Strategic Modification of Gut Microbiota through Oral Bacteriotherapy Influences Hypoxia Inducible Factor-1α: Therapeutic Implication in Alzheimer's Disease

Dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and oral bacteriotherapy represents a promising preventative and therapeutic opportunity to remodel gut microbiota and to delay AD onset and progression by reducing neuroinflammation and amyloid and tau proteins aggregation. Specifically, SLAB51 multi-strain probiotic formulation positively influences multiple neuro-chemical pathways, but exact links between probiotics oral consumption and cerebral beneficial effects remain a gap of knowledge. Considering that cerebral blood oxygenation is particularly reduced in AD and that the decreased neurovascular function contributes to AD damages, hypoxia conditioning represents an encouraging strategy to cure diseases of the central nervous system. In this work, 8-week-old 3xTg-AD and wild-type mice were chronically supplemented with SLAB51 to evaluate effects on hypoxia-inducible factor-1 alpha (HIF-1 alpha), a key molecule regulating host-microbial crosstalk and a potential target in neurodegenerative pathologies. We report evidence that chronic supplementation with SLAB51 enhanced cerebral expression of HIF-1 alpha and decreased levels of prolyl hydroxylase 2 (PHD2), an oxygen dependent regulator of HIF-1 alpha degradation; moreover, it successfully counteracted the increase of inducible nitric oxide synthase (iNOS) brain expression and nitric oxide plasma levels in AD mice. Altogether, the results demonstrate an additional mechanism through which SLAB51 exerts neuroprotective and anti-inflammatory effects in this model of AD.

Automated summary

Dysbiosis contributes to Alzheimer's disease (AD) by affecting gut microbiota, and oral bacteriotherapy with SLAB51 shows potential benefits in reducing AD progression and neuroinflammation. Chronic supplementation with SLAB51 enhances cerebral expression of HIF-1α and reduces the levels of PHD2, effectively counteracting the increase of iNOS brain expression and nitric oxide plasma levels. The results demonstrate an additional mechanism through which SLAB51 exerts neuroprotective and anti-inflammatory effects in AD.