Stanford University School of Medicine scientists explain why two potentially deadly pathogens get a foothold in the forbidding environment of the gut following antibiotic treatment.

The researchers wrote in the journal Nature that their findings may help identify ways to counteract the effects of the depletion of "friendly gut-dwelling bacteria" after antibiotic treatment.

Several gut pathogens can cause serious problems during a course of antibiotics. Senior author, Justin Sonnenburg, PhD, said "Antibiotics open the door for these pathogens to take hold. But how, exactly, that occurs hasn't been well understood."

The authors explained that there is a significant rise in carbohydrate availability in the gut twenty-four hours after administering oral antibiotics. This temporary surplus of carbohydrates, plus a reduction of "good bacteria" in the gut, allows at least two potentially life-threatening pathogens to multiply rapidly.

Over the last ten years, scientists have made enormous progress in understanding what goes on in the "complex microbial ecosystem" that exists in the large intestine of every healthy mammal, including humans'.

Approximately 1,000 different types of microbes coexist harmoniously within a typical healthy human's gut. These bacterial strains that inhabit this challenging but nutrient rich niche have adapted extremely well, so well in fact that we would struggle to survive without them.

Friendly, gut-dwelling bacteria synthesize vitamins, they are key to guiding our immune systems, they are involved in the development and maintenance of our own tissues - they even help regulate blood pressure.

Antibiotic medications devastate this gut-microbe ecosystem. Good bacteria start multiplying rapidly within a few days, and within a month are back to normal numbers. However, according to the authors, "the ecosystem appears to suffer the permanent loss of some of its constituent bacterial strains".

The scientists liken these friendly bacteria to a kind of lawn which beats the weeds (pathogenic bacteria) to the rich fertilizer that courses through our gut. Previous studies have suggested that our friendly bugs secrete chemicals that prevent the pathogenic bacteria from taking control.

There is a theory that when our inner microbial ecosystem is disrupted, our immune system responsiveness suffers.

Sonnenburg said:

"While these hypotheses are by no means mutually exclusive, our work specifically supports the suggestion that our resident microbes hold pathogens at bay by competing for nutrients."

When these defenses are weakened, as usually occurs not long after starting on a course of antibiotics, plundering pathogens, such as Clostridium difficile, are able to establish footholds.

As soon as these two parasitic invaders have multiplied to sufficient numbers, they induce inflammation. While inflammation is not a good environment for restoring good bacteria, C. difficile and salmonella thrive in it.

Sonnenburg and colleagues focused on two particular nutrients in the gut - fucose and sialic acid - both members of the sugar family. These are not sugars most people are familiar with, but they are vital for healthy survival and are produced in every cell in the human body. They are also found in dairy products, eggs and meat.

Intestinal bacteria eat mucus

Cells that line the intestine extrude long chains of familiar and exotic sugars that are linked together to form mucus.

Mucus has two functions:

  • it stops resident microbes from passing through the gut wall into the blood stream
  • it is a vital food source of several sugars, including sialic acid and fucose, for resident microbes

Sonnenburg said "Our gut microbes have become very adept at eating mucus."

Sonnenburg and colleagues experimented on laboratory mice that had been brought up in a germ-free environment. These mice were very different from normal mice - their intestines had no bacteria.

The scientists introduced a single bacterial strain into these germ-free animals - Bacteroides thetaiotaomicron, a friendly bacterial strain that resides in the gut of normal mice and humans. B. theta has enzymes that pry sugar molecules from the mucus chains dangling from the intestinal lining. B. theta lacks the enzymes to break down the molecules that make up sialic acid.

It may seem pointless for B. theta to loosen off sugar molecules it is unable to break down for food. However, in a normal gut there are several other microbes that can break down the sialic acid and fucose molecules. A normal gut is full of microbes that can chop up foods that B. theta can't but needs.

The authors call it a barter system, ecologists call it symbiosis. (Perhaps B. theta loosens these sugar residues to get to other, edible sugar residues underneath.)

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In a number of experiments, the scientists introduced either C. difficile or Salmonella strain S. typhimurium into the previously germ-free mice that had been loaded with B. theta. Both these bacteria strains are potentially life-threatening when they cause illness in patients receiving antibiotics. They also consume sialic acid for energy, but cannot loosen it off the intestinal mucus.

After discovering that C. difficile is neither able to loosen fucose or consume it, the team concentrated on how the two pathogens made use of sialic acid.

The scientists simulate an antibiotic-decimated gut-microbe ecosystem

By introducing one pathogenic and one friendly bacterial strain into the intestines of formerly germ-free mice, the researchers could demonstrate that the levels of sialic acid increased considerably in the absence of a complete microbial gut ecosystem that would have stopped those levels from soaring. Having just one strain of good bacterium in the mice's gut was an approximation of an antibiotic-decimated gut-microbe ecosystem.

Both B theta and S. typhimurium replicated more rapidly in the presence of these sugars and no other competing microbes. B. theta created a sialic-acid surplus, which was a feast for the pathogenic strain.

The scientists then observed what effects antibiotics might have on "normal" mice with intestinal ecosystems. They reported the same increase in sialic acid and a population explosion of pathogenic bacteria. If the mice were only treated with antibiotics and not exposed to the pathogens, the sialic acid levels went back to normal within about three days as good bacteria started to recover.

Sonnenburg said:

"The bad guys in the gut are scavenging nutrients that were liberated by the good guys, who are casualties of the collateral damage incurred by antibiotics. Antibiotics cause our friendly gut bacteria to unwittingly help these pathogens.

We believe that bacterial pathogens in the gut cause disease in two steps. Others have shown that once these pathogens attain sufficient numbers, they use inflammation-triggering tricks to wipe out our resident friendly microbes - at no cost to the pathogens themselves, because they've evolved ways to deal with it. But first, they have to surmount a critical hurdle: In the absence of the inflammation they're trying to induce, they have to somehow reach that critical mass. Our work shows how they go about it after a dose of antibiotics. They take advantage of a temporary spike in available sugars liberated from intestinal mucus left behind by slain commensal microbes."

The team believe that we could one day create a medication that inhibits the enzymes used by friendly gut bacteria to liberate sialic acid from mucus, thus depriving the pathogens of their feast. The medication could then be given alongside antibiotics. They added that probiotics in the form of bacterial strains that digest sialic acid rapidly could also achieve a similar effect.

The study was funded by the Burroughs Wellcome Fund and the National Institutes of Health (grant R01-DK085025).