Science：没有硝烟的战争——肠道中有害菌如何战胜有益菌

科学家们一致很疑惑，在炎症性肠病IBD患者的肠道中，大肠杆菌E. coli这些有害菌是如何战胜众多有益菌取得生长优势的。现在，加州大学Davis分校的研究人员找到了答案，这将帮助人们开发能够更有效治疗IBD的新方法。

这项研究发表在二月八日的Science杂志上，描述了IBD中有害菌战胜有益菌并对肠道造成损害的生长机制。这项成果有望带来与现有IBD疗法相比，副作用更小的新治疗方式。

IBD中，有益菌被免疫系统误杀，而有害菌大量繁殖，导致肠道受损发炎、慢性腹痛、腹泻等多种问题。据美国疾控中心统计，包括溃疡性结肠炎和Crohn病在内的IBD，影响了一百四十万美国人。

研究人员通过体外实验和动物研究，发现肠道中的潜在有害细菌（肠杆菌）能利用硝酸盐大肆生长，硝酸盐是IBD肠道发炎过程中形成的副产物。会加重IBD 肠道损伤的特定E. coli菌株，就是这些肠杆菌中的一员。最终，IBD患者肠道中有害菌泛滥成灾，而正常有益菌的数量大幅减少。

“E. coli可以利用硝酸盐呼吸，产生能量并生长，”文章第一作者，加州大学Davis 分校的医学微生物学和免疫学教授Andreas Baumler说。

“在IBD中，肠道炎症所产生的硝酸盐可以帮助E. coli在营养竞争中胜过有益微生物，”他说。

IBD患者肠道发炎会释放出一氧化氮自由基，而这些一氧化氮自由基很不稳定，最终会分解为硝酸盐，被E. coli这样的细菌用来大肆生长。而肠道中的有益细菌是通过发酵生长，相比之下这是一个更为缓慢的过程。

Baumler认为，确定E. coli等细菌战胜肠道有益菌的机制，对于开发新疗法阻断IBD疾病进程很重要。目前的IBD疗法一般是通过抗生素、类固醇等药物来抑制免疫应答，但这些药物对免疫系统影响很大，其长期副作用限制了这些药物的使用及其对IBD患者的有效性。

研究人员指出，靶标生成一氧化氮和硝酸盐的分子通路，以及其他有害肠道菌生存所需的分子，能够使IBD患者的肠道环境正常化。他们已经在进行研究，尝试用药物阻断IBD赋予有害菌生长优势的多个通路。

“我们可以抑制E. coli等细菌呼吸和生长所需的分子，” Baumler说。“将它们及时扼杀。”

来源：生物通

原文链接：
Scientists Find Key to Growth of 'Bad' Bacteria in Inflammatory Bowel Disease

The researchers discovered a biological mechanism by which harmful bacteria grow, edge out beneficial bacteria and damage the gut in IBD. This new understanding, published in the Feb. 8 issue of Science, may help researchers develop new treatments for IBD with fewer side effects than current therapies.

IBD begins when "good" bacteria are mistakenly killed by the immune system, while harmful bacteria multiply — resulting in inflammation and damage to the intestines, and chronic episodes of abdominal pain, cramping, diarrhea and other changes in bowel habits. It's estimated that IBD, which includes ulcerative colitis and Crohn's disease, affects 1.4 million people in the U.S., according to the Centers for Disease Control and Prevention.

In test-tube and animal studies, the researchers found that potentially harmful bacteria in the intestine called Enterobacteriaceae use nitrate — a byproduct formed during the intestinal inflammation in IBD — to grow and thrive. Enterobacteriaceae strains include certain E. coli bacteria, which can worsen the intestinal damage of IBD. Eventually, the intestines of those with IBD become overrun by harmful bacteria, and the numbers of normal good bacteria in the gut decrease.

"Much like humans use oxygen, E. coli can use nitrate as a replacement for oxygen to respire, produce energy and grow," said lead author Andreas Baumler, a professor of medical microbiology and immunology at UC Davis.

"In IBD, nitrate produced by inflammation in the gut allows E. coli to take a deep 'breath,' and beat out our beneficial microbes in the competition for nutrients," he said.

The inflammation in the intestines of those with IBD leads to the release of nitric oxide radicals that are powerful in attacking bacteria, Baumler explained. Yet these nitric oxide radicals are also very unstable, and eventually decompose into nitrate, which can be used by bacteria like E. coli to thrive and grow. By contrast, good bacteria in the gut grows through fermentation — a much slower process.

Determining the reasons why bacteria like E. coli can edge out good bacteria in the gut is crucial for determining new ways to halt the IBD disease process, according to Baumler. Current treatments for IBD suppress the immune response through antibiotics, corticosteroids or other powerful immune-modifying drugs. But long-term side effects can limit their use and their effectiveness for IBD patients.

The UC Davis team's research indicates that targeting the molecular pathways that generate nitric oxide and nitrate, as well as other molecules that feed harmful gut bacteria, could calm down and normalize the intestinal environment in IBD, Baumler noted. They are already doing research with one candidate drug that could halt the multiple pathways by which harmful bacteria thrive in IBD.

"The idea would be to inhibit all pathways that produce molecules that can be used by bacteria such as E. coli for respiration and growth," Baumler said. "Essentially you could then smother the bacteria."