Looking to the future: Agendas, directions, and resources for nutrition research.

The development and progression of nutrition as a scientific field is ever evolving and complex. Although the history of nutrition research began by exploring specific food components, it has evolved to encompass a more holistic view that considers the impact of dietary patterns over time, interactions with the environment, nutrition's role in disease processes, and public policy related to nutrition health. To guide the future direction of nutrition science, both federal and other professional organizations have established agendas and goals. The Strategic Plan for National Institutes of Health Nutrition Research outlines four goals and five cross-cutting research areas that are priorities to explore between 2020 and 2030. Similarly, the American Society for Parenteral and Enteral Nutrition and other governmental and professional organizations have identified priority areas in their research agendas. Rigorous research studies are needed to explore these areas of interest while also considering practical implementation strategies for translating research into practice. Nutrition clinicians are uniquely positioned to lend expertise in the areas of research design, implementation, advocacy and evidence-based practice; there are numerous resources to support practitioners in these endeavors.

Feasibility and Biological Activity of a Ketogenic/Intermittent-Fasting Diet in Patients With Glioma.

OBJECTIVE: To examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma. METHODS: Twenty-five patients with biopsy-confirmed World Health Organization grade 2 to 4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week Glioma Atkins-Based Diet (GLAD). GLAD consisted of 2 fasting days (calories <20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates ≤20 g/d) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, insulin-like growth factor-1, and magnetic resonance spectroscopy at baseline and week 8. RESULTS: Twenty-one patients (84%) completed the study. Eighty percent of patients reached ≥40 mg/dL urine acetoacetate during the study. Forty-eight percent of patients were adherent by food record. The diet was well tolerated, with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity, including hemoglobin A1c, insulin, and fat body mass, decreased significantly, while lean body mass increased. Magnetic resonance spectroscopy demonstrated increased ketone concentrations (ß-hydroxybutyrate [bHB] and acetone) in both lesional and contralateral brain compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB R s = 0.52, p = 0.05). Subgroup analysis of isocitrate dehydrogenase-mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria. CONCLUSION: The GLAD dietary intervention, while demanding, produced meaningful ketonuria and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02286167.

ALLN-177, oral enzyme therapy for hyperoxaluria.

PURPOSE: To evaluate the potential of ALLN-177, an orally administered, oxalate-specific enzyme therapy to reduce urine oxalate (UOx) excretion in patients with secondary hyperoxaluria. METHODS: Sixteen male and female subjects with both hyperoxaluria and a kidney stone history were enrolled in an open-label study. Subjects continued their usual diets and therapies. During a 3-day baseline period, two 24-h (24-h) urines were collected, followed by a 4-day treatment period with ALLN-177 (7,500 units/meal, 3 × day) when three 24-h urines were collected. The primary endpoint was the change in mean 24-h UOx from baseline. Safety assessments and 24-h dietary recalls were performed throughout. RESULTS: The study enrolled 5 subjects with enteric hyperoxaluria and 11 with idiopathic hyperoxaluria. ALLN-177 was well tolerated. Overall mean (SD) UOx decreased from 77.7 (55.9) at baseline to 63.7 (40.1) mg/24 h while on ALLN-177 therapy, with the mean reduction of 14 mg/24 h, (95% CI - 23.71, - 4.13). The calcium oxalate-relative urinary supersaturation ratio in the overall population decreased from a mean of 11.3 (5.7) to 8.8 (3.8) (- 2.8; 95% CI - 4.9, - 0.79). This difference was driven by oxalate reduction alone, but not any other urinary parameters. Mean daily dietary oxalate, calcium, and fluid intake recorded by frequent diet recall did not differ by study periods. CONCLUSION: ALLN-177 reduced 24-h UOx excretion, and was well tolerated. The results of this pilot study provided justification for further investigation of ALLN-177 in patients with secondary hyperoxaluria. TRIAL REGISTRATION: Clinicaltrials.gov NCT02289755.

A Double-Blind, Placebo Controlled, Randomized Phase 1 Cross-Over Study with ALLN-177, an Orally Administered Oxalate Degrading Enzyme.

BACKGROUND: Hyperoxaluria may result from increased endogenous production or overabsorption of dietary oxalate in the gastrointestinal tract leading to nephrolithiasis and, in some, to oxalate nephropathy and chronic kidney disease. ALLN-177 is an oral formulation of a recombinant, oxalate specific, microbial enzyme oxalate decarboxylase intended to treat secondary hyperoxaluria by degrading dietary oxalate in the gastrointestinal tract, thereby reducing its absorption and subsequent excretion in the urine. METHODS: This double-blind, placebo controlled, randomized, cross-over, phase 1 study of ALLN-177 evaluated the tolerability of ALLN-177 and its effect on urinary oxalate excretion in 30 healthy volunteers with hyperoxaluria induced by ingestion of a high oxalate, low calcium (HOLC) diet. The primary end point was the difference in the mean 24-hour urinary oxalate excretion during the ALLN-177 treatment period compared with the placebo treatment period. RESULTS: The daily urinary oxalate excretion increased in the study population from 27.2 ± 9.5 mg/day during screening to 80.8 ± 24.1 mg/day (mean ± SD) on the HOLC diet before introducing ALLN-177 or placebo therapy for 7 days. Compared to placebo, ALLN-177 treatment reduced urinary oxalate by 11.6 ± 2.7 mg/day, p = 0.0002 (least squares mean ± SD). CONCLUSIONS: In healthy volunteers, with diet-induced hyperoxaluria treatment with ALLN-177, when compared to placebo, significantly reduced urinary oxalate excretion by degrading dietary oxalate in the gastrointestinal tract and thereby reducing its absorption. ALLN-177 may represent a new approach for managing secondary hyperoxaluria and its complications.

Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans.

Integrative multiomics analyses of adipose and muscle tissue transcripts, S, and genotypes revealed novel genetic regulatory mechanisms of insulin resistance in African Americans.

Fish oil supplementation and urinary oxalate excretion in normal subjects on a low-oxalate diet.

OBJECTIVE: To determine if fish oil supplementation reduces endogenous oxalate synthesis in healthy subjects. MATERIALS AND METHODS: Fifteen healthy non-stone-forming adults participated in this study. Subjects first abstained from using vitamins, medications, or foods enriched in omega-3 fatty acids for 30 days. Next, they collected two 24-hour urine specimens while consuming a self-selected diet. Subjects consumed an extremely low-oxalate and normal-calcium diet for 5 days and collected 24-hour urine specimens on the last 3 days of this diet. Next, the subjects took 2 fish oil capsules containing 650-mg eicosapentaenoic acid and 450-mg docosahexaenoic acid twice daily for 30 days. They consumed a self-selected diet on days 1-25 and the controlled diet on days 26-30. Twenty-four-hour urine samples were collected on days 28-30. Excretion levels of urinary analytes including oxalate and glycolate were analyzed. RESULTS: Although there was a significant reduction in urinary oxalate, magnesium, and potassium excretions and an increase in uric acid excretion during the controlled dietary phases compared with the self-selected diet, there were no significant differences in their excretion during controlled diet phases with and without fish oil supplementation. CONCLUSION: These results suggest that fish oil supplementation does not reduce endogenous oxalate synthesis or urinary oxalate excretion in normal adults during periods of extremely low oxalate intake. However, these results do not challenge the previously described reduction in urinary oxalate excretion demonstrated in normal subjects consuming a moderate amount of oxalate in conjunction with fish oil.

Internet program for facilitating dietary modifications limiting kidney stone risk.

INTRODUCTION: Certain dietary modifications limit the risk of stone recurrence. Compliance is an important component of dietary therapy for stone prevention, and self-efficacy is an important ingredient of compliance. We developed an internet program to facilitate dietary compliance for stone prevention and performed a pilot study to assess its effectiveness. MATERIALS AND METHODS: The internet program provides information regarding dietary modifications including increased fluid consumption, limited animal protein, sodium, and oxalate intake, and adequate calcium consumption. Participants record their daily food and fluid intake and receive immediate feedback as to whether they were compliant or not. Five adult calcium stone formers collected three 24 hour urine specimens on self-selected diets, three 24 hour urine specimens while on a stone preventive metabolic diet, and three 24 hour urine specimens after utilizing the internet program for 1 month. Urinary stone risk parameters were measured, and data were analyzed using repeated measures ANOVA and Student's t test. RESULTS: All participants recorded their meals and snacks for each day and found the program easy to navigate. The mean time in hours from food consumption to log in was 35.25 +/- 70.8 hours. There were no statistically significant differences in stone risk factors between the controlled and internet dietary phases. Oxalate excretion was significantly higher during the self-selected dietary intake (p = 0.03). CONCLUSIONS: This pilot study demonstrates that subjects appear to be compliant with utilization of an interactive internet program for stone prevention with dietary modifications. In addition, improvement in certain stone risk parameters occurred.

Acyl chain length, saturation, and hydrophobicity modulate the efficiency of dietary fatty acid absorption in adult humans.

Intestinal fat absorption is known to be, overall, a highly efficient process, but much less is known about the efficiency with which individual dietary fatty acids (FA) are absorbed by the adult small intestine. We therefore measured the absorption efficiency of the major dietary FA using sucrose polybehenate (SPB) as a nonabsorbable marker and analyzed how it is modulated by acyl chain physicochemical properties and polymorphisms of proteins involved in chylomicron assembly. Dietary FA absorption efficiency was measured in 44 healthy subjects fed a standard diet containing 35% fat and 5% SPB. FA and behenic acid (BA) were measured in homogenized diets and stool samples by gas chromatography-mass spectroscopy, and coefficients of absorption for each FA were calculated as 1 - [(FA/BA)feces/(FA/BA)diet]. Absorption coefficients for saturated FA decreased with increasing chain length and hydrophobicity (mean ± SE) and ranged from 0.95 ± 0.02 for myristate (14:0), 0.80 ± 0.03 for stearate (18:0), to 0.26 ± 0.02 for arachidate (20:0). Absorption coefficients for unsaturated FA increased with increasing desaturation from 0.79 ± 0.03 for elaidic acid (18:1t), 0.96 ± 0.01 for linoleate (18:2), to near complete absorption for eicosapentaenoic (20:5) and docosahexaenoic (22:6) acids. Of several common genetic polymorphisms in key proteins involved in the chylomicron assembly pathway, only the intestinal fatty acid-binding protein-2 A54T allele (rs1799883) had any impact on FA absorption. We conclude that acyl chain length, saturation, and hydrophobicity are the major determinants of the efficiency with which dietary FA are absorbed by the adult small intestine.

The impact of dietary calcium and oxalate ratios on stone risk.

OBJECTIVE: To determine whether the ratio of dietary calcium and oxalate consumption at mealtime affects gastrointestinal oxalate absorption and urinary oxalate excretion. METHODS: A study was conducted with 10 non-stone-forming adults placed on controlled diets with daily calcium and oxalate contents of 1000 and 750 mg, respectively. Subjects consumed a balanced calcium/oxalate ratio diet for 1 week, observed a minimum 1-week washout period, and subsequently consumed an imbalanced calcium/oxalate ratio diet for one week. Urine specimens were collected on the last 4 days of each diet. Outcome measures included urinary creatinine, calcium, and oxalate as well as the Tiselius index for assessing urinary calcium oxalate supersaturation. RESULTS: Total daily calcium excretion, oxalate excretion, and Tiselius index were similar between balanced and imbalanced dietary phases. There were significant differences in calcium excretion (mg/g creatinine) between balanced and imbalanced diets in the 1-6 PM (83.1 vs 110.2, P <.04), 6-11 PM (71.3 vs 107.2, P <.02), and 11 PM-8 AM collections (55.0 vs 41.8, P <.02). There was significantly higher oxalate excretion on the balanced diet in the 1-6 pm time period (28.1 vs 16.7, P <.01). There were no differences in the Tiselius index in these collections. CONCLUSION: These results demonstrate that the sequence of ingesting relatively large amounts of oxalate does not significantly affect calcium oxalate stone risk if the recommended daily quantity of dietary calcium is consumed.

Impact of dietary calcium and oxalate, and Oxalobacter formigenes colonization on urinary oxalate excretion.

PURPOSE: Enteric colonization with Oxalobacter formigenes, a bacterium whose main energy source is oxalate, has been demonstrated to decrease the risk of recurrent calcium oxalate kidney stone formation. We assessed the impact of diets controlled in calcium and oxalate contents on urinary and fecal analytes in healthy subjects who were naturally colonized with O. formigenes or not colonized with O. formigenes. MATERIALS AND METHODS: A total of 11 O. formigenes colonized and 11 noncolonized subjects were administered diets controlled in calcium and oxalate contents. We assayed 24-hour urine collections and stool samples obtained on the last 4 days of each 1-week diet for stone risk parameters and O. formigenes levels. Mixed model analysis was used to determine the effects of colonization status on these variables. RESULTS: Urinary calcium and oxalate excretion were significantly altered by the dietary changes in O. formigenes colonized and noncolonized individuals. Mixed model analysis showed significant interaction between colonization status and oxalate excretion on a low calcium (400 mg daily)/moderate oxalate (250 mg daily) diet (p = 0.026). Urinary oxalate excretion was 19.5% lower in O. formigenes colonized subjects than in noncolonized subjects on the low calcium/moderate oxalate diet (mean ± SE 34.9 ± 2.6 vs 43.6 ± 2.6 mg, p = 0.031). CONCLUSIONS: Results suggest that O. formigenes colonization decreases oxalate excretion during periods of low calcium and moderate oxalate intake.

Effect of soda consumption on urinary stone risk parameters.

BACKGROUND AND PURPOSE: Fluid consumption has been demonstrated to influence kidney stone formation. Studies have shown that consumption of cola may be a risk factor for stone disease, while fluids containing citric acid may attenuate stone activity. Diet was not always controlled in these investigations, however. We undertook a study to determine the impact of three different fluids on urinary stone risk factors. SUBJECTS AND METHODS: Six healthy nonstone-forming adults were placed on a standardized metabolic diet and consumed three different types of fluid during three 5-day periods. There was a 2-day washout between each sequence. The three fluids administered during these periods were Le Bleu water, caffeine-free Diet Coke, and Fresca (citrate containing). These two soda preparations were chosen to prevent the known increase in calcium excretion promoted by carbohydrates and caffeine. Twenty-four hour urine specimens were collected on days 4 and 5 of each sequence. The following urinary parameters were measured: Volume, calcium, oxalate, creatinine, uric acid, citrate, sodium, magnesium, phosphorus, sulfate, urea nitrogen, pH, and supersaturation indices. A paired t test was used for statistical analysis. RESULTS: Urinary volumes were significantly higher and supersaturation of calcium oxalate significantly lower compared with a self-selected dietary regimen. A decrease in uric acid was also seen in the Fresca cohort. There were no statistically significant differences for any of the urinary parameters. CONCLUSION: There is no increased risk or benefit to consuming Fresca or caffeine-free Diet Coke compared with Le Bleu bottled water with respect to stone formation.

Effect of exercise intensity on abdominal fat loss during calorie restriction in overweight and obese postmenopausal women: a randomized, controlled trial.

BACKGROUND: Exercise intensity may affect the selective loss of abdominal adipose tissue. OBJECTIVE: This study showed whether aerobic exercise intensity affects the loss of abdominal fat and improvement in cardiovascular disease risk factors under conditions of equal energy deficit in women with abdominal obesity. DESIGN: This was a randomized trial in 112 overweight and obese [body mass index (in kg/m(2)): 25-40; waist circumference >88 cm], postmenopausal women assigned to one of three 20-wk interventions of equal energy deficit: calorie restriction (CR only), CR plus moderate-intensity aerobic exercise (CR + moderate-intensity), or CR plus vigorous-intensity exercise (CR + vigorous-intensity). The diet was a controlled program of underfeeding during which meals were provided at individual calorie levels (approximately 400 kcal/d). Exercise (3 d/wk) involved treadmill walking at an intensity of 45-50% (moderate-intensity) or 70-75% (vigorous-intensity) of heart rate reserve. The primary outcome was abdominal visceral fat volume. RESULTS: Average weight loss for the 95 women who completed the study was 12.1 kg (+/-4.5 kg) and was not significantly different across groups. Maximal oxygen uptake ( O(2)max) increased more in the CR + vigorous-intensity group than in either of the other groups (P < 0.05). The CR-only group lost relatively more lean mass than did either exercise group (P < 0.05). All groups showed similar decreases in abdominal visceral fat (approximately 25%; P < 0.001 for all). However, changes in visceral fat were inversely related to increases in O(2)max (P < 0.01). Changes in lipids, fasting glucose or insulin, and 2-h glucose and insulin areas during the oral-glucose-tolerance test were similar across treatment groups. CONCLUSION: With a similar amount of total weight loss, lean mass is preserved, but there is not a preferential loss of abdominal fat when either moderate- or vigorous-intensity aerobic exercise is performed during caloric restriction. This trial was registered at (ClinicalTrials.gov) as: NCT00664729.

Increased protein intake on controlled oxalate diets does not increase urinary oxalate excretion.

High animal protein intake is a risk factor for calcium oxalate stone disease. The effect of dietary protein on the urinary excretion of calcium, acid and citrate is well established. However, its effect on oxalate excretion is unclear, due in part to an inadequate control of dietary oxalate intake in previous studies. This relationship warrants clarification due to the proposed important role of the metabolism of amino acids in endogenous oxalate synthesis. In this study, 11 normal subjects consumed controlled oxalate diets containing 0.6, 1.2 and 1.8 g protein/kg body weight/day. The analysis of 24 h urine collections confirmed that as protein intake increased, urinary calcium and glycolate increased and urinary pH and citrate decreased. The increased glycolate excretion was due in part to an increased hydroxyproline, but not glycolate consumption. Total daily urinary oxalate excretion did not change. When indexed to creatinine there was a small but significant decrease in oxalate excretion. This is most likely due to hyperfiltration. These results indicate that as dietary protein intake increases, the catabolism of diet-derived amino acids is not associated with an increased endogenous oxalate synthesis in normal subjects.

Lean mass loss is associated with low protein intake during dietary-induced weight loss in postmenopausal women.

The health and quality-of-life implications of overweight and obesity span all ages in the United States. We investigated the association between dietary protein intake and loss of lean mass during weight loss in postmenopausal women through a retrospective analysis of a 20-week randomized, controlled diet and exercise intervention in women aged 50 to 70 years. Weight loss was achieved by differing levels of caloric restriction and exercise. The diet-only group reduced caloric intake by 2,800 kcal/week, and the exercise groups reduced caloric intake by 2,400 kcal/week and expended approximately 400 kcal/week through aerobic exercise. Total and appendicular lean mass was measured using dual energy x-ray absorptiometry. Linear regression analysis was used to examine the association between changes in lean mass and appendicular lean mass and dietary protein intake. Average weight loss was 10.8+/-4.0 kg, with an average of 32% of total weight lost as lean mass. Protein intake averaged 0.62 g/kg body weight/day (range=0.47 to 0.8 g/kg body weight/day). Participants who consumed higher amounts of dietary protein lost less lean mass and appendicular lean mass (r=0.3, P=0.01 and r=0.41, P<0.001, respectively). These associations remained significant after adjusting for intervention group and body size. Therefore, inadequate protein intake during caloric restriction may be associated with adverse body-composition changes in postmenopausal women.