Good bacteria trigger proteins to protect the gut

[Guest guest]

Public release date: 22-Jul-2004

Medical Institute

Good bacteria trigger proteins to protect the gut

New studies by Medical Institute researchers indicate that the

millions of beneficial bacteria living in the human gut may actually be

helping to stave off injury to the lining of the intestines.

According to the researchers, their unexpected findings suggest that the

practice of giving antibiotics to cancer patients to prevent infections

might render the gut more vulnerable to damage ­ a danger that might be

overcome by administering substances that mimic the protective presence of

gut bacteria. The findings may also revise thinking about the treatment of

inflammatory bowel disease (IBD), in which the intestine is believed to

mount an inflammatory response to benign, or commensal, bacteria.

The researchers, led by Medical Institute investigator Ruslan

Medzhitov at Yale University School of Medicine, reported their studies in

the July 23, 2004, issue of the journal Cell.

" Until now, almost everything we knew about the benefits of commensal

bacteria had to do with their biological activity, " said Medzhitov. " They

metabolize nutrients to enable us to absorb them more readily. They aid in

the early development of the gastrointestinal system. And they produce

factors that prevent colonization by pathogenic bacteria. Our work, however,

has revealed a role that is quite different. "

Specifically, Medzhitov and his colleagues discovered that beneficial

bacteria trigger proteins called Toll-like receptors (TLRs) to maintain the

health of intestinal epithelial cells and to activate machinery that

responds to injury. Previously, TLRs were thought to function strictly as

assassins, recognizing molecules on the surface of pathogenic bacteria and

triggering the innate immune system to attack.

" It's always been a major paradox that our immune system evolved to

recognize pathogenic microorganisms and to react to them with a powerful,

destructive response; but at the same time, it tolerates a very close,

continuous contact with myriad commensal bacterial species that share many

molecular characteristics of pathogenic bacteria, " said Medzhitov. The

predominant view, he said, was that TLRs were somehow prevented from

recognizing commensal bacteria, yet unleashed specifically against

pathogenic microbes.

To better understand the interaction between commensal bacteria and TLRs,

the researchers used mice that lacked a key component of the TLR-signaling

machinery, called MyD88. Without this protein, mice are unable to activate

TLR signaling. In initial experiments, they gave the mice a drug called DSS,

which is toxic to epithelial cells in the colon.

Normal mice recovered easily from DSS exposure, but the drug severely

damaged the intestines of the MyD88-deficient mice. The researchers found

essentially the same results when they tested the effects of DSS on mice

lacking the TLR proteins themselves.

" This was the exact opposite of what we expected, because everything we know

about TLRs in mammalian systems has to do with immune response to

infection, " said Medzhitov. " We thought that since these mice couldn't mount

a TLR-dependent inflammatory response to commensal bacteria, they would show

reduced injury from DSS. We had no idea that these receptors might be

involved in protecting these tissues from damage. "

To explore whether the overgrowth of commensal bacteria contributed to the

damage, the researchers depleted the bacteria from the mice's intestines

using antibiotics. These antibiotic-treated MyD88-deficient animals showed

the same DSS-induced damage as MyD88-deficient animals in which bacteria

were allowed to grow normally. The researchers also found no evidence that

the infiltration of white blood cells triggered the increased injury in

MyD88-deficient mice.

The researchers observed a generalized disruption in proliferation and

differentiation of intestinal epithelial cells in the MyD88-deficient mice,

implicating TLRs in overall maintenance of the tissue. The animals'

intestines were particularly sensitive to radiation, which could be

attributed in part to the unusually rapid cell division occurring there.

Furthermore, recovery from radiation-induced damage requires maintenance and

repair processes that, the researchers found, depend on TLRs. They found

that in response to DSS-induced damage, intestinal cells in the normal mice

produced numerous proteins involved in tissue repair. In contrast, mice

lacking a TLR response did not.

The researchers' experiments also demonstrated that commensal bacteria were

necessary for TLR activity. When they used antibiotics to sterilize the

colons of normal mice, they found that these mice were as susceptible to

damage from DSS as MyD88-deficient mice.

Finally, when they treated bacteria-depleted normal mice with only the

bacterial surface molecules by which TLRs recognize the pathogens, they

found these molecules alone were enough to completely protect the mice from

damage by DSS.

" These bacterial products completely rescued the commensal-depleted mice, "

said Medzhitov. " None of them even got sick, and when we analyzed their

colons, they were healthy and normal. This was definitive proof that the

beneficial effects of commensal bacteria were due to their recognition by

TLRs and not their biological activity.

" Now we know that this recognition has a completely unexpected and novel

function -- triggering TLRs to control genes and processes that foster

homeostasis of intestinal epithelium, which confer a protective effect on

these cells and induce tissue repair. " According to Medzhitov, TLRs may work

both by a continual recognition of commensal bacteria and by responding to

damage to initiate a repair process.

Medzhitov said that his team's findings have two major clinical

implications. First, he said, they will likely affect the clinical practice

of treating cancer patients with antibiotics when they receive chemotherapy

or radiation, which weaken the immune system.

" These antibiotics are intended quite correctly to protect patients against

opportunistic infections. However, our work shows that such antibiotics can

have the detrimental effect of preventing the natural and essential pathways

that are important for protection and repair. Thus, it may be that such

patients could be treated with a version of the bacterial cell surface

products that would mimic the presence of commensal bacteria and maintain

TLR activity, " said Medzhitov.

Additionally, the findings may also influence the treatment of inflammatory

bowel disease. " We know that bacteria play a detrimental role in these

diseases, inducing a pathological inflammatory response. Often antibiotics

are used in such cases as Crohn's disease, to eliminate gut bacteria.

However, given our findings, the beneficial role of commensal bacteria might

have to be taken into account in such treatments, " said Medzhitov.

In further studies, Medzhitov and his colleagues are exploring whether the

response of TLRs to bacteria plays a role in maintenance and repair of other

epithelial tissues, including the skin, mouth, lungs and respiratory and

urinary tracts. He said that similar TLR responses may play a role in the

maintenance and repair of internal organs that are not exposed to bacteria,

through a tissue response to endogenous triggering factors.