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慢性壓力如何損害腸道? 新線索出現

圖片來源:Steve Gschmeissner/Science Photo Library via Alamy

應激小鼠腸道中的細菌會干擾抵抗病原體的細胞。

馬克斯‧科茲洛夫 / 2024 年 1 月 23 日 / 新聞 / 自然

小腸內壁含有手指狀結構,有助於吸收營養和液體。

長期以來,精神壓力與腸躁症(IBS)等胃腸道疾病的發作有關。 現在,研究人員發現了壓力損害腸道的一種方式的確切細節——透過引發重塑腸道微生物組的生化層級反應。

費城賓州大學的微生物學家和神經科學家 Christoph Thaiss 表示,他們今天發表在《細胞代謝》雜誌上的研究非常好,因為它強調了大腦儘管遠離胃腸道,仍然可以影響它。

新陳代謝功能障礙

IBS 會導致腹痛和腹瀉,影響十分之一的人。 全球有多達 1000 萬人患有發炎性腸道疾病 (IBD),它會引起腸道發炎並引發類似症狀。 該研究的共同作者、南京中國藥科大學的代謝研究員肖正想要了解細胞層面上發生了什麼觸發這些情況。

為了找到答案,他和他的同事將小鼠置於慢性壓力下兩週,並觀察了效果。 與沒有受到壓力的小鼠相比,這些動物最終有助於保護腸道免受病原體侵害的細胞水平降低。 這是因為通常轉化為這些保護細胞的腸道幹細胞的新陳代謝出現了故障。

慢性壓力會導致腸道發炎——現在科學家知道原因了

為了尋找原因,研究人員轉向動物的微生物群——腸道中有助於消化的細菌和其他微生物的集合。 先前的研究顯示,交感神經系統的活化可以重塑微生物群,交感神經系統負責身體的「戰鬥或逃跑」反應,並且通常由精神壓力觸發。 乳酸桿菌屬的一些細菌自然存在於腸道中,並在壓力條件下增殖,會產生一種稱為吲哚-3-乙酸酯 (IAA) 的化學物質。 研究人員發現,壓力引發的 IAA 水平升高,會阻止小鼠腸道幹細胞成為保護細胞。

儘管這項研究是在小鼠身上進行的,但研究人員收集的證據顯示他們的發現可能適用於人類:研究小組發現,與沒有憂鬱症的人相比,憂鬱症患者的糞便中乳酸菌和IAA 的水平升高。 「當我們承受壓力時,我們的腸道微生物群也會承受壓力,」鄭說。

作者還發現了一種可能的解毒劑,至少在老鼠身上。 當他們給有壓力的小鼠一種名為α-酮戊二酸的補充劑(一些健美運動員服用這種補充劑)時,它啟動了腸道中受損幹細胞的新陳代謝。 Thaiss 警告說,需要做更多的工作來了解該補充劑的長期影響以及它是否可以減輕腸道功能障礙的症狀。

一塊拼圖

Thaiss 補充道,由於壓力會引發體內一系列生化變化,因此僅靠這項研究並不能說明壓力與腸道之間聯繫的全部情況。 在去年《細胞》雜誌上發表的一篇論文中,他和他的同事發現了一條單獨的生化途徑,始於受壓的大腦發送信號,最終導致腸道中的免疫細胞變得過度活躍。 這些機制如何相互作用(如果有的話)尚不清楚。

Thaiss 也表示,IAA 研究僅解決了壓力對腸道的下游影響——需要做更多的工作來了解大腦如何傳遞啟動細菌增殖的訊號。 鄭說,除了進一步測試 α-酮戊二酸的安全性和有效性之外,他和他的同事還計劃下一步研究這些上游影響。

愛爾蘭科克大學神經胃腸病學家 Gerard Clarke 表示,IAA 研究「無疑是拼圖中的一個新部分」,「但這個拼圖中有多少部分仍然是一個懸而未決的問題」。

doi:https://doi.org/10.1038/d41586-024-00188-4

參考文獻:

1. Wei, W. et al. 細胞代謝。 https://doi.org/10.1016/j.cmet.2023.12.026(2024)。

2. Gershon, M. D. & Margolis, K. G.  臨床研究雜誌》 131,e143768 (2021)

3.Schneider, K. M. et al. 細胞》186, 2823–2838 (2023).

How does chronic stress harm the gut? New clues emerge

A bacterium in the intestines of stressed mice interferes with cells that protect against pathogens.

Max Kozlov / 23 January 2024 / NEWS / Nature

The lining of the small intestine contains finger-like structures that help to absorb nutrients and fluid.Credit: Steve Gschmeissner/Science Photo Library via Alamy

Mental stress has long been linked to flare-ups of gastrointestinal conditions such as irritable bowel syndrome (IBS). Now, researchers have uncovered exact details of one way that stress can harm the intestines — by setting off a biochemical cascade that reshapes the gut microbiome.

Their study, published today in Cell Metabolism, is nice, says Christoph Thaiss, a microbiologist and neuroscientist at the University of Pennsylvania in Philadelphia, because it highlights how the brain — despite being far away from the gastrointestinal tract — can still influence it.

Metabolism malfunction

IBS, which causes abdominal pain and diarrhoea, affects one in ten people. Up to ten million people worldwide have inflammatory bowel disease (IBD), which causes inflammation of the intestines and triggers similar symptoms. Study co-author Xiao Zheng, a metabolism researcher at the China Pharmaceutical University in Nanjing, wanted to understand what happens on the cellular level to trigger these conditions.

To find out, he and his colleagues exposed mice to chronic stress for two weeks and observed the effects. The animals ended up with reduced levels of cells that help to protect the intestines from pathogens, compared with mice that weren’t stressed. This is because the metabolism of intestinal stem cells that normally transform into these protector cells was malfunctioning.

Chronic stress can inflame the gut — now scientists know why

Seeking a reason, the researchers turned to the animals’ microbiomes — the collection of bacteria and other microbes in their guts that aid digestion. Previous work2 had shown that the activation of the sympathetic nervous system, which is responsible for the body’s ‘fight or flight’ response and often triggered by mental stress, can reshape the microbiome. Some bacteria of the genus Lactobacillus, which naturally occur in the gut and proliferate under stressful conditions, produce a chemical called indole-3-acetate (IAA). The researchers found that a raised level of IAA, triggered by stress, was preventing the mouse intestinal stem cells from becoming protector cells.

Although this study was conducted in mice, the researchers gathered evidence that their findings might hold true for humans: the team found elevated levels of both Lactobacillus bacteria and IAA in the faeces of people with depression, compared with that of people without it. “When we suffer from stress, our gut microbiome is also suffering from stress,” Zheng says.

The authors also found a possible antidote, in mice at least. When they gave stressed mice a supplement called α-ketoglutarate, which is taken by some bodybuilders, it kick-started the metabolism of the impaired stem cells in their intestines. Thaiss warns that more work is needed to understand the long-term effects of the supplement and whether it reduces the symptoms of gut dysfunction.

A piece of the puzzle

Because stress triggers a raft of biochemical changes in the body, this study alone won’t tell the whole story of the stress–gut connection, Thaiss adds. In a paper published in Cell last year3, he and his colleagues uncovered a separate biochemical pathway that begins with a stressed brain sending a signal and ends with immune cells in the gut becoming overactive. How these mechanisms interact, if at all, is unclear.

Thaiss also says that the IAA study tackled only the downstream effects of stress on the gut — more work is needed to understand how the brain transmits signals that kick off the bacterial proliferation. Zheng says he and his colleagues plan to investigate these upstream effects next, in addition to further testing the safety and efficacy of α-ketoglutarate.

The IAA study “is certainly a new piece of the puzzle”, says Gerard Clarke, a neurogastroenterologist at University College Cork in Ireland, “but how many pieces are in that puzzle is still an open question”.

doi: https://doi.org/10.1038/d41586-024-00188-4

References

  1. Wei, W. et al. Cell Metab. https://doi.org/10.1016/j.cmet.2023.12.026 (2024).
  2. Gershon, M. D. & Margolis, K. G. J. Clin. Invest. 131, e143768 (2021).
  3. Schneider, K. M. et al. Cell 186, 2823–2838 (2023).
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