For eight years, researchers conducted experiments modeling repeated bacterial infections; they made a startling finding. Small infections caused by bacteria that are mild and don’t cause much distress can have a cumulative effect. Repeated rounds of mild food poisoning can trigger a chain reaction that takes time, but can eventually lead to life-threatening diseases like colitis and potentially reveals how inflammatory bowel disease (IBD) arises. An international team of researchers performed this work, that was aiming to uncover the origin of chronic inflammatory disorders; it was published in Science.
It has been established that genetics has a limited influence on the onset of chronic inflammation, as evidenced by twin studies. Unknown environmental factors were thought to play a role. The researchers had also noticed that seasonal bacterial infections in people correlate with an increase in IBD. They wanted to investigate how chronic inflammatory diseases like IBD and colitis arise. The team hypothesized that a recurrence of low-grade bacterial infections could be initiating chronic inflammation.
"Trying to determine the origin of a disease is important as it often indicates more rational and effective preventions and treatments," said Jamey Marth, Ph.D., of Sanford Burnham Prebys Medical Discovery Institute (SBP) and UC Santa Barbara's Center for Nanomedicine (CNM).
Using healthy mice, the scientists modeled repeated bouts of food poisoning by exposing them to small amounts of a common cause of foodborne illness, the pathogen Salmonella Typhimurium. When people experience an infection from this bacterium, it usually causes mild discomfort and does not require hospitalization. It is likely that people suffer this kind of food poisoning many times without necessarily knowing it; the prevalence is probably underestimated.
In the mouse model used for the research, the Salmonella infections were eliminated successfully by the host.
"This type of study had never been done before and the results were shocking," said lead author Won Ho Yang, Ph.D. "We observed the onset of a progressive and irreversible inflammatory disease caused by previous infections. That was quite surprising because the pathogen had been easily cleared by the host."
By the time of a fourth infection that was months apart from the first, inflammation had increased steadily. Colitis was now observed in every subject. Though infections ceased, there was no going back from the diseased state; the damage was done, and no improvement was seen.
"We have discovered an environmental and pathogenic origin of chronic intestinal inflammation in the course of modeling human food poisoning as it occurs repeatedly over the adult lifespan," said Marth. "Remarkably, Salmonella have figured out a way to disrupt a previously unknown protective mechanism in the gut that normally prevents intestinal inflammation."
The mechanism underlying the disease was connected to a deficiency of an intestinal enzyme called alkaline phosphatase (IAP). Salmonella infection caused neuraminidase activity in the small intestine to increase, accelerating the turnover rate of IAP and causing a deficiency of the IAP enzyme in the colon. IAP acts to remove phosphate groups from molecules, in the case of the pro-inflammatory lipopolysaccharide (LPS), converts it from a toxic to a nontoxic chemical.
"These findings are of potential[ly] great concern to the human population," noted Marth. "Food contamination at these low bacterial levels is likely to be more common than we recognize, while symptoms could be nonexistent or mild and disappear in a day or two without treatment. Repeated over time, we find that such minor infections are sufficient to trigger disease months and perhaps years later, depending upon the number and timing of infections an individual has experienced over his or her lifetime."
Luckily, there are ways to raise IAP levels and lower neuraminidase activity. It can be achieved through simple methods as well, such as simply drinking some of the enzyme in water to boost IAP. Neuraminidase inhibition can be achieved with an antiviral neuraminidase inhibitor that is currently available; it is used to prevent flu infections.
"We found that both treatment approaches were similarly effective at preventing the onset of colitis. In fact, published studies by others have recently reported IAP deficiencies and high neuraminidase levels in IBD patients,” explained Mahan.
"There is an unexpected additive effect of previous infections in the likelihood of developing colitis. This environmental factor may be responsible for triggering disease among some segments of the human population,” Marth concluded.