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University of Alabama at Birmingham researchers now report a new model for LOS in an article in Nature Medicine, and they show that disrupting the normal maturation of microbes in the intestine can make newborn mouse pups highly susceptible to LOS. Furthermore, they found they could prevent the deadly infection by giving the pups specific protective bacteria before a challenge with invasive Klebsiella pneumoniae bacteria.

“Our findings offer the possibility for rational design and testing of effective probiotic therapies to protect at-risk ,” said corresponding authors Jeffrey Singer, Ph.D., and Casey Weaver, M.D. “These studies substantiate clinical research suggesting that overgrowth of a single bacterial species, called neonatal dysbiosis, often precedes the development of LOS. Our model should help define mechanisms by which pioneer species of the developing of neonates prevent—or fail to prevent—dysbiosis that predisposes to LOS.”




The UAB researchers placed a virulent K. pneumoniae strain, Kp-43816, into the stomachs of pups. The bacteria carried a bioluminescent marker that allowed researchers to use an imaging system to see where in the the bacteria were growing in live animals, and then measure the microbes’ invasive spread out of the intestine and into the rest of the body. Bioluminescent bacteria in living animals can be seen through nearly an inch of tissue.



This suggested that both strains of K. pneumoniae were capable of spreading out of the gut, but differences in host clearance by the immune defense system after translocation contributed to the differential virulence of these related strains. Indeed, when either strain was injected directly into the peritoneum—bypassing the need for translocation from the intestine—Kp-43816 caused 100 percent mortality in one day, but the Kp-39 caused no mortality in pups and was cleared in a week. The researchers found differences in the capsule surrounding the bacteria that allowed Kp-43816 to resist infection-clearing phagocytosis by immune cells more strongly than Kp-39.


The researchers then found that altering the microbiome of the pups changed susceptibility to dysbiosis and LOS. The normal intestinal microbiome is known to have a critical role in restricting the colonization and spread of a pathogen. Pups without a microbiome, raised in germ-free conditions, were uniformly susceptible to Kp-43816 LOS.

To look further, researchers treated dams with two antibiotics starting one day before delivery and several days thereafter, prior to infecting with Klebsiella. Both antibiotics are poorly absorbed and unlikely to be transmitted to pups; but they would alter the mother’s intestinal microbiomes in different ways, which in turn should alter the microbiome that the pups acquire after birth from the dams. The UAB team found that pups of mothers given gentamicin were markedly more susceptible to sepsis, while pups of mothers given vancomycin were less susceptible to sepsis, compared with controls.


Protective bacteria

The difference? Researchers found that pups of the vancomycin-dams had greater abundance of Lactobacillus bacteria in their intestinal microbiome, and the pups of gentamicin-dams had lesser amounts of Lactobacillus. Thus, presence or absence of lactobacilli appeared to correlate with resistance or susceptibility, respectively, to neonatal dysbiosis and LOS.

DNA analysis showed that the vancomycin-pups were dominated by the species Lactobacillus murinus, while the gentamycin pups were largely devoid of L. murinus. They also found that L. murinus was sensitive to gentamicin and resistant to vancomycin, suggesting that gentamycin treatment killed this protective species in dams, thus preventing its passage to pups through vertical transmission.


The researchers also found that younger pups, like extremely premature infants, have microbiomes dominated by bacteria called facultative anaerobes that can grow in either the presence or the absence of oxygen. As pups grew older, their microbiomes become more like term infants because they are dominated by bacteria called obligate anaerobes, which grow well in the absence of oxygen but die if oxygen is present. The older pups, with a mature microbiome dominated by obligate anaerobes, were resistant to neonatal dysbiosis. It appeared that presence of oxygen in the intestinal lumens of neonate pups prevented colonization by obligate anaerobes. The UAB researchers hypothesized that this might explain why dysbiosis is more prevalent in very-low-birthweight infants.


Gut microbiome of mother found to impact immunity of mice pups

More information:
Jeffrey R. Singer et al, Preventing dysbiosis of the neonatal mouse intestinal microbiome protects against late-onset sepsis, Nature Medicine (2019). DOI: 10.1038/s41591-019-0640-y

Model probes possible treatments for neonatal infection, a common cause of infant death (2019, December 2)
retrieved 2 December 2019
from https://medicalxpress.com/news/2019-12-probes-treatments-neonatal-infection-common.html


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