Refined diet consumption increases neuroinflammatory signalling through bile acid dysmetabolism.

Over recent decades, dietary patterns have changed significantly due to the increasing availability of convenient, ultra-processed refined foods. Refined foods are commonly depleted of key bioactive compounds, which have been associated with several deleterious health conditions. As the gut microbiome can influence the brain through a bidirectional communication system known as the 'microbiota-gut-brain axis', the consumption of refined foods has the potential to affect cognitive health. In this study, multi-omics approaches were employed to assess the effect of a refined diet on the microbiota-gut-brain axis, with a particular focus on bile acid metabolism. Mice maintained on a refined low-fat diet (rLFD), consisting of high sucrose, processed carbohydrates and low fibre content, for eight weeks displayed significant gut microbial dysbiosis, as indicated by diminished alpha diversity metrics (p < 0.05) and altered beta diversity (p < 0.05) when compared to mice receiving a chow diet. Changes in gut microbiota composition paralleled modulation of the metabolome, including a significant reduction in short-chain fatty acids (acetate, propionate and n-butyrate; p < 0.001) and alterations in bile acid concentrations. Interestingly, the rLFD led to dysregulated bile acid concentrations across both the colon (p < 0.05) and the brain (p < 0.05) which coincided with altered neuroinflammatory gene expression. In particular, the concentration of TCA, TDCA and T-α-MCA was inversely correlated with the expression of NF-κB1, a key transcription factor in neuroinflammation. Overall, our results suggest a novel link between a refined low-fat diet and detrimental neuronal processes, likely in part through modulation of the microbiota-gut-brain axis and bile acid dysmetabolism.

The microbiota-gut-brain axis: pathways to better brain health. Perspectives on what we know, what we need to investigate and how to put knowledge into practice.

The gut and brain link via various metabolic and signalling pathways, each with the potential to influence mental, brain and cognitive health. Over the past decade, the involvement of the gut microbiota in gut-brain communication has become the focus of increased scientific interest, establishing the microbiota-gut-brain axis as a field of research. There is a growing number of association studies exploring the gut microbiota's possible role in memory, learning, anxiety, stress, neurodevelopmental and neurodegenerative disorders. Consequently, attention is now turning to how the microbiota can become the target of nutritional and therapeutic strategies for improved brain health and well-being. However, while such strategies that target the gut microbiota to influence brain health and function are currently under development with varying levels of success, still very little is yet known about the triggers and mechanisms underlying the gut microbiota's apparent influence on cognitive or brain function and most evidence comes from pre-clinical studies rather than well controlled clinical trials/investigations. Filling the knowledge gaps requires establishing a standardised methodology for human studies, including strong guidance for specific focus areas of the microbiota-gut-brain axis, the need for more extensive biological sample analyses, and identification of relevant biomarkers. Other urgent requirements are new advanced models for in vitro and in vivo studies of relevant mechanisms, and a greater focus on omics technologies with supporting bioinformatics resources (training, tools) to efficiently translate study findings, as well as the identification of relevant targets in study populations. The key to building a validated evidence base rely on increasing knowledge sharing and multi-disciplinary collaborations, along with continued public-private funding support. This will allow microbiota-gut-brain axis research to move to its next phase so we can identify realistic opportunities to modulate the microbiota for better brain health.

Multi-nutrient interventions and cognitive ageing: are we barking up the right tree?

As we continue to elucidate the mechanisms underlying age-related brain diseases, the reductionist strategy in nutrition­brain function research has focused on establishing the impact of individual foods. However, the biological processes connecting diet and cognition are complex. Therefore, consideration of a combination of nutritional compounds may be most efficacious. One barrier to establishing the efficacy of multi-nutrient interventions is that the area lacks an established set of evidence-based guidelines for studying their effect on brain health. This review is an output of the International Life Sciences Institute (ILSI) Europe. A multi-disciplinary expert group was assembled with the aim of developing a set of considerations to guide research into the effects of multi-nutrient combinations on brain functions. Consensus recommendations converged on six key issues that should be considered to advance research in this area: (1) establish working mechanisms of the combination and contributions of each individual compound; (2) validate the relevance of the mechanisms for the targeted human condition; (3) include current nutrient status, intake or dietary pattern as inclusion/exclusion criteria in the study design; (4) select a participant population that is clinically and biologically appropriate for all nutritional components of the combination; (5) consider a range of cognitive outcomes; (6) consider the limits of reductionism and the 'gold standard' randomised controlled trial. These guiding principles will enhance our understanding of the interactive/complementary activities of dietary components, thereby strengthening the evidence base for recommendations aimed at delaying cognitive decline.

Natural Products and Neuroprotection 3.0.

In recent years, we have been witnessing a dramatic rise in the incidence of neurodegenerative diseases, a phenomenon partly associated with the increase in life expectancy [...].

APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE-TR mice.

The impact of sex and menopausal status in Alzheimer's disease remains understudied despite increasing evidence of greater female risk, particularly in APOE4 carriers. Utilizing female APOE-TR mice maintained on a high-fat diet background we induced ovarian failure through repeated VCD injections, to mimic human menopause. At 12 months of age, recognition memory and spatial memory were assessed using object recognition, Y-maze spontaneous alternation, and Barnes maze. A VCD*genotype interaction reduced the recognition memory (P < .05), with APOE4 VCD-treated animals unable to distinguish between novel and familiar objects. APOE4 mice displayed an additional 37% and 12% reduction in Barnes (P < .01) and Y-maze (P < .01) performance, indicative of genotype-specific spatial memory impairment. Molecular analysis indicated both VCD and genotype-related deficits in synaptic plasticity with BDNF, Akt, mTOR, and ERK signaling compromised. Subsequent reductions in the transcription factors Creb1 and Atf4 were also evident. Furthermore, the VCD*genotype interaction specifically diminished Ephb2 expression, while Fos, and Cnr1 expression reduced as a consequence of APOE4 genotype. Brain DHA levels were 13% lower in VCD-treated animals independent of genotype. Consistent with this, we detected alterations in the expression of the DHA transporters Acsl6 and Fatp4. Our results indicate that the combination of ovarian failure and APOE4 leads to an exacerbation of cognitive and neurological deficits.

The microRNA-455 Null Mouse Has Memory Deficit and Increased Anxiety, Targeting Key Genes Involved in Alzheimer's Disease.

The complete molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) remain to be elucidated. Recently, microRNA-455-3p has been identified as a circulating biomarker of early AD, with increased expression in post-mortem brain tissue of AD patients. MicroRNA-455-3p also directly targets and down-regulates APP, with the overexpression of miR-455-3p suppressing its toxic effects. Here, we show that miR-455-3p expression decreases with age in the brains of wild-type mice. We generated a miR-455 null mouse utilising CRISPR-Cas9 to explore its function further. Loss of miR-455 resulted in increased weight gain, potentially indicative of metabolic disturbances. Furthermore, performance on the novel object recognition task diminished significantly in miR-455 null mice (p = 0.004), indicating deficits in recognition memory. A slight increase in anxiety was also captured on the open field test. BACE1 and TAU were identified as new direct targets for miR-455-3p, with overexpression of miR-455-3p leading to a reduction in the expression of APP, BACE1 and TAU in neuroblastoma cells. In the hippocampus of miR-455 null mice at 14 months of age, the levels of protein for APP, BACE1 and TAU were all increased. Such findings reinforce the involvement of miR-455 in AD progression and demonstrate its action on cognitive performance.

Altered SPMs and age-associated decrease in brain DHA in APOE4 female mice.

An apolipoprotein E (APOE) 4 genotype is the most important, common genetic determinant for Alzheimer disease (AD), and female APOE4 carriers present with an increased risk compared with males. The study quantified cortical and hippocampal fatty acid and phospholipid profiles along with select eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-derived specialized proresolving mediators (SPMs) in 2-, 9-, and 18-mo-old APOE3 and APOE4 male and female mice. A 10% lower cortical DHA was evident in APOE4 females at 18 mo compared with 2 mo, with no significant decrease in APOE3 or APOE4 males. This decrease was associated with a reduction in DHA-phosphatidylethanolamine. Older APOE4 females had a 15% higher oleic acid content compared with young mice. Although no sex*APOE genotype interactions were observed for SPMs expressed as a ratio of their parent compound, higher cortical 18R/S-hydroxy-5Z,8Z,11Z,14Z,16E-EPA, resolvin D3, protectin D1, 10S,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-DHA (10S,17S-diHDHA), maresin 1, 17S-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-DHA, and 14S-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-DHA were evident in females, and lower cortical 17R-resolvin D1, 10S,17S-diHDHA, and 18-HEPE in APOE4. Our findings show a strong association between age, female sex, and an APOE4 genotype, with decreased cortical DHA and a number of SPMs, which together may contribute to the development of cognitive decline and AD pathology.-Martinsen, A., Tejera, N., Vauzour, D., Harden, G., Dick, J., Shinde, S., Barden, A., Mori, T. A., Minihane, A. M. Altered SPMs and age-associated decrease in brain DHA in APOE4 female mice.

APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer's disease pathophysiology.

Apolipoprotein E (APOE) genotype is the strongest prevalent genetic risk factor for Alzheimer's disease (AD). Numerous studies have provided insights into the pathologic mechanisms. However, a comprehensive understanding of the impact of APOE genotype on microflora speciation and metabolism is completely lacking. In this study, we investigated the association between APOE genotype and the gut microbiome composition in human and APOE-targeted replacement (TR) transgenic mice. Fecal microbiota amplicon sequencing from matched individuals with different APOE genotypes revealed no significant differences in overall microbiota diversity in group-aggregated human APOE genotypes. However, several bacterial taxa showed significantly different relative abundance between APOE genotypes. Notably, we detected an association of Prevotellaceae and Ruminococcaceae and several butyrate-producing genera abundances with APOE genotypes. These findings were confirmed by comparing the gut microbiota of APOE-TR mice. Furthermore, metabolomic analysis of murine fecal water detected significant differences in microbe-associated amino acids and short-chain fatty acids between APOE genotypes. Together, these findings indicate that APOE genotype is associated with specific gut microbiome profiles in both humans and APOE-TR mice. This suggests that the gut microbiome is worth further investigation as a potential target to mitigate the deleterious impact of the APOE4 allele on cognitive decline and the prevention of AD.-Tran, T. T. T., Corsini, S., Kellingray, L., Hegarty, C., Le Gall, G., Narbad, A., Müller, M., Tejera, N., O'Toole, P. W., Minihane, A.-M., Vauzour, D. APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer's disease pathophysiology.

Natural Products and Neuroprotection.

Neurodegenerative diseases are among the most serious health problems affecting millions of people worldwide, and their incidence is dramatically growing together with increased lifespan [...].

n-3 Fatty acids combined with flavan-3-ols prevent steatosis and liver injury in a murine model of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults and at present no licensed medication has been approved. Despite its complex patho-physiology, dietary strategies aiming at delaying or preventing NAFLD have taken a reductionist approach, examining the impact of single components. Accumulating evidence suggests that n-3 LC-PUFAs are efficacious in regulating lipogenesis and fatty acid oxidation. In addition, plant derived flavonoids are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising and indirect antioxidant effects. Based on knowledge of their complementary molecular targets, we aimed to demonstrate that the combination of n-3 LC-PUFA (n-3) and flavan-3-ols (FLAV) prevents NAFLD. In a high-fat high-fructose (HF/HFr) fed C57Bl/6J mouse model, the independent and interactive impact of n-3 and FLAV on histologically defined NAFLD, insulin sensitivity, weight gain, intestinal and hepatic gene expression, intestinal bile acids were examined. Only the combination of FLAV and n-3 (FLAVn-3) prevented steatosis as evidenced by a strong reduction in hepatocyte ballooning. While FLAV reduced body (-28-30%), adipose tissue (-45-50%) weights and serum insulin (-22-25%) as observed following an intra-peritoneal glucose tolerance test, n-3 downregulated the expression of Srebf1 and the lipogenic genes (Acaca, Fasn). Significant impacts of interventions on intestinal bile acid metabolism, farnesoid X receptor (Fxr) signalling in the intestine and liver, and hepatic expression of fatty acid transporters (Fabp4, Vldlr, Cd36) were also evident. FLAVn-3 may be a novel intervention for NAFLD. Future research should aim to demonstrate its efficacy in the prevention and treatment of human NAFLD.

Inhibition of PP2A by hesperetin may contribute to Akt and ERK1/2 activation status in cortical neurons.

Flavonoids and their metabolites are well reported to modulate the activation/phosphorylation of various cellular kinases, such as ERK1/2 and JNK, although the mechanism by which they do so is unclear. In this study, we investigated the impact of flavanones on the activation of PI3K/Akt and ERK1/2 and determine whether this is mediated, in part, by the inhibition of phosphatases. Primary cortical neurons were exposed to physiological concentrations of hesperetin and the phosphorylation status of the kinases PI3K/Akt and ERK1/2 and the phosphatases PP2A and PTEN were assessed by immunoblotting after 30 min. Exposure to 100-300 nM hesperetin led to significant increases in the phosphorylation of ERK1/2 and Akt and significant decreases in PP2A levels and enzyme activity. Using in silico docking, hesperetin was found to fit into the active site of PP2A interacting within the hydrophobic cage of the catalytic unit. These data suggest a potential mechanism by which flavanones may lead to increased activation of ERK1/2 and Akt, commonly observed in cell models. Their interaction with and inhibition of cellular phosphatases counteract normal physiological regulation of signaling pathway activation thus facilitating and/or maintaining the activation status of ERK1/2 and Akt, important regulators of brain functions.

The effect of dietary fish oil on weight gain and insulin sensitivity is dependent on APOE genotype in humanized targeted replacement mice.

We investigated the independent and interactive impact of the common APOE genotype and marine n-3 polyunsaturated fatty acids (PUFAs) on the development of obesity and associated cardiometabolic dysfunction in a murine model. Human APOE3 and APOE4 targeted replacement mice were fed either a control high-fat diet (HFD) or an HFD supplemented with 3% n-3 PUFAs from fish oil (HFD + FO) for 8 wk. We established the impact of intervention on food intake, body weight, and visceral adipose tissue (VAT) mass; plasma, lipids (cholesterol and triglycerides), liver enzymes, and adipokines; glucose and insulin during an intraperitoneal glucose tolerance test; and Glut4 and ApoE expression in VAT. HFD feeding induced more weight gain and higher plasma lipids in APOE3 compared to APOE4 mice (P < 0.05), along with a 2-fold higher insulin and impaired glucose tolerance. Supplementing APOE3, but not APOE4, animals with dietary n-3 PUFAs decreased body-weight gain, plasma lipids, and insulin (P < 0.05) and improved glucose tolerance, which was associated with increased VAT Glut4 mRNA levels (P < 0.05). Our findings demonstrate that an APOE3 genotype predisposes mice to develop obesity and its metabolic complications, which was attenuated by n-3 PUFA supplementation.-Slim, K. E., Vauzour, D., Tejera, N., Voshol, P. J., Cassidy, A., Minihane, A. M. The effect of dietary fish oil on weight gain and insulin sensitivity is dependent on APOE genotype in humanized targeted replacement mice.

Differential effects of EPA versus DHA on postprandial vascular function and the plasma oxylipin profile in men.

Our objective was to investigate the impact of EPA versus DHA on arterial stiffness and reactivity and underlying mechanisms (with a focus on plasma oxylipins) in the postprandial state. In a three-arm crossover acute test meal trial, men (n = 26, 35-55 years) at increased CVD risk received a high-fat (42.4 g) test meal providing 4.16 g of EPA or DHA or control oil in random order. At 0 h and 4 h, blood samples were collected to quantify plasma fatty acids, long chain n-3 PUFA-derived oxylipins, nitrite and hydrogen sulfide, and serum lipids and glucose. Vascular function was assessed using blood pressure, reactive hyperemia index, pulse wave velocity, and augmentation index (AIx). The DHA-rich oil significantly reduced AIx by 13% (P = 0.047) with the decrease following EPA-rich oil intervention not reaching statistical significance. Both interventions increased EPA- and DHA-derived oxylipins in the acute postprandial state, with an (1.3-fold) increase in 19,20-dihydroxydocosapentaenoic acid evident after DHA intervention (P < 0.001). In conclusion, a single dose of DHA significantly improved postprandial arterial stiffness as assessed by AIx, which if sustained would be associated with a significant decrease in CVD risk. The observed increases in oxylipins provide a mechanistic insight into the AIx effect.

A Transgenic Camelina sativa Seed Oil Effectively Replaces Fish Oil as a Dietary Source of Eicosapentaenoic Acid in Mice.

BACKGROUND: Fish currently supplies only 40% of the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) required to allow all individuals globally to meet the minimum intake recommendation of 500 mg/d. Therefore, alternative sustainable sources are needed. OBJECTIVE: The main objective was to investigate the ability of genetically engineered Camelina sativa (20% EPA) oil (CO) to enrich tissue EPA and DHA relative to an EPA-rich fish oil (FO) in mammals. METHODS: Six-week-old male C57BL/6J mice were fed for 10 wk either a palm oil-containing control (C) diet or diets supplemented with EPA-CO or FO, with the C, low-EPA CO (COL), high-EPA CO (COH), low-EPA FO (FOL), and high-EPA FO (FOH) diets providing 0, 0.4, 3.4, 0.3, and 2.9 g EPA/kg diet, respectively. Liver, muscle, and brain were collected for fatty acid analysis, and blood glucose and serum lipids were quantified. The expression of selected hepatic genes involved in EPA and DHA biosynthesis and in modulating their cellular impact was determined. RESULTS: The oils were well tolerated, with significantly greater weight gain in the COH and FOH groups relative to the C group (P < 0.001). Significantly lower (36-38%) blood glucose concentrations were evident in the FOH and COH mice relative to C mice (P < 0.01). Hepatic EPA concentrations were higher in all EPA groups relative to the C group (P < 0.001), with concentrations of 0.0, 0.4, 2.9, 0.2, and 3.6 g/100 g liver total lipids in the C, COL, COH, FOL, and FOH groups, respectively. Comparable dose-independent enrichments of liver DHA were observed in mice fed CO and FO diets (P < 0.001). Relative to the C group, lower fatty acid desaturase 1 (Fads1) expression (P < 0.005) was observed in the COH and FOH groups. Higher fatty acid desaturase 2 (Fads2), peroxisome proliferator-activated receptor α (Ppara), and peroxisome proliferator-activated receptor γ (Pparg) (P < 0.005) expressions were induced by CO. No impact of treatment on liver X receptor α (Lxra) or sterol regulatory element-binding protein 1c (Srebp1c) was evident. CONCLUSIONS: Oil from transgenic Camelina is a bioavailable source of EPA in mice. These data provide support for the future assessment of this oil in a human feeding trial.

Low-grade inflammation, diet composition and health: current research evidence and its translation.

The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled 'Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies'. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation-health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on the measurement of inflammatory markers in the circulation, and in particular cytokines in the fasting state, which are recognised as an insensitive and highly variable index of tissue inflammation. Potential novel kinetic and integrated approaches to capture inflammatory status in humans are discussed. Such approaches are likely to provide a more discriminating means of quantifying inflammation-health/disease associations, and the ability of diet to positively modulate inflammation and provide the much needed evidence to develop research portfolios that will inform new product development and associated health claims.

The neurotoxicity of 5-S-cysteinyldopamine is mediated by the early activation of ERK1/2 followed by the subsequent activation of ASK1/JNK1/2 pro-apoptotic signalling.

Parkinson's disease is characterized by the progressive and selective loss of dopaminergic neurons in the substantia nigra. It has been postulated that endogenously formed CysDA (5-S-cysteinyldopamine) and its metabolites may be, in part, responsible for this selective neuronal loss, although the mechanisms by which they contribute to such neurotoxicity are not understood. Exposure of neurons in culture to CysDA caused cell injury, apparent 12-48 h post-exposure. A portion of the neuronal death induced by CysDA was preceded by a rapid uptake and intracellular oxidation of CysDA, leading to an acute and transient activation of ERK2 (extracellular-signal-regulated kinase 2) and caspase 8. The oxidation of CysDA also induced the activation of apoptosis signal-regulating kinase 1 via its de-phosphorylation at Ser967, the phosphorylation of JNK (c-Jun N-terminal kinase) and c-Jun (Ser73) as well as the activation of p38, caspase 3, caspase 8, caspase 7 and caspase 9. Concurrently, the inhibition of complex I by the dihydrobenzothiazine DHBT-1 [7-(2-aminoethyl)-3,4-dihydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid], formed from the intracellular oxidation of CysDA, induces complex I inhibition and the subsequent release of cytochrome c which further potentiates pro-apoptotic mechanisms. Our data suggest a novel comprehensive mechanism for CysDA that may hold relevance for the selective neuronal loss observed in Parkinson's disease.

Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an update.

There is substantial interest in the role of plant secondary metabolites as protective dietary agents. In particular, the involvement of flavonoids and related compounds has become a major topic in human nutrition research. Evidence from epidemiological and human intervention studies is emerging regarding the protective effects of various (poly)phenol-rich foods against several chronic diseases, including neurodegeneration, cancer and cardiovascular diseases. In recent years, the use of HPLC-MS for the analysis of flavonoids and related compounds in foods and biological samples has significantly enhanced our understanding of (poly)phenol bioavailability. These advancements have also led to improvements in the available food composition and metabolomic databases, and consequently in the development of biomarkers of (poly)phenol intake to use in epidemiological studies. Efforts to create adequate standardised materials and well-matched controls to use in randomised controlled trials have also improved the quality of the available data. In vitro investigations using physiologically achievable concentrations of (poly)phenol metabolites and catabolites with appropriate model test systems have provided new and interesting insights on potential mechanisms of actions. This article will summarise recent findings on the bioavailability and biological activity of (poly)phenols, focusing on the epidemiological and clinical evidence of beneficial effects of flavonoids and related compounds on urinary tract infections, cognitive function and age-related cognitive decline, cancer and cardiovascular disease.

Effect of flavonoids on learning, memory and neurocognitive performance: relevance and potential implications for Alzheimer's disease pathophysiology.

Recent evidence has indicated that a group of plant-derived compounds known as flavonoids may exert particularly powerful actions on mammalian cognition and may reverse age-related declines in memory and learning. In addition, growing evidence is also suggestive that flavonoids may delay the development of Alzheimer's disease-like pathology, suggestive of potential dietary strategies in dementia. Although these low-molecular-weight phytochemicals are absorbed to only a limited degree, they have been found to counteract age-related cognitive declines possibly via their ability to interact with the cellular and molecular architecture of the brain responsible for memory. However, the majority of the research has been carried out at rather supraphysiological concentrations and only a few studies have investigated the neuromodulatory effects of physiologically attainable flavonoid concentrations. This review will summarize the evidence for the effects of flavonoids and their metabolites in age-related cognitive decline and Alzheimer's disease. Mechanisms of actions will be discussed and include those activating signalling pathways critical in controlling synaptic plasticity, reducing neuroinflammation and inducing vascular effects potentially capable of causing new nerve cell growth in the hippocampus. Altogether, these processes are known to be important in maintaining optimal neuronal function, to limit neurodegeneration and to prevent or reverse age-dependent deteriorations in cognitive performance.

Do microbes play a role in Alzheimer's disease?

Alzheimer's disease is a complex and progressive condition that affects essential neurological functions such as memory and reasoning. In the brain, neuronal loss, synaptic dysfunction, proteinopathy, neurofibrillary tangles, and neuroinflammation are the hallmarks of Alzheimer's disease pathophysiology. In addition, recent evidence has highlighted that microbes, whether commensal or pathogenic, also have the ability to interact with their host and to regulate its immune system, therefore participating in the exchanges that lead to peripheral inflammation and neuropathology. Because of this intimate relationship, bacteria, viruses, fungi, and protozoa have been implicated in the development of Alzheimer's disease. Here, we bring together current and most recent evidence of the role of microbes in Alzheimer's disease, raising burning questions that need to be addressed to guide therapeutic approaches and potential prophylactic strategies.

Dietary (Poly)phenols and the Gut-Brain Axis in Ageing.

As the population ages, the incidence of age-related neurodegenerative diseases is rapidly increasing, and novel approaches to mitigate this soaring prevalence are sorely needed. Recent studies have highlighted the importance of gut microbial homeostasis and its impact on brain functions, commonly referred to as the gut-brain axis, in maintaining overall health and wellbeing. Nonetheless, the mechanisms by which this system acts remains poorly defined. In this review, we will explore how (poly)phenols, a class of natural compounds found in many plant-based foods and beverages, can modulate the gut-brain axis, and thereby promote neural health. While evidence indicates a beneficial role of (poly)phenol consumption as part of a balanced diet, human studies are scarce and mechanistic insight is still lacking. In this regard, we make the case that dietary (poly)phenols should be further explored to establish their therapeutic efficacy on brain health through modulation of the gut-brain axis, with much greater emphasis on carefully designed human interventions.