Identification of trypsin-degrading commensals in the large intestine

Youxian Li, Eiichiro Watanabe, Yusuke Kawashima, Damian R. Plichta, Zhujun Wang, Makoto Ujike, Qi Yan Ang, Runrun Wu, Munehiro Furuichi, Kozue Takeshita, Koji Yoshida, Keita Nishiyama, Sean M. Kearney, Wataru Suda, Masahira Hattori, Satoshi Sasajima, Takahiro Matsunaga, Xiaoxi Zhang, Kazuto Watanabe, Jun Fujishiro, Jason M. Norman, Bernat Olle, Shutoku Matsuyama, Ho Namkoong, Yoshifumi Uwamino, Makoto Ishii, Koichi Fukunaga, Naoki Hasegawa, Osamu Ohara, Ramnik J. Xavier (), Koji Atarashi () and Kenya Honda ()
Additional contact information
Youxian Li: RIKEN Center for Integrative Medical Sciences
Eiichiro Watanabe: RIKEN Center for Integrative Medical Sciences
Yusuke Kawashima: RIKEN Center for Integrative Medical Sciences
Damian R. Plichta: Broad Institute of MIT and Harvard
Zhujun Wang: RIKEN Center for Integrative Medical Sciences
Makoto Ujike: Nippon Veterinary and Life Science University
Qi Yan Ang: Broad Institute of MIT and Harvard
Runrun Wu: Purdue University
Munehiro Furuichi: Keio University School of Medicine
Kozue Takeshita: Keio University School of Medicine
Koji Yoshida: Keio University School of Medicine
Keita Nishiyama: Keio University School of Medicine
Sean M. Kearney: Keio University School of Medicine
Wataru Suda: RIKEN Center for Integrative Medical Sciences
Masahira Hattori: RIKEN Center for Integrative Medical Sciences
Satoshi Sasajima: Keio University School of Medicine
Takahiro Matsunaga: RIKEN Center for Integrative Medical Sciences
Xiaoxi Zhang: RIKEN Center for Integrative Medical Sciences
Kazuto Watanabe: Keio University School of Medicine
Jun Fujishiro: The University of Tokyo
Jason M. Norman: Vedanta Biosciences
Bernat Olle: Vedanta Biosciences
Shutoku Matsuyama: National Institute of Infectious Diseases
Ho Namkoong: Keio University School of Medicine
Yoshifumi Uwamino: Keio University School of Medicine
Makoto Ishii: Keio University School of Medicine
Koichi Fukunaga: Keio University School of Medicine
Naoki Hasegawa: Keio University School of Medicine
Osamu Ohara: RIKEN Center for Integrative Medical Sciences
Ramnik J. Xavier: Broad Institute of MIT and Harvard
Koji Atarashi: RIKEN Center for Integrative Medical Sciences
Kenya Honda: RIKEN Center for Integrative Medical Sciences

Nature, 2022, vol. 609, issue 7927, 582-589

Abstract: Abstract Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions1–3. However, the players and mechanisms that underlie protease regulation in the intestinal lumen have remained unclear. Here we show that Paraprevotella strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically, Paraprevotella recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis. Paraprevotella colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against Citrobacter rodentium. Moreover, Paraprevotella colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells4,5. Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.

Date: 2022
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DOI: 10.1038/s41586-022-05181-3

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