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Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming.

ABSTRACT: Very-low-carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno-nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T-cell responses. CD4⁺ , CD8⁺ , and regulatory T-cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very-low-carbohydrate diet as a clinical tool to improve human T-cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required.

SUBMITTER: Hirschberger S

PROVIDER: S-EPMC8350890 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming.

Hirschberger Simon S Strauß Gabriele G Effinger David D Marstaller Xaver X Ferstl Alicia A Müller Martin B MB Wu Tingting T Hübner Max M Rahmel Tim T Mascolo Hannah H Exner Nicole N Heß Julia J Kreth Friedrich W FW Unger Kristian K Kreth Simone S

EMBO molecular medicine 20210621 8

Very-low-carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno-nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T-cell responses. CD4<sup>+</sup> , CD8<sup>+</sup> , and regulatory T-cell capacity w ...[more]

PMID: 34151532

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Project description:Emerging evidence has consistently shown that a very low carbohydrate diet (VLCD) can protect against the development of obesity, but the underlying mechanisms are not fully understood. Here we applied a comprehensive metabonomics approach using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry and gas chromatography-time-of-flight mass spectrometry to study the effects of an 8-week dietary intervention with VLCD on serum metabolic profiles in obese subjects. The VLCD intervention resulted in a weight loss and significantly decreased homeostasis model assessment-insulin resistance. The metabonomics analysis identified a number of differential serum metabolites (p < 0.05) primarily attributable to fatty acids, amino acids including branched chain amino acids, amines, lipids, carboxylic acids, and carbohydrates in obese subjects compared to healthy controls. The correlation analysis among time, VLCD intervention, and clinical parameters revealed that the changes of metabolites correlated with the changes of clinical parameters and showed differences in males and females. Fatty acids, amino acids, and carboxylic acids were increased in obese subjects compared with their normal healthy counterparts. Such increased levels of serum metabolites were attenuated after VLCD intake, suggesting that the health beneficial effects of VLCD are associated with attenuation of impaired fatty acid and amino acid metabolism. It also appears that VLCD induced significant metabolic alterations independent of the obesity-related metabolic changes. The altered metabolites in obese subjects post-VLCD intervention include arachidonate, cis-11,14-eicosadienoate, cis-11,14,17-eicosatrienoate, 2-aminobutyrate, acetyl-carnitine, and threonate, all of which are involved in inflammation and oxidation processes. The results revealed favorable shifts in fatty acids and amino acids after VLCD intake in obese subjects, which should be considered biomarkers for evaluating health beneficial effects of VLCD and similar dietary interventions.

Project description:Purpose: We aim to identify transciptional changes of human CD4+/CD8+ T cells due to high fat low carbohydrate ketogenic diet (KD) in vivo. Method: Healthy volunteers conducted a 21 days ketogenic diet, limiting carbohydrate intake to <30g/day. Before the start (T0) and at the end (T1) of the diet, blood samples were taken and PBMC were isolated. PBMCs were obtained by density centrifugation (Histopaque 1077, Sigma-Aldrich, St. Louis, MO, USA). A ViCell analyzer (Beckman Coulter, Fullerton, CA, USA) was used to evaluate the cell count and viability. Only samples exceeding a cell viability of 90% were processed further. PBMCs were subjected to cell cultivation in RPMI 1640 (Invitrogen, Carlsbad, CA, USA) containing 10% heat-inactivated fetal calf serum (Biochrom, Berlin, Germany), 1% HEPES (Sigma-Aldrich, St. Louis, MO) and 1% L-glutamine (Life Technologies, Carlsbad, CA, USA). T cells were stimulated via the addition of CD3/CD28 Dynabeads (Thermo Fisher Scientific, Waltham, MA, USA) with a bead-to-cell ratio of 1:8 for a duration 24 hours. After stimulation, CD3/CD28 Dynabeads were magnetically removed. Pan T cell-, CD4+- and CD8+-cell-isolation was performed by magnetic cell separation (Pan T Cell Isolation Kit, # 130-096-535 | human CD4 MicroBeads, # 130-045-101 | human CD8 MicroBeads, # 130-045-201, Miltenyi Biotec, Bergisch Gladbach, Germany) using an AutoMACS Pro Separator ( # 130-092-545, Miltenyi Biotec, Bergisch-Gladbach, Germany) according to the manufacturer’s instructions. Results: 11.545 expressed genes were identified, for CD4/CD8 T cells, we detected 5.667/ 5.799 up-regulated genes and 5.878/5.746 down-regulated genes. 294/346 genes and 325/252 genes were significantly up/down-regulated for CD4+/CD8+ T cells (p-val. <0.05). Gene set enrichment analysis revealed 117/17 and 22/6 significantly up/down-regulated pathways for CD4+/CD8+ T cells (p-val. <0.05). Genes and Gene sets differentially regulated were relevant for T cell immune response and metabolic function. Conclusion: KD resulted in immunometabolic reprogramming of human CD4+/CD8+ T cells.

Project description:IntroductionThere is limited data on the effects of low carbohydrate diets on renal outcomes particularly in patients with underlying diabetic kidney disease. Therefore, this study determined the safety and effects of very low carbohydrate (VLCBD) in addition to low protein diet (LPD) on renal outcomes, anthropometric, metabolic and inflammatory parameters in patients with T2DM and underlying mild to moderate kidney disease (DKD).Materials and methodsThis was an investigator-initiated, single-center, randomized, controlled, clinical trial in patients with T2DM and DKD, comparing 12-weeks of low carbohydrate diet (<20g daily intake) versus standard low protein (0.8g/kg/day) and low salt diet. Patients in the VLCBD group underwent 2-weekly monitoring including their 3-day food diaries. In addition, Dual-energy x-ray absorptiometry (DEXA) was performed to estimate body fat percentages.ResultsThe study population (n = 30) had a median age of 57 years old and a BMI of 30.68kg/m2. Both groups showed similar total calorie intake, i.e. 739.33 (IQR288.48) vs 789.92 (IQR522.4) kcal, by the end of the study. The VLCBD group showed significantly lower daily carbohydrate intake 27 (IQR25) g vs 89.33 (IQR77.4) g, p<0.001, significantly higher protein intake per day 44.08 (IQR21.98) g vs 29.63 (IQR16.35) g, p<0.05 and no difference in in daily fat intake. Both groups showed no worsening of serum creatinine at study end, with consistent declines in HbA1c (1.3(1.1) vs 0.7(1.25) %) and fasting blood glucose (1.5(3.37) vs 1.3(5.7) mmol/L). The VLCBD group showed significant reductions in total daily insulin dose (39(22) vs 0 IU, p<0.001), increased LDL-C and HDL-C, decline in IL-6 levels; with contrasting results in the control group. This was associated with significant weight reduction (-4.0(3.9) vs 0.2(4.2) kg, p = <0.001) and improvements in body fat percentages. WC was significantly reduced in the VLCBD group, even after adjustments to age, HbA1c, weight and creatinine changes. Both dietary interventions were well received with no reported adverse events.ConclusionThis study demonstrated that dietary intervention of very low carbohydrate diet in patients with underlying diabetic kidney disease was safe and associated with significant improvements in glycemic control, anthropometric measurements including weight, abdominal adiposity and IL-6. Renal outcomes remained unchanged. These findings would strengthen the importance of this dietary intervention as part of the management of patients with diabetic kidney disease.

Dataset Information

Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming.

Publications

Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming.

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