한빛사
>
한빛사논문
한빛사논문
- 조회105
한국과학기술연구원(KIST)
Microbiome, 05 May 2026 | https://doi.org/10.1186/s40168-026-02412-x
Micheliolide ameliorates colon cancer cachexia by modulating gut microbiota–immune signaling via Phocaeicola vulgatus enrichment
Hye-Young Youn1, Sunhee Park2, Huitae Min1, Nguyen Bao Ngoc1, Young Hyun Kim1, Kwang-Hyun Cha2,3, Young Tae Park1,3, Hyog Young Kwon5, Choong-Gu Lee2,3**, and Myungsuk Kim1,3,4*
1Center for Natural Product Efficacy Optimization, Natural Product Drug Development Division, Korea Institute of Science and Technology (KIST), Gangneung, Gangwon-do, Republic of Korea.
2Center for Natural Product Systems Biology, Natural Product Drug Development Division, Korea Institute of Science and Technology (KIST), Gangneung, Gangwon-do, Republic of Korea.
3Natural Product Applied Science, Korea Institute of Science and Technology (KIST) School, University of Science and Technology (UST), Gangneung, Gangwon-do, Republic of Korea.
4Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.
5Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Chungcheongnam-do, Republic of Korea.
*Corresponding author: Myungsuk Kim
**Co-corresponding author: Choong-Gu Lee
1Center for Natural Product Efficacy Optimization, Natural Product Drug Development Division, Korea Institute of Science and Technology (KIST), Gangneung, Gangwon-do, Republic of Korea.
2Center for Natural Product Systems Biology, Natural Product Drug Development Division, Korea Institute of Science and Technology (KIST), Gangneung, Gangwon-do, Republic of Korea.
3Natural Product Applied Science, Korea Institute of Science and Technology (KIST) School, University of Science and Technology (UST), Gangneung, Gangwon-do, Republic of Korea.
4Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.
5Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Chungcheongnam-do, Republic of Korea.
*Corresponding author: Myungsuk Kim
**Co-corresponding author: Choong-Gu Lee
Abstract
Background
Cancer cachexia profoundly impacts patient survival and quality of life. Current treatments fail to halt this trajectory, highlighting an urgent clinical need for host-directed therapies capable of uncoupling skeletal muscle wasting from tumor progression. This study investigated the therapeutic potential of micheliolide (MCL) across distinct tumor contexts.
Methods
We employed immunocompetent murine models of colon cancer (CT26) and lung cancer (LLC) cachexia, pseudo-germ-free (pseudo-GF) mice, murine C2C12 myotubes, and primary human skeletal muscle cells. We evaluated MCL's impact on muscle wasting, systemic inflammation (splenic CD4+ T cell phenotypes), gut microbiota composition, and short-chain fatty acid (SCFA) production. The direct effects of Phocaeicola vulgatus (P. vulgatus) administration were also assessed in the CT26 model.
Results
MCL functions as a potent host-directed therapy, ameliorating muscle wasting in both models—particularly CT26—completely uncoupling muscle preservation from tumor cytotoxicity. In vitro, MCL directly prevented catabolism in both C2C12 and human primary myotubes. In vivo, MCL robustly rescued muscle mass and function. This was associated with the suppression of local muscle NF-κB hyperactivation and a marked reduction in the absolute counts of activated (CD25+) and exhaustion marker-expressing (PD-1+, TIM-3+) splenic CD4+ and CD8+ T cells, resolving splenomegaly. Crucially, targeted microbiota depletion in pseudo-GF mice entirely abrogated these anti-cachectic benefits, establishing the gut microbiome as an indispensable mediator. MCL selectively enriched the beneficial bacterium P. vulgatus while differentially suppressing potential pathobionts like Enterococcus faecalis in CT26 and Streptococcus acidominimus in LLC. Microbial functional analysis indicated MCL increased the predicted potential for biotin biosynthesis in the CT26 model. Correlation analyses linked P. vulgatus abundance and increased SCFAs to reduced cachexia severity and modulated T cell profiles. Validating its functional significance, oral P. vulgatus administration significantly attenuated muscle wasting, increased cecal butyrate, and beneficially altered specific gut bacterial taxa in the CT26 model.
Conclusion
By therapeutically rewiring the gut-immune-muscle axis, MCL exerts pronounced and context-dependent anti-cachectic efficacy. Through dampening of systemic inflammation via T cell modulation, beneficial remodeling of the gut microbiota, and enhancement of predicted microbial biosynthesis pathways, MCL serves as a highly translational, host-directed intervention to mitigate cancer-induced systemic catabolism independent of tumor growth inhibition.
Cancer cachexia profoundly impacts patient survival and quality of life. Current treatments fail to halt this trajectory, highlighting an urgent clinical need for host-directed therapies capable of uncoupling skeletal muscle wasting from tumor progression. This study investigated the therapeutic potential of micheliolide (MCL) across distinct tumor contexts.
Methods
We employed immunocompetent murine models of colon cancer (CT26) and lung cancer (LLC) cachexia, pseudo-germ-free (pseudo-GF) mice, murine C2C12 myotubes, and primary human skeletal muscle cells. We evaluated MCL's impact on muscle wasting, systemic inflammation (splenic CD4+ T cell phenotypes), gut microbiota composition, and short-chain fatty acid (SCFA) production. The direct effects of Phocaeicola vulgatus (P. vulgatus) administration were also assessed in the CT26 model.
Results
MCL functions as a potent host-directed therapy, ameliorating muscle wasting in both models—particularly CT26—completely uncoupling muscle preservation from tumor cytotoxicity. In vitro, MCL directly prevented catabolism in both C2C12 and human primary myotubes. In vivo, MCL robustly rescued muscle mass and function. This was associated with the suppression of local muscle NF-κB hyperactivation and a marked reduction in the absolute counts of activated (CD25+) and exhaustion marker-expressing (PD-1+, TIM-3+) splenic CD4+ and CD8+ T cells, resolving splenomegaly. Crucially, targeted microbiota depletion in pseudo-GF mice entirely abrogated these anti-cachectic benefits, establishing the gut microbiome as an indispensable mediator. MCL selectively enriched the beneficial bacterium P. vulgatus while differentially suppressing potential pathobionts like Enterococcus faecalis in CT26 and Streptococcus acidominimus in LLC. Microbial functional analysis indicated MCL increased the predicted potential for biotin biosynthesis in the CT26 model. Correlation analyses linked P. vulgatus abundance and increased SCFAs to reduced cachexia severity and modulated T cell profiles. Validating its functional significance, oral P. vulgatus administration significantly attenuated muscle wasting, increased cecal butyrate, and beneficially altered specific gut bacterial taxa in the CT26 model.
Conclusion
By therapeutically rewiring the gut-immune-muscle axis, MCL exerts pronounced and context-dependent anti-cachectic efficacy. Through dampening of systemic inflammation via T cell modulation, beneficial remodeling of the gut microbiota, and enhancement of predicted microbial biosynthesis pathways, MCL serves as a highly translational, host-directed intervention to mitigate cancer-induced systemic catabolism independent of tumor growth inhibition.
논문소개전체 설명
1. 연구 배경
암 악액질(Cancer Cachexia)은 암 환자의 체중과 골격근이 급격히 감소하는 전신 대사 붕괴 증후군으로, 전체 암 환자 사망 원인의 최대 30%를 차지할 정도로 치명적입니다. 하지만 현재 임상에서 널리 쓰이는 항암제 중심(Tumor-centric)의 치료는 종양을 사멸시키는 데 집중할 뿐, 숙주(환자)의 전신 대사 붕괴를 막지 못하는 근본적인 한계가 있습니다.
최근 장내 미생물(Gut Microbiome)이 전신 면역 및 대사 기능에 깊이 관여한다는 사실이 밝혀지면서, 장내 환경을 조절하여 악액질을 개선하려는 시도가 주목받고 있습니다. 이에 본 연구팀은 천연물 유래 세스퀴테르펜 락톤(Sesquiterpene lactone) 계열 화합물인 미켈리오라이드(Micheliolide, MCL)가 ‘장-면역-근육 축(Gut-Immune-Muscle Axis)’을 어떻게 조절하며, 종양의 성장과 근육 감소를 어떻게 분리(Uncoupling)해 내는지 그 치료적 잠재력과 기전을 규명하고자 하였습니다.
2. 주요 연구 내용
본 연구는 대장암(CT26) 및 폐암(LLC) 악액질 마우스 모델과 인간 일차 골격근 세포(Primary human skeletal muscle cells)를 활용하여 MCL의 다중 표적 효과를 입증했습니다.
1) 숙주 표적 치료(Host-directed Therapy)를 통한 근위축 방어 및 Uncoupling
MCL은 종양의 크기나 질량에는 영향을 미치지 않으면서도, 훼손된 근육량과 근기능(악력)을 복원했습니다. 이는 MCL이 종양을 직접 공격하는 것이 아니라, 환자의 체력을 보호하는 '숙주 표적 치료제'로 작용함을 의미합니다.
2) 장내 미생물 재편 및 대사 방어막(Metabolic Shield) 형성
MCL 투여는 악액질로 인해 무너진 장내 미생물 생태계를 복원했습니다. 특히, 병원성 균주(Enterococcus faecalis 등)의 증식을 억제하고 유익균인 Phocaeicola vulgatus(P. vulgatus)를 선택적으로 농축시켰습니다. 기능적 메타유전체 분석 결과, 이러한 군집 변화는 단쇄지방산(SCFA, 특히 뷰티르산) 및 비오틴(Biotin) 생합성 경로를 활성화하여 근육 보호를 위한 대사적 방어막을 구축하는 것으로 나타났습니다.
3) 전신 면역 탈진(T cell exhaustion) 및 근육 내 염증 억제
MCL은 비장 비대증(Splenomegaly)을 해소하고, 과도하게 활성화된 CD4+ T세포 및 면역 탈진 마커(PD-1+, Tim-3+)를 발현하는 T세포의 절대적인 수를 감소시켰습니다. 전신 염증이 완화됨에 따라 골격근 내 국소적인 NF-κB 염증 신호전달 또한 억제되었습니다.
4) 마이크로바이옴 의존성 증명 및 프로바이오틱스 적용 가능성
항생제로 장내 미생물을 제거한 'Pseudo-germ-free' 마우스 모델에서는 MCL의 근육 보호 효과가 사라졌습니다. 이는 MCL의 항악액질 효과에 장내 미생물이 'Indispensable mediator'임을 증명합니다. 나아가, MCL 대신 P. vulgatus 생균을 마우스에 경구 투여했을 때에도 MCL과 동일하게 장-비장-근육 축이 안정화되며 근위축이 개선됨을 확인하여, 임상 적용 가능성을 확인했습니다.
3. 연구의 의의 및 기대효과
본 연구는 단순히 근육의 단백질 합성을 촉진하는 기존의 단편적인 접근을 넘어, '장내 미생물-대사체-전신 면역-골격근'으로 이어지는 다차원적인 치료 패러다임을 제시했다는 데 의의가 있습니다.
MCL과 그 핵심 매개균인 P. vulgatus의 발굴은, 종양을 죽이지 않고도 환자의 근육과 체력을 보호하는 'First-in-class 암 악액질 치료제 및 신바이오틱스(Synbiotics)' 개발의 과학적 근거가 될 것이라 생각합니다. 이를 통해 항암 치료를 견뎌내야 하는 전 세계 수많은 암 환자들의 생존율과 삶의 질을 높일 수 있을 것으로 기대합니다.
논문정보
- Research article
- 2026년 05월 (BRIC 등록일 2026-05-06)
- 국내 연구진
- 생명과학 > 생명과학 기타
댓글 작성 로그인
팝업 닫기
![[에펜도르프] 2026 상반기 특별 프로모션 : 프리미엄 에펜도르프 제품을 좋은 혜택으로 만날 수 있는 기회!](/app/board/attach/image/1348816_1772455401000.do?)
