Probiotics modulate the microbiota-gut-brain axis and improve memory deficits in aged SAMP8 mice

Xueqin Yang; Dongke Yu; Li Xue; Hui Li; Junrong Du

doi:10.1016/j.apsb.2019.07.001

Probiotics modulate the microbiota-gut-brain axis and improve memory deficits in aged SAMP8 mice

Acta Pharm Sin B. 2020 Mar;10(3):475-487. doi: 10.1016/j.apsb.2019.07.001. Epub 2019 Jul 7.

Authors

Xueqin Yang¹, Dongke Yu², Li Xue¹, Hui Li¹, Junrong Du¹

Affiliations

¹ Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
² Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, China.

Abstract

ProBiotic-4 is a probiotic preparation composed of Bifidobacterium lactis, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus acidophilus. This study aims to investigate the effects of ProBiotic-4 on the microbiota-gut-brain axis and cognitive deficits, and to explore the underlying molecular mechanism using senescence-accelerated mouse prone 8 (SAMP8) mice. ProBiotic-4 was orally administered to 9-month-old SAMP8 mice for 12 weeks. We observed that ProBiotic-4 significantly improved the memory deficits, cerebral neuronal and synaptic injuries, glial activation, and microbiota composition in the feces and brains of aged SAMP8 mice. ProBiotic-4 substantially attenuated aging-related disruption of the intestinal barrier and blood-brain barrier, decreased interleukin-6 and tumor necrosis factor-α at both mRNA and protein levels, reduced plasma and cerebral lipopolysaccharide (LPS) concentration, toll-like receptor 4 (TLR4) expression, and nuclear factor-κB (NF-κB) nuclear translocation in the brain. In addition, not only did ProBiotic-4 significantly decreased the levels of γ-H2AX, 8-hydroxydesoxyguanosine, and retinoic-acid-inducible gene-I (RIG-I), it also abrogated RIG-I multimerization in the brain. These findings suggest that targeting gut microbiota with probiotics may have a therapeutic potential for the deficits of the microbiota-gut-brain axis and cognitive function in aging, and that its mechanism is associated with inhibition of both TLR4-and RIG-I-mediated NF-κB signaling pathway and inflammatory responses.

Keywords: 8-OHdG, 8-hydroxydesoxyguanosine; AAMI, age-associated memory impairment; AD, Alzheimer's disease; BBB, blood–brain barrier; CFU, colony-forming units; Cognitive decline; ELISA, enzyme-linked immunosorbent assay; F/B, Firmicutes/Bacteroidetes; GFAP, glial fibrillary acidic protein; HE, hematoxylin and eosin; IHC, immunohistochemistry; IL-6, interleukin-6; Iba-1, ionized calcium binding adaptor molecule-1; LPS, lipopolysaccharide; MCI, mild cognitive impairment; Microbiota–gut–brain axis; NF-κB; NF-κB, nuclear factor-κB; NMDS, non-metric multidimensional scaling; OTU, operational taxonomic unit; PAMP, pathogen-associated molecular pattern; Probiotics; RIG-I; RIG-I, retinoic-acid-inducible gene-I; SAMP8 mice; SAMP8, senescence-accelerated mouse prone 8; SYN, synaptophysin; TEM, transmission electron microscopy; TLR4; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α; VE-cadherin, vascular endothelial-cadherin; ZO-1, zona occluden-1.