Dietary whey protein protects against Crohn’s disease by orchestrating cross-kingdom interaction between the gut phageome and bacteriome.

Mar 24, 2025

Experts: Runping Su,Weijie Wen,Yufeng Jin,Zhirui Cao,Zhiyang Feng,Jie Chen,Yu Lu,Guicheng Zhou,Chao Dong,Shanshan Gao,Xue Li,Hu Zhang,Kang Chao,Ping Lan,Xiaojian Wu,Anna Philips,Kun Li,Xiang Gao,Fen Zhang,Tao Zuo

The gut microbiome and diet are important factors in the pathogenesis and management of Crohn’s disease (CD). However, the role of the gut phageome under dietary influences is unknown.
We aim to explore the effect of diet on the gut phageome-bacteriome interaction linking to CD protection.
We recruited CD patients and healthy subjects (n=140) and conducted a multiomics investigation, including paired ileal mucosa phageome and bacteriome profiling, dietary survey and phenome interrogation. We screened for the effect of diet on the gut phageome and bacteriome, as well as its epidemiological association with CD risks. The underlying mechanisms were explored in target phage-bacteria monocultures and cocultures in vitro and in two mouse models in vivo.
On dietary screening in humans, whey protein (WP) consumption was found to profoundly impact the gut phageome and bacteriome (more pronounced on the phageome) and was associated with a lower CD risk. Indeed, the WP reshaped gut phageome can causally attenuate intestinal inflammation, as shown by faecal phageome versus bacteriome transplantation from WP-consuming versus WP-non-consuming mice to recipient mice. Mechanistically, WP induced phage (a newly isolated phage AkkZT003P herein) lysis of the mucin-foraging bacterium , which unleashed the symbiotic bacterium to counteract intestinal inflammation.
Our study charted the importance of cross-kingdom interaction between gut phage and bacteria in mediating the dietary effect on CD protection. Importantly, we uncovered a beneficial dietary WP, a keystone phage AkkZT003P, and a probiotic that can be used in CD management in the future.

© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.

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ABOUT THE EXPERTS

Runping Su,Weijie Wen,Yufeng Jin,Zhirui Cao,Zhiyang Feng,Jie Chen,Yu Lu,Guicheng Zhou,Chao Dong,Shanshan Gao,Xue Li,Hu Zhang,Kang Chao,Ping Lan,Xiaojian Wu,Anna Philips,Kun Li,Xiang Gao,Fen Zhang,Tao Zuo

Runping Su

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Weijie Wen

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Yufeng Jin

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Zhirui Cao

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Zhiyang Feng

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Jie Chen

Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, China.

Yu Lu

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Guicheng Zhou

Department of Food Science and Engineering, College of Life Science and Technology, Jinan University College of Life Science and Technology, Guangzhou, Guangdong, China.

Chao Dong

School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

Shanshan Gao

Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.

Xue Li

Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Hu Zhang

Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.

Kang Chao

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Ping Lan

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Xiaojian Wu

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Anna Philips

Institute of Bioorganic Chemistry Polish Academy of Sciences, Poznan, Poland.

Kun Li

Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China zuot@mail.sysu.edu.cn zfcuhkszri@163.com gxiang@mail.sysu.edu.cn doctor_lee@126.com.

Xiang Gao

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China zuot@mail.sysu.edu.cn zfcuhkszri@163.com gxiang@mail.sysu.edu.cn doctor_lee@126.com.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

Fen Zhang

Department of Food Science and Engineering, College of Life Science and Technology, Jinan University College of Life Science and Technology, Guangzhou, Guangdong, China zuot@mail.sysu.edu.cn zfcuhkszri@163.com gxiang@mail.sysu.edu.cn doctor_lee@126.com.

Tao Zuo

Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China zuot@mail.sysu.edu.cn zfcuhkszri@163.com gxiang@mail.sysu.edu.cn doctor_lee@126.com.

Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, China.

Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong, China.

Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.