Post-weaning A1/A2 β-casein milk intake modulates depressive-like behavior, brain μ-opioid receptors, and the metabolome of rats

Aya Osman,Simone Zuffa,Gemma Walton,Elizabeth Fagbodun,Panos Zanos,Polymnia Georgiou,Ian Kitchen,Jonathan Swann,Alexis Bailey

doi:10.1016/j.isci.2021.103048

Abstract

SummaryThe postnatal period is critical for brain and behavioral development and is sensitive to environmental stimuli, such as nutrition. Prevention of weaning from maternal milk was previously shown to cause depressive-like behavior in rats. Additionally, loss of dietary casein was found to act as a developmental trigger for a population of brain opioid receptors. Here, we explore the effect of exposure to milk containing A1 and A2 β-casein beyond weaning. A1 but not A2 β-casein milk significantly increased stress-induced immobility in rats, concomitant with an increased abundance of Clostridium histolyticum bacterial group in the caecum and colon of A1 β-casein fed animals, brain region-specific alterations of μ-opioid and oxytocin receptors, and modifications in urinary biochemical profiles. Moreover, urinary gut microbial metabolites strongly correlated with altered brain metabolites. These findings suggest that consumption of milk containing A1 β-casein beyond weaning age may affect mood via a possible gut-brain axis mechanism.

Highlights

During the first 2 years of life, the human brain undergoes a period of rapid growth and development, which is sensitive to both genetic and environmental stimuli (Chen and Baram, 2016)
Loss of dietary casein was found to act as a developmental trigger for a population of brain opioid receptors
We have previously demonstrated in rats that weaning on postnatal day (PND) 21, the standard age of weaning in rodents (Cramer et al, 1990), acts as a signal for the developmental activation of a population of opioid receptor subtype (Kitchen et al, 1995)

Summary

Introduction

During the first 2 years of life, the human brain undergoes a period of rapid growth and development, which is sensitive to both genetic and environmental stimuli (Chen and Baram, 2016). We have previously demonstrated in rats that weaning on postnatal day (PND) 21, the standard age of weaning in rodents (Cramer et al, 1990), acts as a signal for the developmental activation of a population of opioid receptor subtype (Kitchen et al, 1995). This effect was shown to be independent of psychological (maternal deprivation) or physiological (suckling) stimuli and is solely dependent on the loss of dietary casein (Goody and Kitchen, 2001). We have demonstrated that preventing the weaning process for 5 days in rats resulted in increased stress-induced immobility during the forced swim test (FST), concomitant with a resistance to stress-induced modulation of oxytocin receptors (OTrs) in amygdala nuclei, indicative of passive stress-coping mechanisms (Farshim et al, 2016)

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