Kefir ameliorates specific microbiota-gut-brain axis impairments in a mouse model relevant to autism spectrum disorder

Marcel van de Wouw; Calum J Walsh; Giulia M D Vigano; Joshua M Lyte; Marcus Boehme; Andreu Gual-Grau; Fiona Crispie; Aaron M Walsh; Gerard Clarke; Timothy G Dinan; Paul D Cotter; John F Cryan

doi:10.1016/j.bbi.2021.07.004

Kefir ameliorates specific microbiota-gut-brain axis impairments in a mouse model relevant to autism spectrum disorder

Brain Behav Immun. 2021 Oct:97:119-134. doi: 10.1016/j.bbi.2021.07.004. Epub 2021 Jul 9.

Authors

Affiliations

¹ APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
² APC Microbiome Ireland, University College Cork, Cork, Ireland; Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland.
³ APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy.
⁴ APC Microbiome Ireland, University College Cork, Cork, Ireland.
⁵ APC Microbiome Ireland, University College Cork, Cork, Ireland; Nutrigenomics Research Group, Biochemistry and Biotechnology Department, Rovira i Virgili University, Tarragona, Spain.
⁶ APC Microbiome Ireland, University College Cork, Cork, Ireland; Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland; School of Microbiology, University College Cork, Cork, Ireland.
⁷ APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.
⁸ APC Microbiome Ireland, University College Cork, Cork, Ireland; Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland. Electronic address: paul.cotter@teagasc.ie.
⁹ APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland. Electronic address: j.cryan@ucc.ie.

PMID: 34252569
DOI: 10.1016/j.bbi.2021.07.004

Abstract

Autism spectrum disorder (ASD) is one of the most severe developmental disorders, affecting on average 1 in 150 children worldwide. There is a great need for more effective strategies to improve quality of life in ASD subjects. The gut microbiome has emerged as a potential therapeutic target in ASD. A novel modulator of the gut microbiome, the traditionally fermented milk drink kefir, has recently been shown to modulate the microbiota and decrease repetitive behaviour, one of the hallmarks of ASD, in mice. As such, we hypothesized that kefir could ameliorate behavioural deficits in a mouse model relevant to ASD; the BTBR T⁺ Itpr3^tf/J mouse strain. To this end, adult mice were administered either kefir (UK4) or a milk control for three weeks as treatment lead-in, after which they were assessed for their behavioural phenotype using a battery of tests. In addition, we assessed systemic immunity by flow cytometry and the gut microbiome using shotgun metagenomic sequencing. We found that indeed kefir decreased repetitive behaviour in this mouse model. Furthermore, kefir prolonged stress-induced increases in corticosterone 60 min post-stress, which was accompanied by an ameliorated innate immune response as measured by LY6C^hi monocyte levels. In addition, kefir increased the levels of anti-inflammatory Treg cells in mesenteric lymph nodes (MLNs). Kefir also increased the relative abundance of Lachnospiraceae bacterium A2, which correlated with reduced repetitive behaviour and increased Treg cells in MLNs. Functionally, kefir modulated various predicted gut microbial pathways, including the gut-brain module S-Adenosylmethionine (SAM) synthesis, as well as L-valine biosynthesis and pyruvate fermentation to isobutanol, which all correlated with repetitive behaviour. Taken together our data show that kefir modulates peripheral immunoregulation, can ameliorate specific ASD behavioural dysfunctions and modulates selective aspects of the composition and function of the gut microbiome, indicating that kefir supplementation might prove a viable strategy in improving quality of life in ASD subjects.

Keywords: Autism spectrum disorder; Behaviour; Immunity; Kefir; Microbiome; Stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autism Spectrum Disorder*
Brain
Gastrointestinal Microbiome*
Kefir*
Mice
Microbiota*
Quality of Life