(P39-07-26) A Novel Gut-Brain Connection: Differential Influence of Conventional vs. A1 Protein-Free Milk Consumption on Inflammation-Related Gene Expression

Objectives: Neuroinflammation is an important contributor to brain disorders across the lifespan and activity of the NLRP3 inflammasome is increased by oxidative stress, which can occur when antioxidant resources are limited. The opioid peptide beta casomorphin-7 (BCM7), which is released upon digestion of A1 beta casein-containing bovine milk, inhibits cysteine uptake and limits production of the antioxidant glutathione (GSH). However, due to a SNP-based genetic difference, digestion of A2 beta casein generates little or no BCM7, allowing unhindered cysteine absorption and GSH production. Thus, A1 vs. A2 milk consumption can alter redox status, which in turn may affect levels of inflammation, but the possible significance of this relationship for brain inflammation status has not been investigated.

Methods: We compared inflammation-related and antioxidant-related gene expression and thiol metabolites in three segments of the small intestine (duodenum, jejunum and ileum), as well as in frontal cortex of weanling male Sprague-Dawley rats fed milk-based diets containing either Conventional milk (mixed A1/A2 beta-casein) or A1 protein-free (A1 PF) milk over a course of 28 days.

Results: IL-1β levels were comparatively higher in duodenum and ileum of A1 PF the group, while IL-4 levels were lower in jejunum but higher in ileum. IL-6 was higher in A1 PF duodenum, but lower in jejunum and ileum and IL-10 was higher in ileum. No significant differences between Conventional and A1-PF group thiol levels were observed in GI or brain tissues. In brain, expression of inflammation-related genes (IL-1β, IL-4, IL-6, IL-10, IL-18 and TGF-β) showed a remarkable pattern of lower expression for A1 PF-fed vs. Conventional milk groups. Lower cytokine expression was accompanied by lower expression of the NLRP3 inflammasome and the P2X7 purine receptor, whose activation by ATP promotes NLRP3 inflammasome activity, as well as lower expression of genes for the transsulfuration enzyme cystathionine gamma lyase and the antioxidant transcription factor Nrf2.

Conclusions: Our findings indicate that consumption of A1 PF milk is associated with lower activation of inflammation-related genes in the brain when compared to Conventional milk consumption.

Funding Sources: This study was supported by a grant from the A2 Milk Company.