this connection. Pierre Pallardy, the French alternative therapist, is certain that the roots of depression lie in the stomach,” Pasricha said. “In his 2007 book ‘Gut Instinct: What Your Stomach Is Trying to Tell You,’ he outlines his belief in the power of the stomach to cause or cure a wide range of physical and mental ailments. Whether our research validates this or not is open to question, but [it] certainly gives food for thought.”


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