腸道微菌叢：人體健康的隱形守護者｜腸胃道在人體攝取食物後，扮演著營養成分消化、吸收與代謝的角色，是維持生命不可或缺的基礎。近二十年來，科學家發現，腸道內寄居著將近 40 兆的共生細菌，種類高達千餘種。這些微小的生命體並非僅是過客，它們在宿主的發育及生理功能調控上扮演著核心角色，無時無刻不在影響著人體於健康與疾病狀態間的動態平衡。

抗生素與心理失調的風險｜隨著醫學發展，抗生素的發現無疑為許多感染性疾病帶來了福音，但其對腸道微生物的擾動也逐漸引起科學界的關注。一項針對丹麥約 110 萬名兒童的大型全國性研究顯示，從出生起經歷的感染及其抗生素治療，與後續罹患心理失調症的風險具有強烈的關聯性。這種關聯特別體現在思覺失調症、強迫症、注意力不集中/過動症以及自閉症等多種精神失調症上。這項大規模研究強烈暗示，抗生素在破壞腸道微生物群後，可能經由「腸-腦軸線」路徑，進而干擾了中樞神經系統的正常運作。

解構腸-腦軸線：發現微生物壓力緩衝器｜近年來，我們研究團隊致力於解開腸-腦軸線的奧秘。在發表於自然期刊的研究中，我們首度證實了腸道微生物叢在調控宿主壓力反應中扮演著不可或缺的角色。當動物缺乏腸道共生菌時，大腦下視丘室旁核的神經元會產生過度反應，導致血液中壓力荷爾蒙濃度異常飆升，進而引發嚴重的行為異常。這項發現明確確立了腸道微環境與大腦壓力中樞之間的直接因果關係。

在進一步探究具體的調控機制時，我們鑑定出「腸球菌」在此神經內分泌過程中扮演了關鍵的心理壓力緩解角色。透過特定微生物定殖實驗，我們發現腸道中腸球菌的存在，能顯著抑制下視丘-腦下垂體-腎上腺軸在面對環境壓力時的過度活化。腸球菌宛如人體內建的壓力緩衝器，能透過特定分子訊號調控大腦神經元，使個體在面臨壓力挑戰時，仍能維持穩定的行為表現。

為了進一步釐清腸球菌抑制心理壓力的特性，我們將不同品系的菌株定殖於微菌叢缺失小鼠體內。研究結果顯示，特定品系的糞腸球菌能顯著緩解由壓力誘發的腸胃蠕動異常。令人驚訝的是，經實驗證實，這種保護效應是直接作用於大腦中樞。

既然細菌身處腸道，它又是如何遠距離與大腦溝通？透過多體學技術，我們揭開了這個謎團。非標的代謝體學分析顯示，不同品系的糞腸球菌會引發「苯丙胺酸」代謝路徑的特異性改變。我們發現了一種由宿主與細菌共同代謝苯丙胺酸所產生的關鍵代謝物。當我們將此代謝物質直接投予急性壓力暴露的小鼠時，發現它能有效減輕壓力誘發的生理異常。透過細菌全基因體定序，我們更發現，具備強效抗壓能力的菌株，其基因體中恰好缺乏了進一步代謝苯丙胺酸的關鍵酵素，從而促使這種具備抗壓特性的代謝物得以在體內累積，並發揮保護作用。

邁向精準醫療：次世代益生菌療法的臨床轉化｜現代社會的高壓環境使心理壓力與精神失調症成為全球性的健康危機。傳統的精神科藥物雖能緩解症狀，卻常伴隨成癮性或去敏化等副作用。基於上述研究發現，我們正致力於將實驗室的基礎科學轉化為臨床可用的精準醫療策略：

1.     開發活體生物藥物：相較於傳統益生菌，我們正開發以特定基因型腸球菌株為核心的神經藥理活性藥物，為高壓族群提供長期的預防與照護。

2.     研發後生元製劑：透過萃取或合成關鍵的神經活性代謝物，開發出針對急性壓力的速效輔助療法。

獲得台灣生技醫藥發展基金會「吳火獅醫學獎」是對我們團隊研究方向的重要肯定。未來，我們將持續推動這些新型微生物療法的臨床轉化，期望能從腸道這個「第二大腦」源頭，為廣大受心理壓力所苦的病患，帶來更安全、有效的治療新曙光。

（110年度TBF吳火獅醫學獎、成大醫學院生理學科暨研究所　吳偉立副教授）

Decoding the Gut-Brain Axis: Enterococcus faecalis and Its Metabolites as a New Opportunity for Psychological Stress Alleviation

Gut Microbiota as the Invisible Guardians of Human Health｜Following food intake, the gastrointestinal tract plays a fundamental role in the digestion, absorption, and metabolism of nutrients, serving as an indispensable foundation for sustaining life. Over the past two decades, scientists have discovered that the gut harbors nearly 40 trillion commensal bacteria, comprising over a thousand distinct species. Far from being mere passengers, these microorganisms play an essential role in the host's physiological and behavioral regulation, continuously shaping the delicate balance between health and disease.

Antibiotics and the Risk of Psychological Disorders｜The discovery of antibiotics has undoubtedly been a medical boon for treating infectious diseases. However, the resulting disruption of the gut microbiota has increasingly garnered attention from the scientific community. A large-scale, nationwide study of approximately 1.1 million children in Denmark demonstrated a strong correlation between childhood infections treated with antibiotics and a subsequent risk of developing psychological disorders¹. This association is particularly evident in the prevalence of various psychiatric conditions, including schizophrenia, obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism. This extensive research strongly suggests that antibiotic-driven disruptions of the gut microbiota may interfere with the central nervous system via the "gut-brain axis."

Decoding the Gut-Brain Axis: Discovering the Microbial Stress Buffer｜Our research team has been dedicated to unraveling the mysteries of this gut-brain axis. In a study published in the journal Nature, we demonstrated for the first time that the gut microbiota plays an indispensable role in regulating the host's stress response. When animals lack these symbiotic gut bacteria, neurons in the paraventricular nucleus of the hypothalamus become hyper-reactive. This leads to an abnormal surge in circulating stress hormones, which subsequently triggers severe behavioral abnormalities. This discovery established a clear, direct causal relationship between the gut microbiome and stress regulation in the brain.

Furthermore, we identified that Enterococcus faecalis plays a key role in mitigating psychological stress. Through specific microbial colonization experiments, we found that the presence of E. faecalis in the gut significantly dampens the overactivation of the hypothalamic-pituitary-adrenal (HPA) axis during psychological stress. Acting as a microbial stress buffer, E. faecalis modulates specific stress-responsive neurons in the brain, allowing the individual to maintain normal behavioral function under stressful conditions.

To further elucidate these stress-suppressing properties, we colonized microbiota-depleted mice with different strains of E. faecalis and subjected them to acute stress. The results showed that specific strains of E. faecalis significantly alleviated stress-induced gut dysmotility. Intriguingly, we confirmed that this protective effect acts directly on the brain.

Since these bacteria reside in the gut, how do they communicate with the brain over such a distance? We unraveled this mystery using multi-omics technology. Untargeted metabolomics revealed that different strains of E. faecalis induce specific alterations in the phenylalanine metabolism pathway. We discovered a key metabolite produced through the co-metabolism of phenylalanine by both the host and E. faecalis. When delivered directly to mice exposed to acute stress, this metabolite effectively mitigated stress-induced physiological abnormalities. Through bacterial whole-genome sequencing, we further discovered that strains with potent anti-stress effects naturally lack a key enzyme involved in phenylalanine metabolism. This genetic absence promotes the accumulation of this stress-resilient metabolite in the body, enabling its protective action.

Toward Precision Medicine: Clinical Translation of Next-Generation Probiotic Therapies｜The intense pressure of modern life has escalated psychological stress and mental disorders into a global health crisis. While traditional psychiatric medications can alleviate symptoms, they are often accompanied by adverse side effects, such as dependency or desensitization. Based on our findings, we are committed to translating basic science into clinically applicable precision medicine strategies:

1.     Development of Live Biotherapeutic Products (LBPs): Unlike traditional probiotics, we are developing neuro-pharmacologically active therapeutics centered on specific genotypes of E. faecalis strains to provide long-term prevention and management of chronic stress.

2.     Development of Postbiotic Formulations: By extracting or synthesizing key neuroactive metabolites, we aim to develop rapid-acting adjuvant therapies for acute stress episodes.

Receiving the Wo Ho-Su Medical Award from the Taiwan Bio-Development Foundation (TBF) is a profound validation of our team's research direction. Moving forward, we will continue to drive the clinical translation of these novel microbial therapies. By targeting the gut, our "second brain", we hope to usher in a safer, more effective new dawn of treatment for the vast number of patients suffering from psychological stress.

References

1. Kohler-Forsberg, O. et al. A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents. JAMA Psychiatry 76, 271-279, doi:10.1001/jamapsychiatry.2018.3428 (2019).
2. Wu, W. L. et al. Microbiota regulate social behaviour via stress response neurons in the brain. Nature 595, 409-414, doi:10.1038/s41586-021-03669-y (2021).
3. Lai, T. T., Liou, C. W., Tsai, Y. H., Lin, Y. Y. & Wu, W. L. Butterflies in the gut: the interplay between intestinal microbiota and stress. J Biomed Sci 30, 92, doi:10.1186/s12929-023-00984-6 (2023).

(2021 TBF Wo Ho-Su Medical Award, Associate Professor Wei-Li Wu)