Environmental enrichment in combination with Bifidobacterium breve HNXY26M4 intervention amplifies neuroprotective benefits in a mouse model of Alzheimer's disease by modulating glutamine metabolism of the gut microbiome

Abstract

The gut microbiota-brain axis has emerged as a novel target for Alzheimer's disease (AD), a neurodegenerative disease characterised by behavioural and cognitive impairment. However, most previous microbiome-based intervention studies have focused on single factors and yielded only modest cognitive improvements. Here, we proposed a multidomain intervention strategy that combined Bifidobacterium breve treatment with environmental enrichment (EE) training. In this study, we found that compared with EE or B. breve treatment alone, B. breve intervention combined with EE amplified its neuroprotective effects on AD mice, as reflected by improved cognition, inhibited neuroinflammation and enhanced synaptic function. Moreover, using microbiome and metabolome profiling, we found that the combination of B. breve and EE treatment restored AD-related gut microbiota dysbiosis and reversed microbial metabolite changes. Finally, by integrating behavioural and neurological data with metabolomic profiles, we revealed that the underlying mechanism may involve the modulation of microbiota-derived glutamine metabolism via gut-brain interactions. Collectively, combined B. breve intervention with EE treatment can alleviate AD-related cognitive impairment and improve brain function by regulating glutamine metabolism of the gut microbiome. Our findings provide a promising multidomain intervention strategy, with a combination of dietary microbiome-based and lifestyle-targeted interventions, to promote brain function and delay the progression of AD.

Potential Therapeutic Effects of Bifidobacterium breve MCC1274 on Alzheimer’s Disease Pathologies in AppNL-G-F Mice

“…In addition, oral administration of Bifidobacterium lactis ameliorates cognitive dysfunction in Aβ-injected mice through attenuation of ERK and JNK phosphorylation [ 55 ]. As well as it has been reported that Lactobacillus species act as protective from environmental stressors [ 56 ], and Bifidobacterium breve alleviated Aβ-induced cognitive impairment and enhanced synaptic function in AD mice [ 57 ]. We previously demonstrated that orally supplemented B. breve MCC1274 mitigated AD pathologies, as indicated by improved memory impairment, reduced amyloidosis and neuroinflammation, and improved synaptic plasticity, in both young AD model and WT mice [ 10 , 12 , 13 ].…”