Oral vancomycin treatment suppresses gut trypsin activity and preserves intestinal barrier function during EAE

Paola Bianchimano; Kacper Iwanowski; Emma M Smith; Adam Cantor; Paola Leone; Gerold Bongers; Carlos G Gonzalez; Yoon Hongsup; Joshua Elias; Howard L Weiner; Jose C Clemente; Stephanie K Tankou

doi:10.1016/j.isci.2023.108143

Oral vancomycin treatment suppresses gut trypsin activity and preserves intestinal barrier function during EAE

iScience. 2023 Oct 6;26(11):108143. doi: 10.1016/j.isci.2023.108143. eCollection 2023 Nov 17.

Authors

Paola Bianchimano^{1

2

3}, Kacper Iwanowski^{1

2

3}, Emma M Smith^{1

2

3}, Adam Cantor^{3

4}, Paola Leone^{1

2

3}, Gerold Bongers³, Carlos G Gonzalez⁵, Yoon Hongsup^{6

7}, Joshua Elias⁸, Howard L Weiner⁹, Jose C Clemente^{3

4}, Stephanie K Tankou^{1

2

3}

Affiliations

¹ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Pharmacology, University of California San Diego, San Diego, CA 92093, USA.
⁶ Institute of Clinical Neuroimmunology, Hospital and Biomedical Center of the Ludwig-Maximilian-University, Martinsried, Germany.
⁷ Hertie Senior Professor Group, Max-Plank-Institute of Neurobiology, Martinsried, Germany.
⁸ Mass Spectrometry Platform, Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁹ Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.

Abstract

Studies have reported increased intestinal permeability in multiple sclerosis (MS) patients and its mouse model experimental autoimmune encephalomyelitis (EAE). However, the mechanisms driving increased intestinal permeability that in turn exacerbate neuroinflammation during EAE remain unclear. Here we showed that vancomycin preserved the integrity of the intestinal barrier, while also suppressing gut trypsin activity, enhancing the relative abundance of specific Lactobacilli and ameliorating disease during EAE. Furthermore, Lactobacilli enriched in the gut of vancomycin-treated EAE mice at day 3 post immunization negatively correlated with gut trypsin activity and EAE severity. In untreated EAE mice, we observed increased intestinal permeability and increased intestinal protease activated receptor 2 (PAR2) expression at day 3 post immunization. Prior studies have shown that trypsin increases intestinal permeability by activating PAR2. Our results suggest that the interaction between intestinal PAR2 and trypsin may be a key modulator of intestinal permeability and disease severity during EAE.

Keywords: Drugs; Human physiology; Microbiome.

Abstract

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