Complementary yet divergent effects of exercise and an exercise mimetic on microbiome in high-fat diet-induced obesity.

Exercise is beneficial for obesity, partially through increased mitochondrial activity and raised nicotinamide adenine dinucleotide (NAD), a coenzyme critical for mitochondrial function and metabolism. Recent work has shown that increasing the availability of NAD through pharmacological means improves metabolic health in rodent models of diet-induced obesity and that the effect of these supplements when administered orally may be modulated by the gut microbiome. The gut microbiome is altered by both diet and exercise and is thought to contribute to some aspects of high-fat diet-induced metabolic dysfunction. We examined the independent and combined effects of treadmill exercise and nicotinamide mononucleotide (NMN) supplementation on the gut microbiome of female C57Bl6/J mice chronically fed a high-fat diet. We showed that 8 wk of treadmill exercise, oral-administered NMN, or combined therapy exert unique effects on gut microbiome composition without changing bacterial species richness. Exercise and NMN exerted additive effects on microbiota composition, and NMN partially or fully restored predicted microbial functions, specifically carbohydrate and lipid metabolism, to control levels. Further research is warranted to better understand the mechanisms underpinning the interactions between exercise and oral NAD+ precursor supplementation on gut microbiome.NEW & NOTEWORTHY Exercise and NAD+ precursor supplementation exerted additive and independent effects on gut microbiota composition and inferred function in female mice with diet-induced obesity. Notably, combining exercise and oral nicotinamide mononucleotide supplementation restored inferred microbial functions to control levels, indicating that this combination may improve high-fat diet-induced alterations to microbial metabolism.

Scaling national and international improvement in virtual gene panel curation via a collaborative approach to discordance resolution.

Clinical validity assessments of gene-disease associations underpin analysis and reporting in diagnostic genomics, and yet wide variability exists in practice, particularly in use of these assessments for virtual gene panel design and maintenance. Harmonization efforts are hampered by the lack of agreed terminology, agreed gene curation standards, and platforms that can be used to identify and resolve discrepancies at scale. We undertook a systematic comparison of the content of 80 virtual gene panels used in two healthcare systems by multiple diagnostic providers in the United Kingdom and Australia. The process was enabled by a shared curation platform, PanelApp, and resulted in the identification and review of 2,144 discordant gene ratings, demonstrating the utility of sharing structured gene-disease validity assessments and collaborative discordance resolution in establishing national and international consensus.

Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms.

PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here, we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation and to support variant classification within the ACMG/AMP framework. METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both Sequence Ontology (SO) and Human Phenotype Ontology (HPO) ontologies. Gene Curation Coalition member groups intend to use or map to these terms in their respective resources. CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

The impact of acute and chronic stress on gastrointestinal physiology and function: a microbiota-gut-brain axis perspective.

The physiological consequences of stress often manifest in the gastrointestinal tract. Traumatic or chronic stress is associated with widespread maladaptive changes throughout the gut, although comparatively little is known about the effects of acute stress. Furthermore, these stress-induced changes in the gut may increase susceptibility to gastrointestinal disorders and infection, and impact critical features of the neural and behavioural consequences of the stress response by impairing gut-brain axis communication. Understanding the mechanisms behind changes in enteric nervous system circuitry, visceral sensitivity, gut barrier function, permeability, and the gut microbiota following stress is an important research objective with pathophysiological implications in both neurogastroenterology and psychiatry. Moreover, the gut microbiota has emerged as a key aspect of physiology sensitive to the effects of stress. In this review, we focus on different aspects of the gastrointestinal tract including gut barrier function as well as the immune, humoral and neuronal elements involved in gut-brain communication. Furthermore, we discuss the evidence for a role of stress in gastrointestinal disorders. Existing gaps in the current literature are highlighted, and possible avenues for future research with an integrated physiological perspective have been suggested. A more complete understanding of the spatial and temporal dynamics of the integrated host and microbial response to different kinds of stressors in the gastrointestinal tract will enable full exploitation of the diagnostic and therapeutic potential in the fast-evolving field of host-microbiome interactions.

The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification.

PURPOSE: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified. METHODS: The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached. RESULTS: The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others. CONCLUSION: Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.

The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources.

PURPOSE: Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed. METHODS: The GenCC drafted harmonized definitions for differing levels of gene-disease validity on the basis of existing resources, and performed a modified Delphi survey with 3 rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members. RESULTS: On the basis of 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contained 15,241 gene-disease assertions on 4569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%. CONCLUSION: Terminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.

Adolescent exposure to a solid high-fat, high-sugar 'cafeteria' diet leads to more pronounced changes in metabolic measures and gut microbiome composition than liquid sugar in female rats.

Adolescence is a dynamic developmental period where unhealthy solid foods and sugar-sweetened beverages are routinely consumed. Regular consumption of solid 'junk' foods rich in fat and refined carbohydrate and sugar-sweetened beverages are independently associated with an increased risk of metabolic disease and altered gut microbiome composition. Here we used a validated rat model to determine the effects of a solid 'cafeteria' diet high in fat and sugar (Caf) and 10% liquid sucrose solution (Suc) on food intake, metabolic measures and gut microbiome composition. Sixty adolescent female Sprague-Dawley rats were fed standard chow with or without continuous access to Caf diet and/or Suc for 13 weeks (n = 15). Exposure to cafeteria diet and liquid sucrose each increased body weight gain and adiposity, with no synergistic effects. Gut microbiome alpha and beta diversity parameters were more strongly affected by exposure to Caf diet than access to liquid Suc. Nonetheless, providing liquid sucrose to rats fed chow altered gut microbiome beta diversity and significantly enriched the abundance of five taxa from order Clostridiales. By contrast, in the two groups fed Caf, Suc did not alter beta diversity, with few differentially abundant taxa between Caf and Caf + Suc groups. In sum, liquid sucrose and solid cafeteria diet exerted largely independent effects on metabolic and gut microbiome measures. Interventions targeting either solid junk foods or sugary beverages are likely to reduce diet-related disease burden.

ClinVar database of global familial hypercholesterolemia-associated DNA variants.

Accurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomic medicine for improved patient care. An essential requirement for achieving standardized and reliable variant interpretation is data sharing, facilitated by a centralized open-source database. Familial hypercholesterolemia (FH) is an exemplar of the utility of such a resource: it has a high incidence, a favorable prognosis with early intervention and treatment, and cascade screening can be offered to families if a causative variant is identified. ClinVar, an NCBI-funded resource, has become the primary repository for clinically relevant variants in Mendelian disease, including FH. Here, we present the concerted efforts made by the Clinical Genome Resource, through the FH Variant Curation Expert Panel and global FH community, to increase submission of FH-associated variants into ClinVar. Variant-level data was categorized by submitter, variant characteristics, classification method, and available supporting data. To further reform interpretation of FH-associated variants, areas for improvement in variant submissions were identified; these include a need for more detailed submissions and submission of supporting variant-level data, both retrospectively and prospectively. Collaborating to provide thorough, reliable evidence-based variant interpretation will ultimately improve the care of FH patients.

The UCL low-density lipoprotein receptor gene variant database: pathogenicity update.

BACKGROUND: Familial hypercholesterolaemia (OMIM 143890) is most frequently caused by variations in the low-density lipoprotein receptor (LDLR) gene. Predicting whether novel variants are pathogenic may not be straightforward, especially for missense and synonymous variants. In 2013, the Association of Clinical Genetic Scientists published guidelines for the classification of variants, with categories 1 and 2 representing clearly not or unlikely pathogenic, respectively, 3 representing variants of unknown significance (VUS), and 4 and 5 representing likely to be or clearly pathogenic, respectively. Here, we update the University College London (UCL) LDLR variant database according to these guidelines. METHODS: PubMed searches and alerts were used to identify novel LDLR variants for inclusion in the database. Standard in silico tools were used to predict potential pathogenicity. Variants were designated as class 4/5 only when the predictions from the different programs were concordant and as class 3 when predictions were discordant. RESULTS: The updated database (http://www.lovd.nl/LDLR) now includes 2925 curated variants, representing 1707 independent events. All 129 nonsense variants, 337 small frame-shifting and 117/118 large rearrangements were classified as 4 or 5. Of the 795 missense variants, 115 were in classes 1 and 2, 605 in class 4 and 75 in class 3. 111/181 intronic variants, 4/34 synonymous variants and 14/37 promoter variants were assigned to classes 4 or 5. Overall, 112 (7%) of reported variants were class 3. CONCLUSIONS: This study updates the LDLR variant database and identifies a number of reported VUS where additional family and in vitro studies will be required to confirm or refute their pathogenicity.

Evidence for a distinct neuro-immune signature in rats that develop behavioural disability after nerve injury.

BACKGROUND: Chronic neuropathic pain is a neuro-immune disorder, characterised by allodynia, hyperalgesia and spontaneous pain, as well as debilitating affective-motivational disturbances (e.g., reduced social interactions, sleep-wake cycle disruption, anhedonia, and depression). The role of the immune system in altered sensation following nerve injury is well documented. However, its role in the development of affective-motivational disturbances remains largely unknown. Here, we aimed to characterise changes in the immune response at peripheral and spinal sites in a rat model of neuropathic pain and disability. METHODS: Sixty-two rats underwent sciatic nerve chronic constriction injury (CCI) and were characterised as either Pain and disability, Pain and transient disability or Pain alone on the basis of sensory threshold testing and changes in post-CCI dominance behaviour in resident-intruder interactions. Nerve ultrastructure was assessed and the number of T lymphocytes and macrophages were quantified at the site of injury on day six post-CCI. ATF3 expression was quantified in the dorsal root ganglia (DRG). Using a multiplex assay, eight cytokines were quantified in the sciatic nerve, DRG and spinal cord. RESULTS: All CCI rats displayed equal levels of mechanical allodynia, structural nerve damage, and reorganisation. All CCI rats had significant infiltration of macrophages and T lymphocytes to both the injury site and the DRG. Pain and disability rats had significantly greater numbers of T lymphocytes. CCI increased IL-6 and MCP-1 in the sciatic nerve. Examination of disability subgroups revealed increases in IL-6 and MCP-1 were restricted to Pain and disability rats. Conversely, CCI led to a decrease in IL-17, which was restricted to Pain and transient disability and Pain alone rats. CCI significantly increased IL-6 and MCP-1 in the DRG, with IL-6 restricted to Pain and disability rats. CCI rats had increased IL-1ß, IL-6 and MCP-1 in the spinal cord. Amongst subgroups, only Pain and disability rats had increased IL-1ß. CONCLUSIONS: This study has defined individual differences in the immune response at peripheral and spinal sites following CCI in rats. These changes correlated with the degree of disability. Our data suggest that individual immune signatures play a significant role in the different behavioural trajectories following nerve injury, and in some cases may lead to persistent affective-motivational disturbances.

The microbiota drives diurnal rhythms in tryptophan metabolism in the stressed gut.

Chronic stress disrupts microbiota-gut-brain axis function and is associated with altered tryptophan metabolism, impaired gut barrier function, and disrupted diurnal rhythms. However, little is known about the effects of acute stress on the gut and how it is influenced by diurnal physiology. Here, we used germ-free and antibiotic-depleted mice to understand how microbiota-dependent oscillations in tryptophan metabolism would alter gut barrier function at baseline and in response to an acute stressor. Cecal metabolomics identified tryptophan metabolism as most responsive to a 15-min acute stressor, while shotgun metagenomics revealed that most bacterial species exhibiting rhythmicity metabolize tryptophan. Our findings highlight that the gastrointestinal response to acute stress is dependent on the time of day and the microbiome, with a signature of stress-induced functional alterations in the ileum and altered tryptophan metabolism in the colon.

Mutation detection in Croatian patients with familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is caused by mutations in the genes for LDLR, APOB or PCSK9, and identification of the causative mutation provides definitive diagnosis so that the patient can be treated, their relatives tested and, therefore, premature heart disease prevented. DNA of eight unrelated individuals with clinically diagnosed FH were analyzed using a High-Resolution Melting method (HRM) for the LDLR gene (coding region, promoter and intron/exon boundaries), the APOB gene (part exon 26) and the PCSK9 gene (exon7). Variations found were sequenced and the effect on function of confirmed variants examined using predictive algorithms. Gross deletions and insertions were analysed using MLPA. Three novel LDLR variants were found, p.(S470C), p.(C698R) and c.2312-2A>C. All were predicted to be pathogenic using predictive algorithms. Three previously reported disease-causing mutations were identified (p.(G20R), p.(N272T) and p.(S286R); the latter was also carried by a hypercholesterolaemic relative. One patient carried the pathogenic APOB variant p.(R3527Q). No large LDLR deletions nor insertions were found, neither were any PCSK9 variants identified. HRM is a sensitive method for screening for mutations. While the causative mutation has been identified in 88% of these clinically defined FH patients, there appears to be a high degree of allelic heterogeneity in Croatian patients.

Obesogenic Diet Cycling Produces Graded Effects on Cognition and Microbiota Composition in Rats.

SCOPE: The effects of diet cycling on cognition and fecal microbiota are not well understood. METHOD AND RESULTS: Adult male Sprague-Dawley rats were cycled between a high-fat, high-sugar "cafeteria" diet (Caf) and regular chow. The impairment in place recognition memory produced by 16 days of Caf diet was reduced by switching to chow for 11 but not 4 days. Next, rats received 16 days of Caf diet in 2, 4, 8, or 16-day cycles, each separated by 4-day chow cycles. Place recognition memory declined from baseline in all groups and was impaired in the 16- versus 2-day group. Finally, rats received 24 days of Caf diet continuously or in 3-day cycles separated by 2- or 4-day chow cycles. Any Caf diet access impaired cognition and increased adiposity relative to controls, without altering hippocampal gene expression. Place recognition and adiposity were the strongest predictors of global microbiota composition. Overall, diets with higher Caf > chow ratios produced greater spatial memory impairments and larger shifts in gut microbiota species richness and beta diversity. CONCLUSION: Results suggest that diet-induced cognitive deficits worsen in proportion to unhealthy diet exposure, and that shifting to a healthy chow for at least a week is required for recovery under the conditions tested here.

Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms.

PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework. METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition (GenCC) members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both sequence ontology (SO) and human phenotype ontology (HPO) ontologies. GenCC member groups intend to use or map to these terms in their respective resources. CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment.

Familial hypercholesterolemia (FH) is caused predominately by variants in the low-density lipoprotein receptor gene (LDLR). We report here an update of the UCL LDLR variant database to include variants reported in the literature and in-house between 2008 and 2010, transfer of the database to LOVDv.2.0 platform (https://grenada.lumc.nl/LOVD2/UCL-Heart/home.php?select_db=LDLR) and pathogenicity analysis. The database now contains over 1288 different variants reported in FH patients: 55% exonic substitutions, 22% exonic small rearrangements (<100 bp), 11% large rearrangements (>100 bp), 2% promoter variants, 10% intronic variants and 1 variant in the 3' untranslated sequence. The distribution and type of newly reported variants closely matches that of the 2008 database, and we have used these variants (n= 223) as a representative sample to assess the utility of standard open access software (PolyPhen, SIFT, refined SIFT, Neural Network Splice Site Prediction Tool, SplicePort and NetGene2) and additional analyses (Single Amino Acid Polymorphism database, analysis of conservation and structure and Mutation Taster) for pathogenicity prediction. In combination, these techniques have enabled us to assign with confidence pathogenic predictions to 8/8 in-frame small rearrangements and 8/9 missense substitutions with previously discordant results from PolyPhen and SIFT analysis. Overall, we conclude that 79% of the reported variants are likely to be disease causing.

Rewiring bugs: Diet, the gut microbiome, and nerve regeneration.

Microbiome-to-nervous-system interactions are gaining much attention in fields that study health and disease, and diet is considered to be a key mediator in this communication. In a recent issue of Nature, Serger et al. show that, following nerve crush injury, intermittent fasting improves axonal regeneration through increased production of the microbially derived metabolite indole-3-propionate.

Gut microbiota-drug interactions in cancer pharmacotherapies: implications for efficacy and adverse effects.

INTRODUCTION: The gut microbiota is involved in host physiology and health. Reciprocal microbiota-drug interactions are increasingly recognized as underlying some individual differences in therapy response and adverse events. Cancer pharmacotherapies are characterized by a high degree of interpatient variability in efficacy and side effect profile and recently, the microbiota has emerged as a factor that may underlie these differences. AREAS COVERED: The effects of cancer pharmacotherapy on microbiota composition and function are reviewed with consideration of the relationship between baseline microbiota composition, microbiota modification, antibiotics exposure, and cancer therapy efficacy. We assess the evidence implicating the microbiota in cancer therapy-related adverse events including impaired gut function, cognition, and pain perception. Finally, potential mechanisms underlying microbiota-cancer drug interactions are described, including direct microbial metabolism, and microbial modulation of liver metabolism and immune function. This review focused on preclinical and clinical studies conducted in the last 5 years. EXPERT OPINION: Preclinical and clinical research supports a role for baseline microbiota in cancer therapy efficacy, with emerging evidence that the microbiota modification may assist in side effect management. Future efforts should focus on exploiting this knowledge toward the development of microbiota-targeted therapies. Finally, a focus on specific drug-microbiota-cancer interactions is warranted.

Microbiota and body weight control: Weight watchers within?

BACKGROUND: Despite several decades of research, managing body weight remains an unsolved clinical problem. Health problems associated with dysregulated body weight, such as obesity and cachexia, exhibit several gut microbiota alterations. There is an increased interest in utilising the gut microbiota for body weight control, as it responds to intervention and plays an important role in energy extraction from food, as well as biotransformation of nutrients. SCOPE OF THE REVIEW: This review provides an overview of the role of the gut microbiota in the physiological and metabolic alterations observed in two body weight dysregulation-related disorders, namely obesity and cachexia. Second, we assess the available evidence for different strategies, including caloric restriction, intermittent fasting, ketogenic diet, bariatric surgery, probiotics, prebiotics, synbiotics, high-fibre diet, and fermented foods - effects on body weight and gut microbiota composition. This approach was used to give insights into the possible link between body weight control and gut microbiota configuration. MAJOR CONCLUSIONS: Despite extensive associations between body weight and gut microbiota composition, limited success could be achieved in the translation of microbiota-related interventions for body weight control in humans. Manipulation of the gut microbiota alone is insufficient to alter body weight and future research is needed with a combination of strategies to enhance the effects of lifestyle interventions.

Unravelling the impacts of western-style diets on brain, gut microbiota and cognition.

The steady rise in the prevalence of obesity has been fostered by modern environments that reduce energy expenditure and encourage consumption of 'western'-style diets high in fat and sugar. Obesity has been consistently associated with impairments in executive function and episodic memory, while emerging evidence indicates that high-fat, high-sugar diets can impair aspects of cognition within days, even when provided intermittently. Here we review the detrimental effects of diet and obesity on cognition and the role of inflammatory and circulating factors, compromised blood-brain barrier integrity and gut microbiome changes. We next evaluate evidence for changing risk profiles across life stages (adolescence and ageing) and other populations at risk (e.g. through maternal obesity). Finally, interventions to ameliorate diet-induced cognitive deficits are discussed, including dietary shifts, exercise, and the emerging field of microbiome-targeted therapies. With evidence that poor diet and obesity impair cognition via multiple mechanisms across the human lifespan, the challenge for future research is to identify effective interventions, in addition to diet and exercise, to prevent and ameliorate adverse effects.