GASTROENTEROLOGY

Molecular Defender Disarms Gut Bacteria

Enzyme Action Tames Threat From Trillions of Intestinal Bugs

Even people who cannot eat need to get food into their stomachs. A little bit of nutritious liquid down a feeding tube for critically ill patients can help prevent potentially deadly bacterial infections in ways that intravenous solutions cannot.

Graham Ramsay

A gut mucosal defense factor helps detoxify the bacterial molecule that otherwise triggers a potentially damaging innate immune response, report Richard Hodin (left), William (Jay) Austen, and their colleagues.

Now surgeon-researchers may have a partial molecular explanation for this phenomenon. Their findings could have broader health implications. A factor released by the fed gut, but absent from the starving gut, appears to detoxify intestinal bacteria and may do more to keep them safely confined there, according to a paper in the March 4 Proceedings of the National Academy of Sciences.

The newly recognized gut mucosal defense factor, intestinal alkaline phosphatase (IAP), disarms a troublemaking molecule found on the surface of most normal gut bacteria, and also on many pathogenic species, and exerts its effects throughout the length of the gut.

“It’s pretty remarkable that our bodies have evolved a mechanism to alter the bacteria,” said senior author Richard Hodin, a gastrointestinal and endocrine surgeon at Massachusetts General Hospital. “Our paper shows the enzyme functions as a gut barrier to fight bacteria in the lumen of the gut and prevent them from causing harm.”

The targeted bacterial molecule, lipopolysaccharide (LPS), taunts the host’s innate immune system, usually eliciting a successful local infection-fighting response and sometimes triggering a damaging inflammatory response. If it infiltrates the blood stream, LPS alone without bacteria is sufficient to trigger the extremely low blood pressure and organ failure typical of sepsis in animal models, Hodin said. Normal gut bacteria that somehow breach the thin intestinal lining and infect the blood could be partially to blame.

Reining In Immunity
The latest study has its roots in a 1994 analysis by Hodin and his colleagues that fingered IAP as one of several genes silenced in the starving gut compared to the fed gut. “We didn’t know anything about its function at the time,” said Hodin, HMS professor of surgery. A few years later, researchers documented IAP activity against LPS in a report that captured the attention of Hodin and other investigators. More recently, a co-author in southern California developed an IAP-knockout mouse that enabled in vivo studies.

In experiments on human intestinal cells, IAP worked as reported by plucking a phosphate group off the barbed end of LPS, the MGH team found. Further biochemical studies showed the deactivated LPS blocked the innate immune system sensitivity to the bacterial toxin. In mouse studies, IAP percolated from cells lining the upper part of the small intestine and stayed active in stool all the way down to the rectum.

A Bug’s Life
Hodin’s paper comes on the heels of a University of Oregon zebrafish study also concluding that IAP plays a crucial role in promoting mucosal tolerance to resident gut bacteria by preventing inflammatory responses. Now it appears IAP functions similarly on mammalian intestinal surfaces.

“It’s a nice molecular explanation for how people maintain tolerance to trillions of bacteria in their intestines,” said Lora Hooper, assistant professor of immunology and microbiology at the University of Texas Southwestern Medical Center at Dallas. She studies how gut epithelial cells sense and respond to commensal and pathogenic bacteria.

Resident microflora contribute to human health by aiding digestion, synthesizing essential vitamins, occupying niches that might otherwise harbor pathogens, and directing immune system development. “We humans are inhabited by a vast complex microbial ecosystem,” Hooper said. “The key question is, how does a thin layer of cells cope with trillions of bacteria?”

The starved gut seems to lose this important coping mechanism. In mice, two days on a water-only fast was enough to suppress IAP expression and its LPS-detoxifying activity, which bounced back upon feeding normal chow. Mice without IAP did not respond to the fast.

“We believe that the ‘trophic feeding’ that has become standard treatment in the intensive care setting likely works by maintaining IAP expression and therefore the ability of the organism to protect itself from gut-derived sepsis,” Hodin said.
IAP may have a broader protective role in the gut by unknown molecular mechanisms, according to other observations reported by the MGH team. The researchers explored the role of IAP in pathological conditions, mimicking clinically observed human gut responses to surgery or injury elsewhere in the body. The presence of IAP prevented much of the bacteria from crossing the mucosal barrier and entering the local lymph nodes.

In future studies, Hodin and his colleagues will be exploring how to harness the power of IAP in the gut to prevent infection and possibly treat inflammatory diseases, such as ulcerative colitis and Crohn’s disease, he said.

—Carol Cruzan Morton

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