Sexual dimorphism in the context of nutrition and health

The diets and dietary constituents that we consume have a considerable impact on disease risk. Intriguingly these effects may be modulated to some extent by sex. Lack of female representation in nutritional studies as well as a lack of stratification by sex, has and continues to limit our understanding of these sex*diet interactions. Here we provide an overview of the current and available literature describing how exposure to certain dietary patterns (western style diet, Mediterranean diet, vegetarian/vegan, ketogenic diet) and dietary constituents (dietary fibre, polyunsaturated fatty acid and plant bioactive) influences disease risk in sex specific manner. Interestingly these sex differences appear to be highly disease specific. The identification of such sex differences in response to diet stresses the importance of sex stratification in nutritional research

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 cir-culating 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 overexpres-sion of miR-455-3p suppressing its toxic effects. Here, we show that miR-455-3p expression de-creases 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

Citrus polyphenols in brain health and disease: Current perspectives

In addition to essential micronutrients such as vitamin C, citrus fruits represent a considerably rich source of non-essential bioactive compounds, in particular flavanones which form a sub-set of the flavonoid group. Preclinical studies have demonstrated the neuroprotective potential of citrus flavonoids and have highlighted both the well-established (anti-inflammatory and anti-oxidative properties), and newly emerging (influence upon blood-brain barrier function/integrity) mechanistic actions by which these neurological effects are mediated. Encouragingly, results from human studies, although limited in number, appear to support this preclinical basis, with improvements in cognitive performance and disease risk observed across healthy and disease states. Therefore, citrus fruits – both as whole fruit and 100% juices – should be encouraged within the diet for their potential neurological benefit. In addition, there should be further exploration of citrus polyphenols to establish therapeutic efficacy, particularly in the context of well-designed human interventions

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

Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia

A consequence of our progressively ageing global population is the increasing prevalence of worldwide age-related cognitive decline and dementia. In the absence of effective therapeutic interventions, identifying risk factors associated with cognitive decline becomes increasingly vital. Novel perspectives suggest that a dynamic bidirectional communication system between the gut, its microbiome, and the central nervous system, commonly referred to as the microbiota-gut-brain axis, may be a contributing factor for cognitive health and disease. However, the exact mechanisms remain undefined. Microbial-derived metabolites produced in the gut can cross the intestinal epithelial barrier, enter systemic circulation and trigger physiological responses both directly and indirectly affecting the central nervous system and its functions. Dysregulation of this system (i.e., dysbiosis) can modulate cytotoxic metabolite production, promote neuroinflammation and negatively impact cognition. In this review, we explore critical connections between microbial-derived metabolites (secondary bile acids, trimethylamine-N-oxide (TMAO), tryptophan derivatives and others) and their influence upon cognitive function and neurodegenerative disorders, with a particular interest in their less-explored role as risk factors of cognitive decline

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

Differential influence of soluble dietary fibres on iIntestinal and hepatic carbohydrate response

Refined foods are commonly depleted in certain bioactive components that are abundant in ‘natural’ (plant) foods. Identification and addition of these ‘missing’ bioactives in the diet is, therefore, necessary to counteract the deleterious impact of convenience food. In this study, multiomics approaches were employed to assess the addition of the popular supplementary soluble dietary fibers inulin and psyllium, both in isolation and in combination with a refined animal feed. A 16S rRNA sequencing and 1H NMR metabolomic investigation revealed that, whilst inulin mediated an increase in Bifidobacteria, psyllium elicited a broader microbial shift, with Parasutterella and Akkermansia being increased and Enterorhabdus and Odoribacter decreased. Interestingly, the combination diet benefited from both inulin and psyllium related microbial changes. Psyllium mediated microbial changes correlated with a reduction of glucose (R −0.67, −0.73, respectively, p < 0.05) and type 2 diabetes associated metabolites: 3-methyl-2-oxovaleric acid (R −0.72, −0.78, respectively, p < 0.05), and citrulline (R −0.77, −0.71, respectively, p < 0.05). This was in line with intestinal and hepatic carbohydrate response (e.g., Slc2a2, Slc2a5, Khk and Fbp1) and hepatic lipogenesis (e.g., Srebf1 and Fasn), which were significantly reduced under psyllium addition. Although established in the liver, the intestinal response associated with psyllium was absent in the combination diet, placing greater significance upon the established microbial, and subsequent metabolomic, shift. Our results therefore highlight the heterogeneity that exists between distinct dietary fibers in the context of carbohydrate uptake and metabolism, and supports psyllium containing combination diets, for their ability to negate the impact of a refined diet

DHA-enriched fish oil ameliorates deficits in cognition associated with menopause and the APOE4 genotype in rodents

Female APOE4 carriers have a greater predisposition to developing Alzheimer’s disease (AD) compared to their male counterparts, which may partly be attributed to menopause. We previously reported that a combination of menopause and APOE4 led to an exacerbation of cognitive and neurological deficits, which were associated with reduced brain DHA and DHA:AA ratio. Here, we explored whether DHA-enriched fish oil (FO) supplementation mitigated the detrimental impact of these risk factors. Whilst DHA-enriched fish oil improved recognition memory (NOR) in APOE4 VCD (4-vinylcyclohexene diepoxide)-treated mice (p < 0.05), no change in spatial working memory (Y-maze) was observed. FO supplementation increased brain DHA and nervonic acid and the DHA:AA ratio. The response of key bioenergetic and blood–brain barrier related genes and proteins provided mechanistic insights into these behavioural findings, with increased BDNF protein concentration as well as mitigation of aberrant Erβ, Cldn1 and Glut-5 expression in APOE4 mice receiving fish oil supplementation (p < 0.05). In conclusion, supplementation with a physiologically relevant dose of DHA-enriched fish oil appears to offer protection against the detrimental effects of menopause, particularly in “at-risk” APOE4 female carriers

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

Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain

Background: Altered intestinal microbiota composition in later life is associated with inflammaging, declining tissue function, and increased susceptibility to age-associated chronic diseases, including neurodegenerative dementias. Here, we tested the hypothesis that manipulating the intestinal microbiota influences the development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. Methods: Using fecal microbiota transplantation, we exchanged the intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice. Whole metagenomic shotgun sequencing and metabolomics were used to develop a custom analysis workflow, to analyze the changes in gut microbiota composition and metabolic potential. Effects of age and microbiota transfer on the gut barrier, retina, and brain were assessed using protein assays, immunohistology, and behavioral testing. Results: We show that microbiota composition profiles and key species enriched in young or aged mice are successfully transferred by FMT between young and aged mice and that FMT modulates resulting metabolic pathway profiles. The transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation, retinal inflammation, and cytokine signaling and promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability. Conversely, these detrimental effects can be reversed by the transfer of young donor microbiota. Conclusions: These findings demonstrate that the aging gut microbiota drives detrimental changes in the gut–brain and gut–retina axes suggesting that microbial modulation may be of therapeutic benefit in preventing inflammation-related tissue decline in later life. [MediaObject not available: see fulltext.] Graphical abstract: [Figure not available: see fulltext.