Pathobionts, Dysbiosis, and IBD

Saw an article about some research at Caltech. Biologists have identified bacteria that lie between the traditional categories of "symbionts" and "pathogens". An example is the Helicobacter hepaticus bacterium. An excerpt:

"The bacteria appear to have struck a deal with their host," Mazmanian says. They keep their own numbers low so they don't overwhelm the immune system, and in return, the immune system leaves them alone. "The bacteria need the secretion system to put the host in 'don't attack' mode." In return, the presence of the bacteria does not induce inflammation, as would be the case with a pathogen that has not evolved a similar "agreement."

"There has to be communication. It could be peaceful—as is the case for symbionts—or it could be an argument—as is the case for pathogens. But when this molecular dialogue breaks down, it's probably harmful to both microbe and man," Mazmanian says.

Disrupt that communication, and the balance gets thrown out of whack. "Inflammation leads to cancer, and this bacterium has been associated with inflammation and colon cancer in animals," he says. Understanding if dysbiosis causes disease in humans could lead to therapies based on restoring the healthy microbial balance in the gut.

Stress Aggravates IBD

Saw this article commenting on an upcoming study that will be published in the American Journal of Gasteroenterology. The study found that stress was linked to a more than twofold increase in the risk of symptom flare ups in IBD sufferers. Here's an excerpt:

Stress had long been among the main environmental factors linked to the flare-up of symptoms in some individuals. This theory, however, had never been clinically proven.

According to the study published in the American Journal of Gastroenterology, stress is associated with a more than twofold increase in the risk of symptom flare ups in sufferers.

Such a link was not seen in other factors suspected of triggering IBD symptoms such as the use of antibiotics or non-steroidal anti-inflammatory painkillers, and infections including colds, pneumonia and urinary tract infections.

"This is among the first evidence to show that the perception of stress had a direct association with disease course," said lead researcher Charles N. Bernstein, stressing that learning better stress management methods could help treat the condition more effectively.

Here's an excerpt from another article on the same topic suggesting a possible reason for the connection:

There are biological reasons to believe that a person's response to stress would trigger or worsen IBD symptoms, Bernstein and his colleagues note.

The sympathetic nervous system, which jumps into action during times of stress, acts on the lining of the colon, and might exacerbate existing inflammation. There is also evidence that stress hormones may help harmful bacteria take up residence in the intestines, which might, in turn, affect symptoms.

Combination Drug Therapy for Crohn's

Read a few articles (USNews, WebMD) about a new study that showed that a combination of azathioprine and biologics are more effective in treating Crohn's Disease than taking each individually in succession. Normally doctors treat Crohn's by prescribing steroids. If steroids don't work, doctors will move on to azathioprines and then finally biologics if the other two don't work.

Here's an excerpt:

Doctors now start treatment of Crohn's disease with steroids, Sandborn said. If the steroids do not provide relief from the abdominal pain, nausea, fever, weight loss, diarrhea and othersymptoms of the condition, the next step is to use azathioprine, which reduces immune system activity broadly. Only if that fails will they try biologics, newer treatments that include monoclonal antibodies such as infliximab (Remicade). These drugs target a specific part of the immune system.

The trial showed that the azathioprine-alone step should be skipped. "This study suggests that the therapy that follows steroids should include a biologic," Sandborn added.

Therapy with both azathioprine and infliximab appears to be the treatment of choice if steroids are not effective, Sandborn said.

"What this trial shows is that the most effective strategy is combination therapy," he said.

Definitely an interesting finding and good that doctors are finding a more optimal way to treat with traditional medicine.

Genetic Variation Not the Only Cause of Crohn's Disease

Saw an article that commented on a recent study of Danish people and thought it was interesting. The basic conclusion was that the NOD2/CARD15 gene variations previously considered a marker for Crohn's Disease actually do not have a statistically significant association with the disease ... at least for the Danish population. This certainly runs counter to previous studies.

Here's an excerpt:

The study, was conducted to estimate the likelihood that three particular genetic variants in the NOD2/CARD15 gene are related to the risk Crohn disease in the general population.

The population-based study genotyped 43 596 Danish people followed between January 1976 and July 2007. Using a logistic regression model (used to predict the probability of an occurrence) physicians estimated the risk of Crohn disease in the general population.

"Surprisingly, we found no statistically significant association between NOD2/CARD15 genetic variants and Crohn disease in either of the two general population studies that we analyzed, which suggests a low penetrance of the genetic variants in the European general population," write Dr. Børge G. Nordestgaard, Herlev Hospital, University of Copenhagen, Denmark and coauthors. (Penetrance is the degree to which the gene causes the disease.)

The authors conclude that the penetrance of NO2D/CARD15 genetic variants in relation to risk of Crohn for the Danish population was lower than might have been expected from previous European case-control studies. This should be considered when advising healthy individuals in whom these genetic variants are discovered.

What might this mean? Does this mean that genetic variations do not play a role in Crohn's Disease. Not necessarily. More likely it means that there are many contributing factors and many possible causes - not just one genetic variation. Another excerpt from the note:

In a related commentary http://www.cmaj.ca/embargo/cmaj100300.pdf, Dr. Katherine A. Siminovitch and coauthors write that these research findings reinforce the fact that common diseases have many causes and that in these diseases, the effect of any single gene variant on risk is usually small. This underscores the current challenge in realizing the potential of personalized medicine (use of an individual's specific information to select or optimize preventive care and therapy).

It'll be interesting to see how the research community comments on this in relation to previous studies.