Microbiota regulate innate immune signaling and protective immunity against cancer

Changsheng Xing; Mingjun Wang; Adebusola A Ajibade; Peng Tan; Chuntang Fu; Lang Chen; Motao Zhu; Zhao-Zhe Hao; Junjun Chu; Xiao Yu; Bingnan Yin; Jiahui Zhu; Wan-Jou Shen; Tianhao Duan; Helen Y Wang; Rong-Fu Wang

doi:10.1016/j.chom.2021.03.016

Microbiota regulate innate immune signaling and protective immunity against cancer

Cell Host Microbe. 2021 Jun 9;29(6):959-974.e7. doi: 10.1016/j.chom.2021.03.016. Epub 2021 Apr 23.

Authors

Changsheng Xing¹, Mingjun Wang², Adebusola A Ajibade², Peng Tan³, Chuntang Fu⁴, Lang Chen⁵, Motao Zhu¹, Zhao-Zhe Hao⁶, Junjun Chu¹, Xiao Yu², Bingnan Yin¹, Jiahui Zhu⁷, Wan-Jou Shen⁸, Tianhao Duan¹, Helen Y Wang⁹, Rong-Fu Wang¹⁰

Affiliations

¹ Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
² Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
³ Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA.
⁴ Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA.
⁵ Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of General Surgery, Third Xiangya Hospital, XiangYa School of Medicine, Central South University, Changsha 410013, China.
⁶ Jan and Dan Duncan Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, South East University, Nanjing 210096, China.
⁸ Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
⁹ Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
¹⁰ Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address: rongfuwa@usc.edu.

Abstract

Microbiota play critical roles in regulating colitis and colorectal cancer (CRC). However, it is unclear how the microbiota generate protective immunity against these disease states. Here, we find that loss of the innate and adaptive immune signaling molecule, TAK1, in myeloid cells (Tak1^ΔM/ΔM) yields complete resistance to chemical-induced colitis and CRC through microbiome alterations that drive protective immunity. Tak1^ΔM/ΔM mice exhibit altered microbiota that are critical for resistance, with antibiotic-mediated disruption ablating protection and Tak1^ΔM/ΔM microbiota transfer conferring protection against colitis or CRC. The altered microbiota of Tak1^ΔM/ΔM mice promote IL-1β and IL-6 signaling pathways, which are required for induction of protective intestinal Th17 cells and resistance. Specifically, Odoribacter splanchnicus is abundant in Tak1^ΔM/ΔM mice and sufficient to induce intestinal Th17 cell development and confer resistance against colitis and CRC in wild-type mice. These findings identify specific microbiota strains and immune mechanisms that protect against colitis and CRC.

Keywords: Bacteroides sp. D20; Odoribacter splanchnicus; TAK1 signaling; Th17 cells; acute colitis; colon cancer; innate immunity; microbiota.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bacteroidetes / metabolism*
Colitis / chemically induced
Colitis / metabolism
Colitis / microbiology*
Colorectal Neoplasms / chemically induced
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / microbiology*
Cytokines / physiology*
Disease Models, Animal
Feces / microbiology
Female
Gastrointestinal Microbiome*
Host Microbial Interactions
Immunity, Innate
Interleukin-1beta / physiology
Interleukin-6 / physiology
MAP Kinase Kinase Kinases / genetics
MAP Kinase Kinase Kinases / physiology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Cells / metabolism
Signal Transduction
Th17 Cells / immunology
Th17 Cells / metabolism*

Substances

Cytokines
Interleukin-1beta
Interleukin-6
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7

Supplementary concepts

Odoribacter splanchnicus

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding