Pasteurized Akkermansia muciniphila improves irritable bowel syndrome-like symptoms and related behavioral disorders in mice

ABSTRACT

Gut – brain communications disorders in irritable bowel syndrome (IBS) are associated with intestinal microbiota composition, increased gut permeability, and psychosocial disturbances. Symptoms of IBS are difficult to medicate, and hence much research is being made into alternative approaches. This study assesses the potential of a treatment with pasteurized Akkermansia muciniphila for alleviating IBS-like symptoms in two mouse models of IBS with different etiologies. Two clinically relevant animal models were used to mimic IBS-like symptoms in C57BL6/J mice: the neonatal maternal separation (NMS) paradigm and the Citrobacter rodentium infection model. In both models, gut permeability, colonic sensitivity, fecal microbiota composition and colonic IL-22 expression were evaluated. The cognitive performance and emotional state of the animals were also assessed by several tests in the C. rodentium infection model. The neuromodulation ability of pasteurized A. muciniphila was assessed on primary neuronal cells from mice dorsal root ganglia using a ratiometric calcium imaging approach. The administration of pasteurized A. muciniphila significantly reduced colonic hypersensitivity in both IBS mouse models, accompanied by a reinforcement of the intestinal barrier function. Beneficial effects of pasteurized A. muciniphila treatment have also been observed on anxiety-like behavior and memory defects in the C. rodentium infection model. Finally, a neuroinhibitory effect exerted by pasteurized A. muciniphila was observed on neuronal cells stimulated with two algogenic substances such as capsaicin and inflammatory soup. Our findings demonstrate novel anti-hyperalgesic and neuroinhibitory properties of pasteurized A. muciniphila, which therefore may have beneficial effects in relieving pain and anxiety in subjects with IBS.

KEYWORDS:

• Pasteurized Akkermansia muciniphila
• IBS
• colonic hypersensitivity
• anxiety-like disorders
• memory impairment
• neuroinhibition

Acknowledgments

Abdelkrim Alloui (Animal Facilities) for animal care.

Disclosure statement

P.D.C., W.M.dV. and A.B. are inventors on patent applications dealing with the use of specific bacteria and components in the treatment of different diseases. P.D.C. and W.M.dV. are co-founders of The Akkermansia Company SA. P.D.C. is co-founder of Enterosys. A.B., P.S. and W.M.dV. are employees of or associated with The Akkermansia Company. The other authors have declared no conflicting interest..

Author contributions

MaeM, VD, and FAC performed the experiments, analyzed the data wrote the manuscript and created the figures. GM, SG, MatM, JB, and YA performed experiments, analyzed the data, and provided technical support. SL provided technical support for calcium imaging analyses. MVH performed microbiota analysis. MB and DA critically revised the manuscript for important intellectual content, approved the drafting, and funded the project. WMdV and PS provided materials, interpreted results, critically revised the discussion, and reviewed the manuscript for important intellectual content. AB and PDC contributed to the design of the study, provided materials, and revised the manuscript. FAC designed, analyzed, supervised, funded the study, and revised the manuscript. All authors approved the final manuscript.

Data availability statement

The raw amplicon sequencing data analyzed in this study have been deposited in the EMBL-EBI European Nucleotide Archive (ENA) under accession number PRJEB53668 (https://www.ebi.ac.uk/ena/browser/view/PRJEB68376). The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2298026

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by co-financing from The Akkermansia Company™ (Belgium) and supported by a research agreement from the Walloon Region (agreement 8206), the French Ministère de la Recherche et de la Technologie (NeuroDol laboratory [INSERM 1107]), the Region Auvergne-Rhône-Alpes and FEDER, No. Thématiques émergentes, Pack Ambition Recherche; the French Government IDEX-ISITE Initiative, No. 16-IDEX-0001-CAP 20-25, and the Clermont Auvergne Métropole, No “Recherche-Action” project. P.D.C. is research director for the FNRS and recipient of a Projet de Recherche PDR-convention: FNRS T.0030.21 and FRFS-WELBIO: WELBIO-CR-2022A-02, EOS: program no. 40007505.