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1.
A Guide to Dietary Pattern-Microbiome Data Integration.
Choi, Y, Hoops, SL, Thoma, CJ, Johnson, AJ
The Journal of nutrition. 2022;(5):1187-1199
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Abstract
The human gut microbiome is linked to metabolic and cardiovascular disease risk. Dietary modulation of the human gut microbiome offers an attractive pathway to manipulate the microbiome to prevent microbiome-related disease. However, this promise has not been realized. The complex system of diet and microbiome interactions is poorly understood. Integrating observational human diet and microbiome data can help researchers and clinicians untangle the complex systems of interactions that predict how the microbiome will change in response to foods. The use of dietary patterns to assess diet-microbiome relations holds promise to identify interesting associations and result in findings that can directly translate into actionable dietary intake recommendations and eating plans. In this article, we first highlight the complexity inherent in both dietary and microbiome data and introduce the approaches generally used to explore diet and microbiome simultaneously in observational studies. Second, we review the food group and dietary pattern-microbiome literature focusing on dietary complexity-moving beyond nutrients. Our review identified a substantial and growing body of literature that explores links between the microbiome and dietary patterns. However, there was very little standardization of dietary collection and assessment methods across studies. The 54 studies identified in this review used ≥7 different methods to assess diet. Coupled with the variation in final dietary parameters calculated from dietary data (e.g., dietary indices, dietary patterns, food groups, etc.), few studies with shared methods and assessment techniques were available for comparison. Third, we highlight the similarities between dietary and microbiome data structures and present the possibility that multivariate and compositional methods, developed initially for microbiome data, could have utility when applied to dietary data. Finally, we summarize the current state of the art for diet-microbiome data integration and highlight ways dietary data could be paired with microbiome data in future studies to improve the detection of diet-microbiome signals.
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Characterisation, procedures and heritability of acute dietary intake in the Twins UK cohort: an observational study.
Leeming, ER, Mompeo, O, Turk, P, Bowyer, RCE, Louca, P, Johnson, AJ, Spector, TD, Le Roy, C, Gibson, R
Nutrition journal. 2022;(1):13
Abstract
BACKGROUND Estimated food records (EFR) are a common dietary assessment method. This investigation aimed to; (1) define the reporting quality of the EFR, (2) characterise acute dietary intake and eating behaviours, (3) describe diet heritability. METHODS A total of 1974 one-day EFR were collected from 1858 participants in the TwinsUK cohort between 2012 and 2017. EFR were assessed using a six-point scoring system to determine reporting quality. The frequency and co-occurrence of food items was examined using word clouds and co-occurrence networks. The impact of eating behaviours on weight, BMI and nutrient intake were explored using mixed-effect linear regression models. Finally, diet heritability was estimated using ACE modelling. RESULTS We observed that 75% of EFR are of acceptable reporting quality (score > 5). Black tea and semi-skimmed milk were the most consumed items, on an individual basis (respectively 8.27, 6.25%) and paired (0.21%) as co-occurring items. Breakfast consumption had a significantly (p = 5.99 × 10- 7) greater impact on energy (kcal) (mean 1874.67 (±SD 532.42)) than skipping breakfast (1700.45 (±SD 620.98)), however only length of eating window was significantly associated with body weight (kg) (effect size 0.21 (±SD 0.10), p = 0.05) and BMI (effect size 0.08 (±SD 0.04), p = 0.04) after adjustment for relevant covariates. Lastly, we reported that both length of eating window (h2 = 33%, CI 0.24; 0.41), and breakfast consumption (h2 = 11%, CI 0.02; 0.21) were weakly heritable. CONCLUSIONS EFR describing acute dietary intake allow for eating behaviour characterisation and can supplement habitual diet intake assessments. Novel findings of heritability warrant further investigation.
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Diet-microbiome interactions in cancer treatment: Opportunities and challenges for precision nutrition in cancer.
Greathouse, KL, Wyatt, M, Johnson, AJ, Toy, EP, Khan, JM, Dunn, K, Clegg, DJ, Reddy, S
Neoplasia (New York, N.Y.). 2022;:100800
Abstract
Dietary patterns contribute to cancer risk. Separately, microbial factors influence the development of several cancers. However, the interaction of diet and the microbiome and their joint contribution to cancer treatment response needs more research. The microbiome significantly impacts drug metabolism, immune activation, and response to immunotherapy. One of the critical factors affecting the microbiome structure and function is diet. Data demonstrate that the diet and microbiome composition affects the immune response. Moreover, malnutrition is a significant confounder to cancer therapy response. There is little understanding of the interaction of malnutrition with the microbiome in the context of cancer. This review aims to address the current knowledge of dietary intake patterns and malnutrition among cancer patients and the impact on treatment outcomes. Second, this review will provide evidence linking the microbiome to cancer treatment response and provide evidence of the potentially strong effect that diet could have on this interaction. This review will formulate critical questions that will need further research to understand the diet-microbiome relationship in cancer treatment response and directions for future research to guide us to precision nutrition therapy to improve cancer outcomes.
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Optimizing Chronic Pain Treatment with Enhanced Neuroplastic Responsiveness: A Pilot Randomized Controlled Trial.
Pratscher, S, Mickle, AM, Marks, JG, Rocha, H, Bartsch, F, Schmidt, J, Tejera, L, Garcia, S, Custodero, C, Jean, F, et al
Nutrients. 2021;(5)
Abstract
Chronic pain affects mental and physical health and alters brain structure and function. Interventions that reduce chronic pain are also associated with changes in the brain. A number of non-invasive strategies can promote improved learning and memory and increase neuroplasticity in older adults. Intermittent fasting and glucose administration represent two such strategies with the potential to optimize the neurobiological environment to increase responsiveness to recognized pain treatments. The purpose of the pilot study was to test the feasibility and acceptability of intermittent fasting and glucose administration paired with a recognized pain treatment activity, relaxation and guided imagery. A total of 32 adults (44% W, 56% M), 50 to 85 years of age, with chronic knee pain for three months or greater participated in the study. Four sessions were completed over an approximate two-week period. Findings indicate the ability to recruit, randomize, and retain participants in the protocol. The procedures and measures were reasonable and completed without incident. Participant adherence was high and exit interview feedback positive. In summary, the pilot study was feasible and acceptable, providing the evidence necessary to move forward with a larger clinical trial.
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A Guide to Diet-Microbiome Study Design.
Johnson, AJ, Zheng, JJ, Kang, JW, Saboe, A, Knights, D, Zivkovic, AM
Frontiers in nutrition. 2020;:79
Abstract
Intense recent interest in understanding how the human gut microbiome influences health has kindled a concomitant interest in linking dietary choices to microbiome variation. Diet is known to be a driver of microbiome variation, and yet the precise mechanisms by which certain dietary components modulate the microbiome, and by which the microbiome produces byproducts and secondary metabolites from dietary components, are not well-understood. Interestingly, despite the influence of diet on the gut microbiome, the majority of microbiome studies published to date contain little or no analysis of dietary intake. Although an increasing number of microbiome studies are now collecting some form of dietary data or even performing diet interventions, there are no clear standards in the microbiome field for how to collect diet data or how to design a diet-microbiome study. In this article, we review the current practices in diet-microbiome analysis and study design and make several recommendations for best practices to provoke broader discussion in the field. We recommend that microbiome studies include multiple consecutive microbiome samples per study timepoint or phase and multiple days of dietary history prior to each microbiome sample whenever feasible. We find evidence that direct effects of diet on the microbiome are likely to be observable within days, while the length of an intervention required for observing microbiome-mediated effects on the host phenotype or host biomarkers, depending on the outcome, may be much longer, on the order of weeks or months. Finally, recent studies demonstrating that diet-microbiome interactions are personalized suggest that diet-microbiome studies should either include longitudinal sampling within individuals to identify personalized responses, or should include an adequate number of participants spanning a range of microbiome types to identify generalized responses.
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Effect of Diet on the Gut Microbiota: Rethinking Intervention Duration.
Leeming, ER, Johnson, AJ, Spector, TD, Le Roy, CI
Nutrients. 2019;(12)
Abstract
The human gut is inhabited by trillions of microorganisms composing a dynamic ecosystem implicated in health and disease. The composition of the gut microbiota is unique to each individual and tends to remain relatively stable throughout life, yet daily transient fluctuations are observed. Diet is a key modifiable factor influencing the composition of the gut microbiota, indicating the potential for therapeutic dietary strategies to manipulate microbial diversity, composition, and stability. While diet can induce a shift in the gut microbiota, these changes appear to be temporary. Whether prolonged dietary changes can induce permanent alterations in the gut microbiota is unknown, mainly due to a lack of long-term human dietary interventions, or long-term follow-ups of short-term dietary interventions. It is possible that habitual diets have a greater influence on the gut microbiota than acute dietary strategies. This review presents the current knowledge around the response of the gut microbiota to short-term and long-term dietary interventions and identifies major factors that contribute to microbiota response to diet. Overall, further research on long-term diets that include health and microbiome measures is required before clinical recommendations can be made for dietary modulation of the gut microbiota for health.
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Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death.
Boczek, NJ, Ye, D, Jin, F, Tester, DJ, Huseby, A, Bos, JM, Johnson, AJ, Kanter, R, Ackerman, MJ
Circulation. Arrhythmia and electrophysiology. 2015;(5):1122-32
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Abstract
BACKGROUND A portion of sudden cardiac deaths can be attributed to structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long-QT syndrome (LQTS); however, the underlying molecular mechanisms are distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, sudden cardiac death, and congenital heart defects. METHODS AND RESULTS Whole exome sequencing in combination with Ingenuity variant analysis was completed on 3 affected individuals and 1 unaffected individual from a large pedigree with concomitant LQTS, HCM, and congenital heart defects and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes and identified 2 additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in CaV1.2 and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current. CONCLUSIONS Through whole exome sequencing and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and congenital heart defects annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and cosegregation with disease in these pedigrees provide evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype.
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IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells.
Dong, S, Guinn, D, Dubovsky, JA, Zhong, Y, Lehman, A, Kutok, J, Woyach, JA, Byrd, JC, Johnson, AJ
Blood. 2014;(24):3583-6
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Abstract
Chronic lymphocytic leukemia (CLL) displays constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of B-cell receptor (BCR) signaling. Previous studies have shown that an oral PI3K p110δ inhibitor idelalisib exhibits promising activity in CLL. Here, we demonstrate that a dual PI3K p110δ and p110γ inhibitor, IPI-145, antagonizes BCR crosslinking activated prosurvival signals in primary CLL cells. IPI-145 causes direct killing in primary CLL cells in a dose- and time-dependent fashion, but does not generate direct cytotoxicity to normal B cells. However, IPI-145 does reduce the viability of normal T and natural killer cells and decrease activated T-cell production of various inflammatory and antiapoptotic cytokines. Furthermore, IPI-145 overcomes the ibrutinib resistance resulting from treatment-induced BTK C481S mutation. Collectively, these studies provide rationale for ongoing clinical evaluation of IPI-145 as a targeted therapy for CLL and related B-cell lymphoproliferative disorders.
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How membrane permeation is affected by donor delivery solvent.
Binks, BP, Fletcher, PD, Johnson, AJ, Elliott, RP
Physical chemistry chemical physics : PCCP. 2012;(44):15525-38
Abstract
We investigate theoretically and experimentally how the rate and extent of membrane permeation is affected by switching the donor delivery solvent from water to squalane for different permeants and membranes. In a model based on rate-limiting membrane diffusion, we derive explicit equations showing how the permeation extent and rate depend mainly on the membrane-donor and membrane-receiver partition coefficients of the permeant. Permeation results for systems containing all combinations of hydrophilic or hydrophobic donor solvents (aqueous solution or squalane), permeants (caffeine or testosterone) and polymer membranes (cellulose or polydimethylsiloxane) have been measured using a cell with stirred donor and re-circulating receiver compartments and continuous monitoring of the permeant concentration in the receiver phase. Relevant partition coefficients are also determined. Quantitative comparison of model and experimental results for the widely-differing permeation systems successfully enables the systematic elucidation of all possible donor solvent effects in membrane permeation. For the experimental conditions used here, most of the permeation systems are in agreement with the model, demonstrating that the model assumptions are valid. In these cases, the dominant donor solvent effects arise from changes in the relative affinities of the permeant for the donor and receiver solvents and the membrane and are quantitatively predicted using the separately measured partition coefficients. We also show how additional donor solvent effects can arise when switching the donor solvent causes one or more of the model assumptions to be invalid. These effects include a change in rate-limiting step, permeant solution non-ideality and others.
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Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein.
Hofmeister, CC, Yang, X, Pichiorri, F, Chen, P, Rozewski, DM, Johnson, AJ, Lee, S, Liu, Z, Garr, CL, Hade, EM, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;(25):3427-34
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Abstract
PURPOSE Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM. PATIENTS AND METHODS A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions. RESULTS Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum-tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P-glycoprotein [P-gp]) substrate. CONCLUSION The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide.