Study Title:

Friendly Flora and Immunity

Study Abstract

Humans are colonized by a large and diverse bacterial flora (the microbiota) essential for the development of the gut immune system1, 2, 3. A broader role for the microbiota as a major modulator of systemic immunity has been proposed4, 5; however, evidence and a mechanism for this role have remained elusive. We show that the microbiota are a source of peptidoglycan that systemically primes the innate immune system, enhancing killing by bone marrow–derived neutrophils of two major pathogens: Streptococcus pneumoniae and Staphylococcus aureus. This requires signaling via the pattern recognition receptor nucleotide-binding, oligomerization domain–containing protein-1 (Nod1, which recognizes meso-diaminopimelic acid (mesoDAP)-containing peptidoglycan found predominantly in Gram-negative bacteria), but not Nod2 (which detects peptidoglycan found in Gram-positive and Gram-negative bacteria) or Toll-like receptor 4 (Tlr4, which recognizes lipopolysaccharide)6, 7. We show translocation of peptidoglycan from the gut to neutrophils in the bone marrow and show that peptidoglycan concentrations in sera correlate with neutrophil function. In vivo administration of Nod1 ligands is sufficient to restore neutrophil function after microbiota depletion. Nod1−/− mice are more susceptible than wild-type mice to early pneumococcal sepsis, demonstrating a role for Nod1 in priming innate defenses facilitating a rapid response to infection. These data establish a mechanism for systemic immunomodulation by the microbiota and highlight potential adverse consequences of microbiota disruption by broad-spectrum antibiotics on innate immune defense to infection.

From press release:

Scientists have long pondered the seeming contradiction that taking broad-spectrum antibiotics over a long period of time can lead to severe secondary bacterial infections. Now researchers from the University of Pennsylvania School of Medicine may have figured out why.

The investigators show that "good" bacteria in the gut keep the immune system primed to more effectively fight infection from invading pathogenic bacteria. Altering the intricate dynamic between resident and foreign bacteria -- via antibiotics, for example -- compromises an animal's immune response, specifically, the function of white blood cells called neutrophils.

Senior author Jeffrey Weiser, MD, professor of Microbiology and Pediatrics, likens these findings to starting a car: It's much easier to start moving if a car is idling than if its engine is cold. Similarly, if the immune system is already warmed up, it can better cope with pathogenic invaders. The implication of these initial findings in animals, he says, is that prolonged antibiotic use in humans may effectively throttle down the immune system, such that it is no longer at peak efficiency.

"Neutrophils are being primed by innate bacterial signals, so they are ready to go if a microbe invades the body," Weiser explains. "They are sort of 'idling', and the baseline system is already turned on."

Weiser and first author Thomas Clarke, PhD, a postdoctoral fellow in the Weiser lab, recently published their findings in Nature Medicine.

"One of the complications of antibiotic therapy is secondary infection," Weiser explains. "This is a huge problem in hospitals, but there hasn't been a mechanistic understanding of how that occurs. We suggest that if the immune system is on idle, and you treat someone with broad-spectrum antibiotics, then you turn the system off. The system is deprimed and will be less efficient at responding quickly to new infections."

The findings also provide a potential explanation for the anecdotal benefits of probiotic therapies because keeping your immune system primed by eating foods enhanced with "good" bacteria may help counteract the negative effects of sickness and antibiotics.

Researchers have for many years understood that most bacteria in the body are not "bad." In fact, humans (and mice) have a symbiotic relationship with their resident microbes that significantly impacts, among other things, metabolism and weight homeostasis. As shown in this study, microbes also affect the innate immune response, via the cellular protein Nod1.

Present within neutrophils, Nod1 is a receptor that recognizes parts of the cell wall of bacteria. Weiser and his colleagues found that neutrophils derived from mice engineered to lack Nod1 are less effective at killing two common pathogens, Streptococcus pneumoniae and Staphylococcus aureus, than neutrophils from mice that do express the receptor.

In addition, neutrophils from mice that were raised in a germ-free environment or on antibiotics were likewise diminished in their immune responses, but this effect was not permanent: Re-exposure of these mice to a conventional environment (that is, one containing normal bacteria) restored immune function.

The team provided evidence for a potential mechanism for these observations by showing that bacterial cell wall material could be detected in the blood of normal mice, and that it influences neutrophils in the bone marrow. Finally, the team demonstrated they could improve immune function by treating both antibiotic-treated mice and human neutrophils with the Nod1 ligand -- a finding that suggests it may be possible to counter the adverse consequences of antibiotics in humans

From press release:

Study Information

Thomas B Clarke, Kimberly M Davis, Elena S Lysenko, Alice Y Zhou, Yimin Yu & Jeffrey N Weiser.
Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity
Nature Medicine
2010 January
University of Pennsylvania School of Medicine

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