To understand GI infections, learn the language

TEXAS A&M (US)—New technology is able to mimic the unique bacteria-laden environment of the human GI tract because it knows how to decode the complex way cells “talk” to each other, a new study reports.

The system, developed by Arul Jayaraman, assistant professor in the Artie McFerrin Department of Chemical Engineering at Texas A&M University, will help scientists understand how certain pathogenic bacteria strains such as E. coli cause infection in humans.

The technology represents a significant step in understanding bacterial interactions in the GI tract because it accurately simulates conditions within that area by enabling human epithelial cells to grow in balance with the naturally occurring bacteria (termed “commensal”) that reside in the GI tract.

Traditionally, growing both types of these cells simultaneously in a laboratory environment has been difficult because bacteria reproduce at a much faster rate than epithelial cells and tend to monopolize the nutrients needed by the epithelial cells, says Jayaraman.

“If you try to achieve this in a cell-culture dish what happens is that you have a very nutrient-rich environment that bacteria basically thrive in, dividing rapidly,” Jayaraman explains.

“You can start with the same number of cells, relatively in proportion, but the bacteria will keep dividing, taking up all of the nutrients. Epithelial cells then do not get what they need. They are typically more finicky than bacterial cells. The numbers then kick in, and it is an exponential process where you will soon have millions of bacteria outnumbering epithelial cells, which will soon die.”

That doesn’t happen in Jayaraman’s model, which grows the epithelial and commensal cell colonies separately before allowing them to interact as they would in the gut. Once the two types of cells are interacting in the right balance, Jayaraman can recreate the sequence of events in a GI tract infection by introducing a foreign pathogen, in this case, Enterohemorrhagic E. coli, to the cells within his model.

Previous studies have just added pathogenic bacteria into colonies of endothelial cells, but this approach does not replicate the cellular interactions and chemical signals present in the human GI tract, says Jayaraman.

“If you really want to understand how the commensal bacteria that are in the GI tract either prevent or enhance infection, you need to have a way in which you can actually recreate the system with both components present – the commensal cells and the epithelial cells,” Jayaraman says.

“To our knowledge, this is the first report describing co-culture of bacteria and epithelial cells and its application to investigate pathogen colonization and infection.”

Commensal bacteria, he explains, produce a wide range of bacterial signals, and the concentration of these signals in the GI tract is extremely high.

These signals, he adds, are given off during normal metabolic processes of the cells. While there is no evidence to suggest that they were created specifically for defensive purposes, some of these signals have evolved to act as a line of defense.

Others may actually enhance a pathogen’s infectious potential, he says. For the invading pathogen, it’s a matter of “talking” to the right cells and avoiding the “wrong” ones.

It’s a game of “push and pull” that is further complicated by the fact that the strength of these signal levels varies, Jayaraman says. For example, a person may be under a lot of stress, which can cause stress hormones to be high and might in turn diminish the signals that aid in defense against a pathogen. Other times, a gastric disease might kill some of these cells that are emitting a protective signal, lowering the overall strength of the signal and making a person more susceptible to serious infection, Jayaraman notes.

So far, Jayaraman’s model has yielded some interesting findings, shedding light on the constant array of signals being emitted within the GI tract and their effects on invading pathogens. One of those findings reveals how indole, a chemical produced by commensal cells within the GI tract, acts a signal to foreign pathogens.

“Indole already has been shown as an important signal for communication between bacteria,” Jayaraman says. “We are looking at how pathogens might also be affected by indole, and we are seeing that they are indeed affected.”

Specifically, if a pathogen passes through bacteria that produce indole, the pathogen will become less infectious, Jayaraman explains. Conversely, if it passes through bacteria where there is no indole, the pathogen retains it same degree of virulence.

“In a sense, the pathogen is looking for weak points in a ‘wall’ of defense,” Jayaraman says. “We believe this can be applied to several other signals. There might be signals that increase a pathogen’s infectiousness. Does it choose a location in the wall where it can pass through without decreasing its infectious potential, or does it look for a place where its infectiousness is enhanced?”

The system is detailed in Lab on a Chip, a scientific journal published by the Royal Society of Chemistry, the largest organization in Europe for advancing the chemical sciences.

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