母乳可能有助于预防早产儿败血症 Breast milk may help prevent sepsis in preemies

News Release 16-Mar-2020

Keeps gut bacteria from moving into bloodstream

Washington University School of Medicine

A component of breast milk may help protect premature babies from developing sepsis, a fast-moving, life-threatening condition triggered by infection. Researchers at Washington University School of Medicine in St. Louis and Mayo Clinic in Rochester, Minn., have found — in newborn mice — that a molecule called epidermal growth factor in breast milk activates receptors on intestinal cells to keep dangerous gut bacteria from migrating into the bloodstream, where such microbes can prompt sepsis.

The researchers also found that breast milk with higher levels of this epidermal growth factor, especially from the earliest days of lactation following birth, is most effective in preventing dangerous bacteria from getting into the bloodstream.

The findings are published March 16 in the Proceedings of the National Academy of Sciences.

“Late-onset sepsis is a major problem in premature babies,” said senior author Rodney D. Newberry, MD, a Washington University gastroenterologist and professor of medicine. “These findings give us a better understanding of one of the scenarios that triggers sepsis, and a potential new tool to combat this condition.”

The study looked at late-onset sepsis, which strikes at least 72 hours after a baby is born and up to 60 days after birth and accounts for 26% of all deaths in infants born prematurely. About 10% of infants born preterm experience late-onset sepsis, and 30% to 50% of those who develop the infections die. Much of the focus on preventing late-onset sepsis relies on improving aseptic techniques, such as making sure a baby’s skin is bacteria free and that intravenous lines and other life-saving tubes don’t harbor potentially deadly bacteria.

“The idea, initially, was that these infants became septic from their intravenous lines and that bacteria got into the blood through breaches in the skin,” Newberry said. “That is true in some cases, but improving sterilization techniques hasn’t eliminated these infections.”

Newberry and his former postdoctoral fellow, Kathryn A. Knoop, PhD, now an assistant professor of immunology at Mayo Clinic, were curious about whether gut bacteria play a role in sepsis that develops in newborns, particularly when such microbes migrate into the bloodstream.

The culprits allowing the bacteria to move into the blood are intestinal cells called goblet cells. These cells secrete mucus to help prevent harmful bacteria from getting into the gut, but they also chaperone bacteria out of the gut, across the immature intestinal lining of a preemie. That scenario provides an entryway for sepsis-causing bacteria to gain access to the bloodstream.

“The critical realization here is that bacteria from the gut can invade the bloodstream,” said co-investigator Phillip I. Tarr, MD, the Melvin E. Carnahan Professor of Pediatrics and director of the Pediatric Division of Gastroenterology, Hepatology and Nutrition. “Understanding how bacteria moves from the gut into the blood gives us an opportunity to do something about these infections. And the study suggests that breast milk, preferably a mother’s own breast milk from her earliest days of breastfeeding, appears to be a very effective way to fend off these infections.”

In this study, the researchers gave newborn mice a solution containing Escherichia coli bacteria isolated from the bloodstream of a late-onset sepsis patient shortly after birth. The mouse pups then were nursed either by their own mother or another mother who had given birth to pups at an earlier time, resulting in her breast milk containing lower amounts of epidermal growth factor.

The mice that developed blood infections were those nursed by females that had been lactating for longer periods of time and, therefore, had lower levels of epidermal growth factor in their milk.

“One of the big implications is not only the necessity of using breast milk to feed preemies whenever possible,” said Knoop, the paper’s first author, “but milk with higher concentrations of epidermal growth factor.”

Newberry said it may be possible to add epidermal growth factor to donor breast milk or formula that has lower amounts of the important substance.

“Frequently, donor milk is donated by women near the end of their lactation,” he said. “But that milk may not be maximally beneficial to premature babies. We think it may be possible to increase the concentration of epidermal growth factor in the milk that lacks adequate amounts so that we can give that fortified milk to premature infants.”

Unlike antibiotics that tend to kill bacteria indiscriminately, breast milk containing higher amounts of epidermal growth factor would not kill harmful or beneficial bacteria in the gut, but might keep such bacteria out of the bloodstream.

“This probably is not a strategy that we would use to treat an infection,” Tarr said. “But it may well be useful in the near future to prevent potentially deadly infections.”

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Knoop KA, Coughlin PE, Floyd AN, Ndao IM, Hall-Moore C, Shaikh N, Gasparrini AJ, Rusconi B, Escobedo M, Good M, Warner BB, Tarr PI, Newberry RD. Maternal activation of the EGFR prevents translocation of gut-residing pathogenic Escherichia coli in a model of late-onset neonatal sepsis. Proceedings of the National Academy of Sciences, March 16, 2020.

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and the National Institute of Minority Health and Health Disparities of the National Institutes of Health (NIH). Grant numbers DK109006, AI144721, AI095542, DK097317, AI112626, AI40755, AI131342, UH3 AI083265, MD-II-2009-201, MD-II-2018-723 and P30 DK052574. Additional funding from the MIST Scholars Award and the Washington University Digestive Diseases Research Core Center.

Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

母乳可能有助于预防早产儿败血症

母乳中的一种成分可能有助于保护早产婴儿免于发生败血症，败血症是由感染引发的快速发展，危及生命的疾病。位于圣路易斯华盛顿大学医学院和明尼苏达州罗切斯特市梅奥诊所的研究人员在新生小鼠中发现，母乳中一种叫做表皮生长因子的分子激活肠细胞上的受体，以阻止危险的肠道细菌迁移到体内。在血液中，这些微生物会促使败血症。

研究人员还发现，具有较高表皮生长因子水平的母乳，尤其是从出生后泌乳初期开始的母乳中，对预防危险细菌进入血液最为有效。

研究结果于3月16日发表在《美国国家科学院院刊》上。

华盛顿大学胃肠病学家，医学教授，资深作者罗德尼·纽伯里（Rodney D. Newberry）医学博士说：“迟发性败血症是早产婴儿的主要问题。” “这些发现使我们对引发败血症的一种情况有了更好的了解，并为应对这种情况提供了一种潜在的新工具。”

该研究研究了迟发性败血症，它在婴儿出生后至少72小时到出生后60天发作，占早产婴儿死亡总数的26％。早产早产儿中约有10％会发生败血症，而感染的人中有30％至50％会死亡。预防迟发性败血症的大部分重点在于改进无菌技术，例如确保婴儿的皮肤无细菌，静脉输液管和其他救生管不会藏有可能致命的细菌。

纽伯里说：“最初的想法是，这些婴儿从静脉输液中变成败血病，并且细菌通过皮肤破裂进入血液。” “在某些情况下是正确的，但是改善灭菌技术并不能消除这些感染。”

Newberry和他的前博士后研究员Kathryn A. Knoop博士现在是Mayo Clinic的免疫学助理教授，他对肠道细菌是否在新生儿败血症中发挥作用感到好奇，特别是当这种微生物迁移到血液中时。

允许细菌进入血液的罪魁祸首是被称为杯状细胞的肠细胞。这些细胞分泌粘液，以帮助防止有害细菌进入肠道，但它们也陪伴伴侣细菌从肠道中穿过早产儿未成熟的肠壁。这种情况为引起败血症的细菌提供了进入血液的通道。

共同研究者Phillip I. Tarr医学博士，Melvin E. Carnahan儿科学教授兼胃肠病，肝病学和营养学儿科主任说：“这里的关键认识是肠道细菌可以侵入血液。” “了解细菌是如何从肠道进入血液的，这为我们提供了对这些感染采取某些措施的机会。该研究表明，母乳，最好是母亲在母乳喂养的最初几天就拥有的母乳，是抵御这些感染的一种非常有效的方法。”

在这项研究中，研究人员给新生小鼠提供了一种溶液，该溶液含有从出生后不久就从迟发性败血症患者的血液中分离出来的大肠杆菌的溶液。然后，由其自己的母亲或另一个在较早的时间出生过幼崽的母亲对这些幼崽进行哺乳，导致母乳中的表皮生长因子含量降低。

发生血液感染的小鼠是哺乳期较长的雌性哺乳小鼠，因此其牛奶中的表皮生长因子水平较低。

该论文的第一作者克努普说：“最大的影响之一不仅是尽可能使用母乳喂养早产婴儿，而且还有表皮生长因子浓度较高的牛奶。”

纽伯里（Newberry）表示，有可能向供体母乳或配方中添加较少量重要物质的表皮生长因子。

他说：“通常，哺乳期结束后，妇女会捐献捐赠者的牛奶。” “但是，牛奶可能对早产婴儿没有最大的好处。我们认为有可能增加缺乏足够量牛奶中表皮生长因子的浓度，以便我们可以将这种强化牛奶提供给早产儿。”

与倾向于不加选择地杀死细菌的抗生素不同，含有较高表皮生长因子的母乳不会杀死肠道中的有害或有益细菌，但可能会使此类细菌脱离血液。

“这可能不是我们用来治疗感染的策略，”塔尔说。 “但是在不久的将来防止潜在的致命感染可能很有用。”