Distinct Actions of the Fermented Beverage Kefir on Host Behaviour, Immunity and Microbiome Gut-Brain Modules in the Mouse

Mounting evidence suggests a role for the gut microbiota in modulating brain physiology and behavior through bi-directional communication along the gut-brain axis. As such, the gut microbiota represents a potential therapeutic target for influencing centrally-mediated events and host behavior. It is thus notable that the fermented foods, such as the milk beverage kefir, have recently been shown to modulate the composition of the gut microbiota in mice. It is unclear whether foods such as kefirs, which include both microbial fermentation products and live probiotic microbes, have differential effects on microbiota-gut-brain axis and whether they can modulate host behaviour per se. To address this, two distinct kefirs (Fr1 and UK4) or unfermented milk control were administered to mice that underwent a battery of tests to characterise their behavioural phenotype. In addition, shotgun metagenomic sequencing of ileal, cecal and faecal matter was performed, as was faecal metabolome analysis. Fr1 ameliorated the stress-induced decrease in serotonergic signalling in the colon and reward-seeking behaviour in the saccharin preference test. On the other hand, UK4 decreased repetitive behaviour and ameliorated stress-induced deficits in reward-seeking behaviour. Furthermore, UK4 increased fear-dependent contextual memory, yet decreased milk gavage-induced improvements long-term spatial learning. In the peripheral immune system, UK4 increased the prevalence of Treg cells and interleukin 10 levels, whereas Fr1 ameliorated the milk gavage stress-induced elevation in neutrophil levels and CXCL1 levels. Analysis of the gut microbiota revealed that both kefirs significantly changed the composition and functional capacity of the host microbiota, where specific bacterial species were changed in a kefir-dependent manner. Furthermore, both kefirs increased the capacity of the gut microbiota to produce GABA, which was linked to an increased prevalence in Lactobacillus reuteri. Altogether, these data show that probiotic fermentation products such as kefir can signal through the microbiota-gut-immune-brain axis and modulate host behaviour. In addition, different products may direct the microbiota toward distinct immunological and behavioural modulatory effects. These results indicate that kefir can positively modulate specific aspects of the microbiota gut-brain axis and support the broadening of the definition of psychobiotic to include fermented foods.