Gut microbiota to counteract metabolic disorders and neuroinflammation : Impact of dietary factors and their potential to prevent Alzheimer’s disease

Sammanfattning: Alzheimer’s disease (AD) is the most common form of dementia. Increased accumulations of senile plaques and tangles are the known neuropathological hallmarks of AD. However, the exact triggers for such protein accumulations, leading to cognitive impairment and important morphological alteration in AD, are still elusive. Ageing and genetic risk factors do not completely explain the global increase in the AD prevalence. Different environmental risk factors, including lifestyle and diet, as well as cluster risk factors of the metabolic syndrome (MetS) have been identified to influence the progression of the disease. Emerging evidence has suggested the important role of the commensal gut microbiota in brain development and function, affecting development of brain-related disorders. Hence, understanding the impact that gut microbiota may have on the risk factors for AD may provide possible preventive or therapeutic strategies for such neurodegenerative disease.Studies included in this thesis aimed to evaluate whether the gut microbiota may have influences on AD risk factors and how a healthy gut microbiota, amending gut-brain interaction, may be composed. The shifts of gut microbiota upon dietary changes, and their relation to neurodegenerative and metabolic disturbances in rodents and humans were investigated.The results showed that a mouse model of cerebral amyloidosis (APPPS1) displayed a distinct gut microbiota profile, as compared to that of healthy wild-type (WT) mice. Absence of the gut microbiota (germ-free, GF) in APPPS1 mice resulted in reduction of amyloid-beta (Aβ) deposition. Colonization of GF mice with the gut microbiota from APPPS1 mice resulted in increased Aβ pathology, relative to that seen with colonization of WT microbiota. Increased influx of inflammatory components seemed to be associated with Aβ pathology. A study in a neonatal rat model showed that dietary disturbances before weaning period affected the normal establishment of the gut microbiota, as well as gut barrier and blood-brain barrier (BBB) functions. Such disruption of a normal establishment of the gut microbiota early in life may have potential long-term adverse consequences. In human adults, whose gut microbial community has already established, a short-term dietary intervention with a multifunctional diet (MFD), including several active ingredients that may serve as substrates for the gut microbiota, seemed to be insufficient to produce a broad switch in the gut microbiota composition. Yet specific gut microbial genera that associated with the positive impact of the diet were identified. Studies in apolipoprotien E knockout (ApoE-/-) mice showed that high-fat (HF) feedings with inclusion of dietary fibres from lingonberries (Vaccinium vítis-idaéa) affect the gut microbiota, associated with the lingonberries’ positive effects to counteract the impaired metabolic functions induced by HF diets. Inclusion of lingonberries also decreased levels of gut- and neuro-inflammation and increased synaptic density in the hippocampus of mice fed HF diets.The results of these studies suggest that the gut microbiota may be involved in the progression of AD by triggering systemic inflammatory responses. Chronic inflammation and ageing have been shown to increase vulnerability of the BBB. Inclusion of lingonberries in HF diets counteracted negative effects of the HF diets on metabolic and neuroinflammatory markers. Therefore, lingonberries may be included as a part of a functional diet to target specific gut microbiota associated with improved risk factors for developing AD or even other neurogenerative diseases.