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Title:
Early Pleistocene faunivorous hominins were not kleptoparasitic, and this impacted the evolution of human anatomy and socio-ecology
Authors:
Domínguez-Rodrigo, Manuel; Baquedano, Enrique; Organista, Elia; Cobo-Sánchez, Lucía; Mabulla, Audax; Maskara, Vivek; Gidna, Agness; Pizarro-Monzo, Marcos; Aramendi, Julia; Galán, Ana Belén; Cifuentes-Alcobendas, Gabriel; Vegara-Riquelme, Marina; Jiménez-García, Blanca; Abellán, Natalia; Barba, Rebeca; Uribelarrea, David; Martín-Perea, David; Diez-Martin, Fernando; Maíllo-Fernández, José Manuel; Rodríguez-Hidalgo, Antonio; Courtenay, Lloyd; Mora, Rocío; Maté-González, Miguel Angel; González-Aguilera, Diego
Abstract:
Humans are unique in their diet, physiology and socio-reproductive behavior compared to other primates. They are also unique in the ubiquitous adaptation to all biomes and habitats. From an evolutionary perspective, these trends seem to have started about two million years ago, coinciding with the emergence of encephalization, the reduction of the dental apparatus, the adoption of a fully terrestrial lifestyle, resulting in the emergence of the modern anatomical bauplan, the focalization of certain activities in the landscape, the use of stone tools, and the exit from Africa. It is in this period that clear taphonomic evidence of a switch in diet with respect to Pliocene hominins occurred, with the adoption of carnivory. Until now, the degree of carnivorism in early humans remained controversial. A persistent hypothesis is that hominins acquired meat irregularly (potentially as fallback food) and opportunistically through klepto-foraging. Here, we test this hypothesis and show, in contrast, that the butchery practices of early Pleistocene hominins (unveiled through systematic study of the patterning and intensity of cut marks on their prey) could not have resulted from having frequent secondary access to carcasses. We provide evidence of hominin primary access to animal resources and emphasize the role that meat played in their diets, their ecology and their anatomical evolution, ultimately resulting in the ecologically unrestricted terrestrial adaptation of our species. This has major implications to the evolution of human physiology and potentially for the evolution of the human brain.
Published:
August 9, 2021
Title:
A multiphase dietetic protocol incorporating an improved ketogenic diet enhances weight loss and alters the gut microbiome of obese people
Authors:
Yuan, Weiwei; Lu, Wenwei; Wang, Hongchao; Wu, Wenjun; Zhou, Qunyan; Chen, Yutao; Lee, Yuan Kun; Zhao, Jianxin; Zhang, Hao; Chen, Wei
Abstract:
The prevalence of obesity and its associated diseases is increasing. In the current study, 15 obese subjects took part in a 12-week multiphase dietetic protocol incorporating an improved ketogenic diet (MDP-i-KD) (KYLLKS 201806). We investigated the effects of the MDP-i-KD on the anthropometric parameters and the gut microbiota of obese subjects. Our results showed that the MDP-i-KD led to significant reductions in body mass index in obese subjects. The MDP-i-KD significantly decreased the relative abundance of the Lachnospiraceae_ND3007_group, the Eubacterium_hallii_group, and Pseudomonas and Blautia. In addition, gut microbiota co-occurrence networks in obese subjects were restructured to a more healthy condition after weight loss. These results show that the MDP-i-KD enhanced weight loss, which may be associated with dietary-induced changes in the gut microbiome. Our results emphasise the importance of determining the interaction between the host and microbial cells to comprehensively understand the mechanism by which diet affects host physiology and the microbiota.
Published:
August 6, 2021
Title:
The effects of fat consumption on low-density lipoprotein particle size in healthy individuals: a narrative review
Authors:
Froyen, Erik
Abstract:
Cardiovascular disease (CVD) is the number one contributor to death in the United States and worldwide. A risk factor for CVD is high serum low-density lipoprotein cholesterol (LDL-C) concentrations; however, LDL particles exist in a variety of sizes that may differentially affect the progression of CVD. The small, dense LDL particles, compared to the large, buoyant LDL subclass, are considered to be more atherogenic. It has been suggested that replacing saturated fatty acids with monounsaturated and polyunsaturated fatty acids decreases the risk for CVD. However, certain studies are not in agreement with this recommendation, as saturated fatty acid intake did not increase the risk for CVD, cardiovascular events, and/or mortality. Furthermore, consumption of saturated fat has been demonstrated to increase large, buoyant LDL particles, which may explain, in part, for the differing outcomes regarding fat consumption on CVD risk. Therefore, the objective was to review intervention trials that explored the effects of fat consumption on LDL particle size in healthy individuals. PubMed and Web of Science were utilized during the search process for journal articles. The results of this review provided evidence that fat consumption increases large, buoyant LDL and/or decreases small, dense LDL particles, and therefore, influences CVD risk.
Published:
August 6, 2021
Title:
Effect of low glycaemic index or load dietary patterns on glycaemic control and cardiometabolic risk factors in diabetes: systematic review and meta-analysis of randomised controlled trials
Authors:
Chiavaroli, Laura; Lee, Danielle; Ahmed, Amna; Cheung, Annette; Khan, Tauseef A.; Blanco, Sonia; Mejia; Mirrahimi, Arash; Jenkins, David J. A.; Livesey, Geoffrey; Wolever, Thomas M. S.; Rahelić, Dario; Kahleová, Hana; Salas-Salvadó, Jordi; Kendall, Cyril W. C.; Sievenpiper, John L.
Abstract:
Objective To inform the update of the European Association for the Study of Diabetes clinical practice guidelines for nutrition therapy. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, and the Cochrane Library searched up to 13 May 2021. Eligibility criteria for selecting studies Randomised controlled trials of three or more weeks investigating the effect of diets with low glycaemic index (GI)/glycaemic load (GL) in diabetes. Outcome and measures The primary outcome was glycated haemoglobin (HbA1c). Secondary outcomes included other markers of glycaemic control (fasting glucose, fasting insulin); blood lipids (low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), non-HDL-C, apo B, triglycerides); adiposity (body weight, BMI (body mass index), waist circumference), blood pressure (systolic blood pressure (SBP) and diastolic blood pressure (DBP)), and inflammation (C reactive protein (CRP)). Data extraction and synthesis Two independent reviewers extracted data and assessed risk of bias. Data were pooled by random effects models. GRADE (grading of recommendations assessment, development, and evaluation) was used to assess the certainty of evidence. Results 29 trial comparisons were identified in 1617 participants with type 1 and 2 diabetes who were predominantly middle aged, overweight, or obese with moderately controlled type 2 diabetes treated by hyperglycaemia drugs or insulin. Low GI/GL dietary patterns reduced HbA1c in comparison with higher GI/GL control diets (mean difference −0.31% (95% confidence interval −0.42 to −0.19%), P<0.001; substantial heterogeneity, I2=75%, P<0.001). Reductions occurred also in fasting glucose, LDL-C, non-HDL-C, apo B, triglycerides, body weight, BMI, systolic blood pressure (dose-response), and CRP (P<0.05), but not blood insulin, HDL-C, waist circumference, or diastolic blood pressure. A positive dose-response gradient was seen for the difference in GL and HbA1c and for absolute dietary GI and SBP (P
Published:
August 5, 2021
Title:
Effect of low glycaemic index or load dietary patterns on glycaemic control and cardiometabolic risk factors in diabetes: systematic review and meta-analysis of randomised controlled trials
Authors:
Chiavaroli, Laura; Lee, Danielle; Ahmed, Amna; Cheung, Annette; Khan, Tauseef A.; Blanco, Sonia; Mejia; Mirrahimi, Arash; Jenkins, David J. A.; Livesey, Geoffrey; Wolever, Thomas M. S.; Rahelić, Dario; Kahleová, Hana; Salas-Salvadó, Jordi; Kendall, Cyril W. C.; Sievenpiper, John L.
Abstract:
Objective To inform the update of the European Association for the Study of Diabetes clinical practice guidelines for nutrition therapy. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, and the Cochrane Library searched up to 13 May 2021. Eligibility criteria for selecting studies Randomised controlled trials of three or more weeks investigating the effect of diets with low glycaemic index (GI)/glycaemic load (GL) in diabetes. Outcome and measures The primary outcome was glycated haemoglobin (HbA1c). Secondary outcomes included other markers of glycaemic control (fasting glucose, fasting insulin); blood lipids (low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), non-HDL-C, apo B, triglycerides); adiposity (body weight, BMI, waist circumference), blood pressure (systolic blood pressure (SBP) and diastolic blood pressure (DBP)), and inflammation (C reactive protein (CRP)). Data extraction and synthesis Two independent reviewers extracted data and assessed risk of bias. Data were pooled by random effects models. GRADE (grading of recommendations assessment, development, and evaluation) was used to assess the certainty of evidence. Results 29 trial comparisons were identified in 1617 participants with type 1 and 2 diabetes who were predominantly middle aged, overweight, or obese with moderately controlled type 2 diabetes treated by hyperglycaemia drugs or insulin. Low GI/GL dietary patterns reduced HbA1c in comparison with higher GI/GL control diets (mean difference −0.31% (95% confidence interval −0.42 to −0.19%), P<0.001; substantial heterogeneity, I2=75%, P<0.001). Reductions occurred also in fasting glucose, LDL-C, non-HDL-C, apo B, triglycerides, body weight, BMI, and CRP (P<0.05), but not blood insulin, HDL-C, waist circumference, or blood pressure. A positive dose-response gradient was seen for the difference in GL and HbA1c and for absolute dietary GI and SBP (P
Published:
August 5, 2021
Title:
Gut-microbiota-targeted diets modulate human immune status
Authors:
Wastyk, Hannah C.; Fragiadakis, Gabriela K.; Perelman, Dalia; Dahan, Dylan; Merrill, Bryan D.; Yu, Feiqiao B.; Topf, Madeline; Gonzalez, Carlos G.; Treuren, William Van; Han, Shuo; Robinson, Jennifer L.; Elias, Joshua E.; Sonnenburg, Erica D.; Gardner, Christopher D.; Sonnenburg, Justin L.
Abstract:
Published:
August 5, 2021
Title:
Partial Substitution of Meat with Insect (Alphitobius diaperinus) in a Carnivore Diet Changes the Gut Microbiome and Metabolome of Healthy Rats
Authors:
Lanng, Sofie Kaas; Zhang, Yichang; Christensen, Kristine Rothaus; Hansen, Axel Kornerup; Nielsen, Dennis Sandris; Kot, Witold; Bertram, Hanne Christine
Abstract:
Insects are suggested as a sustainable protein source of high nutritional quality, but the effects of insect ingestion on processes in the gastrointestinal tract and gut microbiota (GM) remain to be established. We examined the effects of partial substitution of meat with insect protein (Alphitobius diaperinus) in a four-week dietary intervention in a healthy rat model (n = 30). GM composition was characterized using' 16S rRNA gene amplicon profiling while the metabolomes of stomach, small intestine, and colon content, feces and blood were investigated by 1H-NMR spectroscopy. Metabolomics analyses revealed a larger escape of protein residues into the colon and a different microbial metabolization pattern of aromatic amino acids when partly substituting pork with insect. Both for rats fed a pork diet and rats fed a diet with partial replacement of pork with insect, the GM was dominated by Lactobacillus, Clostridium cluster XI and Akkermansia. However, Bray-Curtis dissimilarity metrics were different when insects were included in the diet. Introduction of insects in a common Western omnivore diet alters the gut microbiome diversity with consequences for endogenous metabolism. This finding highlights the importance of assessing gastrointestinal tract effects when evaluating new protein sources as meat replacements.
Published:
August 5, 2021
Title:
Excess dietary carbohydrate affects mitochondrial integrity as observed in brown adipose tissue
Authors:
Waldhart, Althea N.; Muhire, Brejnev; Johnson, Ben; Pettinga, Dean; Madaj, Zachary B.; Wolfrum, Emily; Dykstra, Holly; Wegert, Vanessa; Pospisilik, J. Andrew; Han, Xianlin; Wu, Ning
Abstract:
Published:
August 3, 2021
Title:
Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation
Authors:
Koronowski, Kevin B.; Greco, Carolina M.; Huang, He; Kim, Jin-Kwang; Fribourgh, Jennifer L.; Crosby, Priya; Mathur, Lavina; Ren, Xuelian; Partch, Carrie L.; Jang, Cholsoon; Qiao, Feng; Zhao, Yingming; Sassone-Corsi, Paolo
Abstract:
Published:
August 3, 2021
Title:
Very-low-calorie ketogenic diet: An alternative to a pharmacological approach to improve glycometabolic and gonadal profile in men with obesity
Authors:
Mongioì, Laura M.; Cimino, Laura; Greco, Emanuela; Cannarella, Rossella; Condorelli, Rosita A.; La Vignera, Sandro; Calogero, Aldo E.
Abstract:
Obesity and metabolic diseases have become a worrying reality, especially in more developed societies. They are associated with the development of many comorbidities, such as type 2 diabetes mellitus, hypogonadism, hypertension, cerebrovascular and cardiovascular diseases, neoplasia, obstructive sleep apnea, and non-alcoholic fatty liver disease. Therefore, weight loss is of paramount importance. A promising therapeutic option to achieve this goal is the very-low-calorie ketogenic diet. This review aims to summarize the main effects of very-low-calorie-ketogenic diet on the glycometabolic and gonadal profiles of men with overweight/obesity.
Published:
August 3, 2021
Title:
Contrasting effects of Western vs Mediterranean diets on monocyte inflammatory gene expression and social behavior in a primate model
Authors:
Johnson, Corbin SC; Shively, Carol; Michalson, Kristofer T; Lea, Amanda J; DeBo, Ryne J; Howard, Timothy D; Hawkins, Gregory A; Appt, Susan E; Liu, Yongmei; McCall, Charles E; Herrington, David M; Ip, Edward H; Register, Thomas C; Snyder-Mackler, Noah
Abstract:
Dietary changes associated with industrialization increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease. This relationship is often attributed to an ‘evolutionary mismatch’ between human physiology and modern nutritional environments. Western diets enriched with foods that were scarce throughout human evolutionary history (e.g. simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to ancestral human hunter-gatherer diets, such as a Mediterranean diet. Peripheral blood monocytes, precursors to macrophages and important mediators of innate immunity and inflammation, are sensitive to the environment and may represent a critical intermediate in the pathway linking diet to disease. We evaluated the effects of 15 months of whole diet manipulations mimicking Western or Mediterranean diet patterns on monocyte polarization in a well-established model of human health, the cynomolgus macaque (Macaca fascicularis). Monocyte transcriptional profiles differed markedly between diets, with 40% of transcripts showing differential expression (FDR
Published:
August 2, 2021
Title:
Effect of a very low-carbohydrate ketogenic diet vs recommended diets in patients with type 2 diabetes: a meta-analysis
Authors:
Rafiullah, Mohamed; Musambil, Mohthash; David, Satish Kumar
Abstract:
There is renewed interest in using very low-carbohydrate ketogenic (VLCK) diets to manage diabetes. Many clinical trials have been published, often with mixed results.This meta-analysis compares the effect of a VLCK diet on glycemic control, body weight, lipid profile, medication use, and dropouts with that of recommended diets for 12 weeks or longer in people with type 2 diabetes.Ovid MEDLINE, Ovid Embase, CENTRAL, and CINAHL databases were searched (January 1980 through September 2019).Two authors independently reviewed search results to select randomized controlled trials (RCTs) comparing a VLCK diet (carbohydrate intake < 50 g/d or < 10% of total energy) with any recommended diet for type 2 diabetes in adults. Discrepancies were resolved after consulting with the third author.Eight RCTs with 648 participants were identified.Compared with control diets, the VLCK diet resulted in a greater decrease in hemoglobin A1c after 3 months (weighted mean difference[WMD]: −6.7 mmol/mol; 95%CI, −9.0 to −4.4) (WMD: −0.61%; 95%CI, −0.82 to −0.40; P < 0.001; moderate-certainty evidence) and after 6 months (WMD: −6.3 mmol/mol; 95%CI, −9.3 to −3.5) (WMD: −0.58%; 95%CI, −0.85 to −0.32; low-certainty evidence). There was a significantly greater weight loss with the VLCK diet after 3 months (WMD: −2.91 kg; 95%CI, −4.88 to −0.95; low-certainty evidence) and after 6 months (WMD: −2.84 kg; 95%CI, −5.29 to −0.39; low-certainty evidence). The VLCK diet was not better than a control diet after 12 months. It was superior in decreasing triglyceride levels, increasing high-density lipoprotein cholesterol levels, and reducing the use of antidiabetic medications for up to 12 months.The VLCK diet appears to control glycemia and decrease body weight for up to 6 months in people with obesity and diabetes. Beneficial changes in serum triglycerides and high-density lipoprotein cholesterol, along with reductions in antidiabetic medications, continued in the VLCK group until 12 months. However, the quality of currently available evidence is not sufficient to recommend VLCK diets. A major limitation of the VLCK diet is patients’ lack of adherence to carbohydrate restriction.PROSPERO registration number CRD42020154700
Published:
August 2, 2021
Title:
Hippocampal Volume Reduction is Associated with Direct Measure of Insulin Resistance in Adults
Authors:
Frangou, Sophia; Abbasi, Fahim; Watson, Katie; Haas, Shalaila S.; Antoniades, Mathilde; Modabbernia, Amirhossein; Myoraku, Alison; Robakis, Thalia; Rasgon, Natalie
Abstract:
Hippocampal integrity Is highly susceptible to metabolic dysfunction, yet its mechanisms are not well defined. We studied 126 healthy individuals aged 23-61 years. Insulin resistance (IR) was quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Body mass index (BMI), adiposity, fasting insulin, glucose, leptin as well as structural neuroimaing with automatic hippocampal subfields segmentation were performed. Data analysis using unsupervised machine learning (k-means clustering) identified two subgroups reflecting a pattern of more pronounced hippocampal volume reduction being concurrently associated with greater adiposity and insulin resistance; the hippocampal volume reductions were uniform across subfields. Individuals in the most deviant subgroup were predominantly women (79 versus 42%) with higher BMI [27.9 (2.5) versus 30.5 (4.6) kg/m2], IR (SSPG concentration, [156 (61) versus 123 (70) mg/dL] and leptinemia [21.7 (17.0) versus 44.5 (30.4) µg/L]. The use of person-based modeling in healthy individuals suggests that adiposity, insulin resistance and compromised structural hippocampal integrity behave as a composite phenotype; female sex emerged as risk factor for this phenotype.
Published:
August 2, 2021
Title:
Association between ketosis and metabolic adaptation at the level of resting metabolic rate
Authors:
Martins, Catia; Roekenes, Jessica; Hunter, Gary R.; Gower, Barbara A.
Abstract:
Summary
Background
The ketone body β-hydroxybutyrate (βHB) has been shown to act as a signaling molecule that regulates metabolism and energy homeostasis during starvation in animal models. A potential association between βHB and metabolic adaptation (a reduction in energy expenditure below predicted levels) in humans has never been explored.
Objective
To determine if metabolic adaptation at the level of resting metabolic rate (RMR) was associated with the magnitude of ketosis induced by a very-low energy diet (VLED). A secondary aim was to investigate if the association was modulated by sex.
Methods
Sixty-four individuals with obesity (BMI: 34.5 ± 3.4 kg/m2; age: 45.7 ± 8.0 years; 31 males) enrolled in a 1000 kcal/day diet for 8 weeks. Body weight/composition, RMR and βHB (as a measure of ketosis) were determined at baseline and week 9 (W9). Metabolic adaptation was defined as a significantly lower measured versus predicted RMR (from own regression model).
Results
Participants lost on average 14.0 ± 3.9 kg and were ketotic (βHB: 0.76 ± 0.51 mM) at W9. A significant metabolic adaptation was seen (−84 ± 106 kcal/day, P < 0.001), with no significant differences between sexes. [βHB] was positively correlated with the magnitude of metabolic adaptation in females (r = 0.432, P = 0.012, n = 33), but not in males (r = 0.089, P = 0.634, n = 31).
Conclusion
In females with obesity, but not males, the larger the [βHB] under VLED, the greater the metabolic adaptation at the level of RMR. More studies are needed to confirm these findings and to explore the mechanisms behind the sex difference in the association between ketosis and metabolic adaptation.
Trial registration name
Clinicaltrials.gov.
Study registration ID
NCT02944253.
URL
Published:
August 1, 2021
Title:
Diets Varying in Carbohydrate Content Differentially Alter Brain Activity in Homeostatic and Reward Regions in Adults
Authors:
Holsen, Laura M; Hoge, W Scott; Lennerz, Belinda S; Cerit, Hilâl; Hye, Taryn; Moondra, Priyanka; Goldstein, Jill M; Ebbeling, Cara B; Ludwig, David S
Abstract:
Obesity has one of the highest refractory rates of all chronic diseases, in part because weight loss induced by calorie restriction, the first-line treatment for obesity, elicits biological adaptations that promote weight regain. Although acute feeding trials suggest a role for macronutrient composition in modifying brain activity related to hunger and satiety, relevance of these findings to weight-loss maintenance has not been studied.We investigated effects of weight-loss maintenance diets varying in macronutrient content on regional cerebral blood flow (rCBF) in brain regions involved in hunger and reward.In conjunction with a randomized controlled feeding trial, we investigated the effects of weight-loss maintenance diets varying in carbohydrate content [high, 60% of total energy: n = 20; 6 men/14 women; mean age: 32.5 y; mean BMI (in kg/m 2): 27.4; moderate, 40% of total energy: n = 22; 10 men/12 women; mean age: 32.5 y; mean BMI: 29.0; low, 20% of total energy: n = 28; 12 men/16 women; mean age: 33.2 y; mean BMI: 27.7] on rCBF in brain regions involved in hunger and reward preprandial and 4 h postprandial after 14–20 wk on the diets. The primary outcome was rCBF in the nucleus accumbens (NAcc) at 4 h postprandial; the secondary outcome was preprandial rCBF in the hypothalamus.Consistent with a priori hypothesis, at 4 h postprandial, NAcc rCBF was 43% higher in adults assigned to the high- compared with low-carbohydrate diet {P[family-wise error (FWE)-corrected] < 0.05}. Preprandial hypothalamus rCBF was 41% higher on high-carbohydrate diet [P(FWE-corrected) < 0.001]. Exploratory analyses revealed that elevated rCBF on high-carbohydrate diet was not specific to prandial state: preprandial NAcc rCBF [P(FWE-corrected) < 0.001] and 4 h postprandial rCBF in hypothalamus [P(FWE-corrected) < 0.001]. Insulin secretion predicted differential postprandial activation of the NAcc by diet.We report significant differences in rCBF in adults assigned to diets varying in carbohydrate content for several months, which appear to be partially associated with insulin secretion. These findings suggest that chronic intake of a high-carbohydrate diet may affect brain reward and homeostatic activity in ways that could impede weight-loss maintenance. This trial was registered at clinicaltrials.gov as NCT02300857.
Published:
August 1, 2021
Title:
Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia
Authors:
Olson, Christine A.; Iñiguez, Alonso J.; Yang, Grace E.; Fang, Ping; Pronovost, Geoffrey N.; Jameson, Kelly G.; Rendon, Tomiko K.; Paramo, Jorge; Barlow, Jacob T.; Ismagilov, Rustem F.; Hsiao, Elaine Y.
Abstract:
Many genetic and environmental factors increase susceptibility to cognitive impairment (CI), and the gut microbiome is increasingly implicated. However, the identity of gut microbes associated with CI risk, their effects on CI, and their mechanisms remain unclear. Here, we show that a carbohydrate-restricted (ketogenic) diet potentiates CI induced by intermittent hypoxia in mice and alters the gut microbiota. Depleting the microbiome reduces CI, whereas transplantation of the risk-associated microbiome or monocolonization with Bilophila wadsworthia confers CI in mice fed a standard diet. B. wadsworthia and the risk-associated microbiome disrupt hippocampal synaptic plasticity, neurogenesis, and gene expression. The CI is associated with microbiome-dependent increases in intestinal interferon-gamma (IFNg)-producing Th1 cells. Inhibiting Th1 cell development abrogates the adverse effects of both B. wadsworthia and environmental risk factors on CI. Together, these findings identify select gut bacteria that contribute to environmental risk for CI in mice by promoting inflammation and hippocampal dysfunction.
Published:
July 30, 2021
Title:
High triglyceride-glucose index is associated with early recurrent ischemic lesion in acute ischemic stroke
Authors:
Nam, Ki-Woong; Kwon, Hyung-Min; Lee, Yong-Seok
Abstract:
The triglyceride-glucose (TyG) index has been associated with various metabolic, cardiovascular, and cerebrovascular diseases. We evaluated the association between the TyG index and early recurrent ischemic lesions (ERILs) in patients with acute ischemic stroke (AIS). We included consecutive patients diagnosed with AIS between 2010 and 2016. ERILs were defined as new diffusion-weighted imaging lesions outside the initial symptomatic lesion area. The TyG index was calculated using the following formula: log scale of fasting triglyceride × fasting glucose/2. A total of 176 patients with AIS were evaluated. In the multivariable analysis, the TyG index remained significant (adjusted odds ratio [aOR] 2.63, 95% confidence interval [CI] 1.34–5.15). This close correlation between the TyG index and ERIL was pronounced in ERIL-same group (aOR 2.84, 95% CI 1.40–5.78), but not in ERIL-different group. When comparing the relationship between the TyG index and ERIL by stroke mechanisms, only the intracranial- and extracranial-large artery atherosclerosis groups showed significantly higher TyG index values in patients with ERIL than those without. In conclusion, a higher TyG index was associated with ERIL, especially ERIL-same, in patients with AIS. The TyG index appears to be involved in ERIL occurrence by a mechanism related to atherosclerosis.
Published:
July 28, 2021
Title:
Enterically derived high-density lipoprotein restrains liver injury through the portal vein
Authors:
Han, Yong-Hyun; Onufer, Emily J.; Huang, Li-Hao; Sprung, Robert W.; Davidson, W. Sean; Czepielewski, Rafael S.; Wohltmann, Mary; Sorci-Thomas, Mary G.; Warner, Brad W.; Randolph, Gwendalyn J.
Abstract:
Intestinal HDL is hepatoprotective High-density lipoprotein (HDL) is important for cholesterol metabolism and may have anti-inflammatory and antimicrobial properties. Although HDL is mainly produced by the liver, the intestine is also a source. Han et al. show in mice that intestinal HDL is not routed to the systemic circulation. Rather, in the form of HDL3, it is directly transported to the liver through the hepatic portal vein. There, it sequesters bacterial lipopolysaccharide from the gut that can trigger inflammation and liver damage. In various models of liver injury, loss of enteric HDL exacerbated pathology. By contrast, drugs elevating intestinal HDL improved disease outcomes. HDL3 is enriched in human portal venous blood, suggesting that enteric HDL may be targetable for the treatment of liver disease. Science, abe6729, this issue p. eabe6729 Structured Abstract INTRODUCTIONHigh-density lipoprotein (HDL) participates in cholesterol homeostasis and may also have anti-inflammatory or anti-microbial roles through its interaction with numerous plasma proteins. The liver synthesizes most HDL in the body, but the intestine also produces HDL. However, a role for intestinal HDL distinct from that produced by the liver has not been identified. While remodeling its cargo, HDL particles circulate through tissue spaces, but so far, HDL trafficking within tissues has been scarcely studied. RATIONALEWe reasoned that understanding HDL-trafficking patterns might bring insight into its roles in health and disease, including whether HDL made by the intestine is functionally redundant with that produced by the liver. Using a knock-in mouse that we previously generated to phototag HDL in any tissue location, we aimed to trace the fate of HDL synthesized by the intestine. RESULTSPhototagged HDL derived from small bowel enterocytes was generated most abundantly by the ileum and did not travel into draining lymphatic vessels as enterocyte-derived chylomicrons do. Instead, intestinal HDL rapidly entered the portal vein, the major blood supply to the liver. This finding raised the issue of whether the liver might benefit from intestinal HDL and pointed us to an older concept that HDL might neutralize a key microbial signal that can escape a permeable gut: lipopolysaccharide (LPS) from Gram-negative bacteria. Past studies using multiple models have shown that LPS engagement of its receptor, Toll-like receptor 4 (TLR4), in the liver drives significant liver pathology, including inflammation that progresses to fibrosis. Using biochemical, proteomic, and functional approaches, we observed that the intestine produces a particular subspecies of HDL called HDL3. Unlike another HDL subspecies (HDL2), HDL3 sequestered LPS so efficiently that it could not bind to TLR4+ liver macrophages. In this way, HDL3 produced by the intestine protected the liver from the inflammation and fibrosis observed in a variety of mouse models of liver injury that parallel clinically relevant conditions in humans, including surgical resection of the small bowel, alcohol consumption, or high-fat diets. Administration of an oral drug targeting the transcription factor liver X receptor, the master regulator of genes associated with HDL biogenesis, raised enteric HDL levels and protected the mice from liver pathology. This protection was lost if mice did not express enterically derived HDL, indicating that intestinal HDL was a key target of the drug. Six samples of human portal venous blood with matched systemic venous blood confirmed the enrichment of HDL3.Mechanistically, LPS-binding protein (LBP) was enriched in HDL3 particles and was required for HDL3 to mask LPS from detection by TLR4. This finding was unexpected because LBP otherwise promotes TLR4 signaling by shuttling LPS to CD14, which then shuttles it to TLR4. Thus, HDL3 interacts with a known component of the TLR4-signaling platform, LBP, to hide LPS from detection. Without binding to TLR4, the HDL3-LBP-LPS complex was not retained in liver. Instead, it exited the liver while the LPS associated with it was inactivated. The enzyme acyloxyacyl hydrolase, which is produced in part by liver macrophages and which deacylates critical fatty acid residues in LPS for TLR4 activation, could still access and act upon HDL3-associated LPS to detoxify it. Low-density lipoprotein bound LPS, but not LBP, and was thus unable to prevent LPS activation of liver macrophages. LBP is in the same family of lipid-binding proteins as phospholipid transfer protein and cholesterol ester transfer protein, which have well-established roles in remodeling the lipid configuration of HDL. Another microbial lipid, lipoteichoic acid from Gram-positive bacteria, is known to bind LBP. We found that it too complexed with HDL3 and suppressed the activation of liver macrophages. CONCLUSIONThe production of HDL by small bowel enterocytes in a form that potently masks LPS comprises a disease tolerance strategy to protect the liver from injury of enteric origin. Enteric HDL may thus be a suitable pharmacologic target for protecting the liver against gut-derived LPS leakage in alcoholic and nonalcoholic settings. 
Download high-res image Open in new tab Download Powerpoint Trafficking and functional properties of enteric HDL.Enterocytes express ABCA1 to promote HDL biogenesis. The nascent HDL enters portal venous blood bearing LBP, which allows it to hide LPS from recognition by TLR4+ macrophages. Failed recognition prevents macrophage activation. Although its ability to trigger macrophages is suppressed by HDL3, LPS in the HDL3 complex can still be inactivated by acyloxyacyl hydrolase. Figure was drawn with BioRender. The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL3 subspecies form, in complex with lipopolysaccharide (LPS)–binding protein (LBP). HDL3, but not HDL2 or low-density lipoprotein, prevented LPS binding to and inflammatory activation of liver macrophages and instead supported extracellular inactivation of LPS. In mouse models involving surgical, dietary, or alcoholic intestinal insult, loss of intestine-derived HDL worsened liver injury, whereas outcomes were improved by therapeutics that elevated and depended upon raising intestinal HDL. Thus, protection of the liver from injury in response to gut-derived LPS is a major function of intestinally synthesized HDL. High-density lipoprotein from the ileum shields the liver from inflammation and fibrosis. High-density lipoprotein from the ileum shields the liver from inflammation and fibrosis.
Download high-res image Open in new tab Download Powerpoint Trafficking and functional properties of enteric HDL.Enterocytes express ABCA1 to promote HDL biogenesis. The nascent HDL enters portal venous blood bearing LBP, which allows it to hide LPS from recognition by TLR4+ macrophages. Failed recognition prevents macrophage activation. Although its ability to trigger macrophages is suppressed by HDL3, LPS in the HDL3 complex can still be inactivated by acyloxyacyl hydrolase. Figure was drawn with BioRender. The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL3 subspecies form, in complex with lipopolysaccharide (LPS)–binding protein (LBP). HDL3, but not HDL2 or low-density lipoprotein, prevented LPS binding to and inflammatory activation of liver macrophages and instead supported extracellular inactivation of LPS. In mouse models involving surgical, dietary, or alcoholic intestinal insult, loss of intestine-derived HDL worsened liver injury, whereas outcomes were improved by therapeutics that elevated and depended upon raising intestinal HDL. Thus, protection of the liver from injury in response to gut-derived LPS is a major function of intestinally synthesized HDL. High-density lipoprotein from the ileum shields the liver from inflammation and fibrosis. High-density lipoprotein from the ileum shields the liver from inflammation and fibrosis.Published:
July 23, 2021
Title:
On the causal relationships between hyperinsulinaemia, insulin resistance, obesity and dysglycaemia in type 2 diabetes
Authors:
Johnson, James D.
Abstract:
Hundreds of millions of people are affected by hyperinsulinaemia, insulin resistance, obesity and the dysglycaemia that mark a common progression from metabolic health to type 2 diabetes. Although the relative contribution of these features and the order in which they appear may differ between individuals, the common clustering and seemingly progressive nature of type 2 diabetes aetiology has guided research and clinical practice in this area for decades. At the same time, lively debate around the causal relationships between these features has continued, as new data from human trials and highly controlled animal studies are presented. This ‘For debate’ article was prompted by the review in Diabetologia by Esser, Utzschneider and Kahn (https://doi.org/10.1007/s00125-020-05245-x), with the purpose of reviewing established and emerging data that provide insight into the relative contributions of hyperinsulinaemia and impaired glucose-stimulated insulin secretion in progressive stages between health, obesity and diabetes. It is concluded that these beta cell defects are not mutually exclusive and that they are both important, but at different stages.
Published:
July 22, 2021
Title:
Cardiovascular disease in diabetes, beyond glucose
Authors:
Eckel, Robert H.; Bornfeldt, Karin E.; Goldberg, Ira J.
Abstract:
Despite the decades-old knowledge that diabetes mellitus is a major risk factor for cardiovascular disease, the reasons for this association are only partially understood. While this association is true for both type 1 and type 2 diabetes, different pathophysiological processes may be responsible. Lipids and other risk factors are indeed important, whereas the role of glucose is less clear. This lack of clarity stems from clinical trials that do not unambiguously show that intensive glycemic control reduces cardiovascular events. Animal models have provided mechanisms that link diabetes to increased atherosclerosis, and evidence consistent with the importance of factors beyond hyperglycemia has emerged. We review clinical, pathological, and animal studies exploring the pathogenesis of atherosclerosis in humans living with diabetes and in mouse models of diabetes. An increased effort to identify risk factors beyond glucose is now needed to prevent the increased cardiovascular disease risk associated with diabetes.
Published:
July 21, 2021
Title:
Cardiovascular disease in diabetes, beyond glucose
Authors:
Eckel, Robert H.; Bornfeldt, Karin E.; Goldberg, Ira J.
Abstract:
Despite the decades-old knowledge that diabetes mellitus is a major risk factor for cardiovascular disease, the reasons for this association are only partially understood. While this association is true for both type 1 and type 2 diabetes, different pathophysiological processes may be responsible. Lipids and other risk factors are indeed important, whereas the role of glucose is less clear. This lack of clarity stems from clinical trials that do not unambiguously show that intensive glycemic control reduces cardiovascular events. Animal models have provided mechanisms that link diabetes to increased atherosclerosis, and evidence consistent with the importance of factors beyond hyperglycemia has emerged. We review clinical, pathological, and animal studies exploring the pathogenesis of atherosclerosis in humans living with diabetes and in mouse models of diabetes. An increased effort to identify risk factors beyond glucose is now needed to prevent the increased cardiovascular disease risk associated with diabetes.
Published:
July 21, 2021
Title:
Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study
Authors:
Quispe, Renato; Martin, Seth Shay; Michos, Erin Donelly; Lamba, Isha; Blumenthal, Roger Scott; Saeed, Anum; Lima, Joao; Puri, Rishi; Nomura, Sarah; Tsai, Michael; Wilkins, John; Ballantyne, Christie Mitchell; Nicholls, Stephen; Jones, Steven Richard; Elshazly, Mohamed Badreldin
Abstract:
Emerging evidence suggests that remnant cholesterol (RC) promotes atherosclerotic cardiovascular disease (ASCVD). We aimed to estimate RC-related risk beyond low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) in patients without known ASCVD.We pooled data from 17 532 ASCVD-free individuals from the Atherosclerosis Risk in Communities study (n = 9748), the Multi-Ethnic Study of Atherosclerosis (n = 3049), and the Coronary Artery Risk Development in Young Adults (n = 4735). RC was calculated as non-high-density lipoprotein cholesterol (non-HDL-C) minus calculated LDL-C. Adjusted Cox models were used to estimate the risk for incident ASCVD associated with log RC levels. We also performed discordance analyses examining relative ASCVD risk in RC vs. LDL-C discordant/concordant groups using difference in percentile units (>10 units) and clinically relevant LDL-C targets. The mean age of participants was 52.3 ± 17.9 years, 56.7% were women and 34% black. There were 2143 ASCVD events over the median follow-up of 18.7 years. After multivariable adjustment including LDL-C and apoB, log RC was associated with higher ASCVD risk [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.45–1.89]. Moreover, the discordant high RC/low LDL-C group, but not the low RC/high LDL-C group, was associated with increased ASCVD risk compared to the concordant group (HR 1.21, 95% CI 1.08–1.34). Similar results were shown when examining discordance across clinical cutpoints.In ASCVD-free individuals, elevated RC levels were associated with ASCVD independent of traditional risk factors, LDL-C, and apoB levels. The mechanisms of RC association with ASCVD, surprisingly beyond apoB, and the potential value of targeted RC-lowering in primary prevention need to be further investigated.
Published:
July 19, 2021
Title:
Ketogenic diet for depression: A potential dietary regimen to maintain euthymia?
Authors:
Włodarczyk, Adam; Cubała, Wiesław J.; Stawicki, Mateusz
Abstract:
Approximately 30% of patients with major depressive disorder (MDD) present resistance to current pharmacological therapies. There is the possibility that an appropriate nutritional regimen can maintain euthymia. Poor dietary pattern and lack of nutritional knowledge are common among today's population; nutrient-rich foods are being replaced by highly processed foods that lead to a higher risk of developing chronic diseases such as metabolic syndrome, hypercholesterolemia, and diabetes. There is growing evidence of the beneficial role of vitamins and dietary supplements for improving symptoms in a range of affective disorders by regulating the gut microbiome, gut-brain axis, and neurotransmitter levels. Reduced GABA neurotransmission is regularly observed in MDD. Moreover, positive allosteric GABA modulators (i.e benzodiazepines) are widely prescribed to alleviate depression symptoms, but their use needs to be limited, as it can lead to addiction. An alternative option may be the adherence to a ketogenic diet, which consists of low-carbohydrate, moderate-protein, and high-fat intake. It is mainly known for its beneficial role in weight-loss, refractory epilepsy treatment, and balancing glucose levels. A ketogenic diet can also increase GABA levels to aid the mechanism of action of monoaminergic drugs. Thus, it could potentially be used in the treatment for affective disorders due to its potential role in GABA/glutamate balance. While more research is needed before this regimen can be regularly recommended to patients, here we discuss evidence that may encourage physicians to prescribe ketogenic diet as an adjuvant for patients receiving psychotherapy and pharmacology.
Published:
July 13, 2021
Title:
Genome-scale sequencing and analysis of human, wolf, and bison DNA from 25,000-year-old sediment
Authors:
Gelabert, Pere; Sawyer, Susanna; Bergström, Anders; Margaryan, Ashot; Collin, Thomas C.; Meshveliani, Tengiz; Belfer-Cohen, Anna; Lordkipanidze, David; Jakeli, Nino; Matskevich, Zinovi; Bar-Oz, Guy; Fernandes, Daniel M.; Cheronet, Olivia; Özdoğan, Kadir T.; Oberreiter, Victoria; Feeney, Robin N. M.; Stahlschmidt, Mareike C.; Skoglund, Pontus; Pinhasi, Ron
Abstract:
Published:
July 12, 2021
Title:
Different environmental variables predict body and brain size evolution in Homo
Authors:
Will, Manuel; Krapp, Mario; Stock, Jay T.; Manica, Andrea
Abstract:
Increasing body and brain size constitutes a key macro-evolutionary pattern in the hominin lineage, yet the mechanisms behind these changes remain debated. Hypothesized drivers include environmental, demographic, social, dietary, and technological factors. Here we test the influence of environmental factors on the evolution of body and brain size in the genus Homo over the last one million years using a large fossil dataset combined with global paleoclimatic reconstructions and formalized hypotheses tested in a quantitative statistical framework. We identify temperature as a major predictor of body size variation within Homo, in accordance with Bergmann’s rule. In contrast, net primary productivity of environments and long-term variability in precipitation correlate with brain size but explain low amounts of the observed variation. These associations are likely due to an indirect environmental influence on cognitive abilities and extinction probabilities. Most environmental factors that we test do not correspond with body and brain size evolution, pointing towards complex scenarios which underlie the evolution of key biological characteristics in later Homo.
Published:
July 8, 2021
Title:
Different environmental variables predict body and brain size evolution in Homo
Authors:
Will, Manuel; Krapp, Mario; Stock, Jay T.; Manica, Andrea
Abstract:
Increasing body and brain size constitutes a key macro-evolutionary pattern in the hominin lineage, yet the mechanisms behind these changes remain debated. Hypothesized drivers include environmental, demographic, social, dietary, and technological factors. Here we test the influence of environmental factors on the evolution of body and brain size in the genus Homo over the last one million years using a large fossil dataset combined with global paleoclimatic reconstructions and formalized hypotheses tested in a quantitative statistical framework. We identify temperature as a major predictor of body size variation within Homo, in accordance with Bergmann’s rule. In contrast, net primary productivity of environments and long-term variability in precipitation correlate with brain size but explain low amounts of the observed variation. These associations are likely due to an indirect environmental influence on cognitive abilities and extinction probabilities. Most environmental factors that we test do not correspond with body and brain size evolution, pointing towards complex scenarios which underlie the evolution of key biological characteristics in later Homo.
Published:
July 8, 2021
Title:
Association between ketosis and metabolic adaptation at the level of resting metabolic rate
Authors:
Martins, Catia; Roekenes, Jessica; Hunter, Gary R.; Gower, Barbara A.
Abstract:
BACKGROUND: The ketone body β-hydroxybutyrate (βHB) has been shown to act as a signaling molecule that regulates metabolism and energy homeostasis during starvation in animal models. A potential association between βHB and metabolic adaptation (a reduction in energy expenditure below predicted levels) in humans has never been explored. OBJECTIVE: To determine if metabolic adaptation at the level of resting metabolic rate (RMR) was associated with the magnitude of ketosis induced by a very-low energy diet (VLED). A secondary aim was to investigate if the association was modulated by sex. METHODS: Sixty-four individuals with obesity (BMI: 34.5 ± 3.4 kg/m2; age: 45.7 ± 8.0 years; 31 males) enrolled in a 1000 kcal/day diet for 8 weeks. Body weight/composition, RMR and βHB (as a measure of ketosis) were determined at baseline and week 9 (W9). Metabolic adaptation was defined as a significantly lower measured versus predicted RMR (from own regression model). RESULTS: Participants lost on average 14.0 ± 3.9 kg and were ketotic (βHB: 0.76 ± 0.51 mM) at W9. A significant metabolic adaptation was seen (-84 ± 106 kcal/day, P
Published:
July 6, 2021
Title:
A 51,000-year-old engraved bone reveals Neanderthals’ capacity for symbolic behaviour
Authors:
Leder, Dirk; Hermann, Raphael; Hüls, Matthias; Russo, Gabriele; Hoelzmann, Philipp; Nielbock, Ralf; Böhner, Utz; Lehmann, Jens; Meier, Michael; Schwalb, Antje; Tröller-Reimer, Andrea; Koddenberg, Tim; Terberger, Thomas
Abstract:
While there is substantial evidence for art and symbolic behaviour in early Homo sapiens across Africa and Eurasia, similar evidence connected to Neanderthals is sparse and often contested in scientific debates. Each new discovery is thus crucial for our understanding of Neanderthals’ cognitive capacity. Here we report on the discovery of an at least 51,000-year-old engraved giant deer phalanx found at the former cave entrance of Einhornhöhle, northern Germany. The find comes from an apparent Middle Palaeolithic context that is linked to Neanderthals. The engraved bone demonstrates that conceptual imagination, as a prerequisite to compose individual lines into a coherent design, was present in Neanderthals. Therefore, Neanderthal’s awareness of symbolic meaning is very likely. Our findings show that Neanderthals were capable of creating symbolic expressions before H. sapiens arrived in Central Europe.
Published:
July 5, 2021
Title:
A metabolomics comparison of plant-based meat and grass-fed meat indicates large nutritional differences despite comparable Nutrition Facts panels
Authors:
van Vliet, Stephan; Bain, James R.; Muehlbauer, Michael J.; Provenza, Frederick D.; Kronberg, Scott L.; Pieper, Carl F.; Huffman, Kim M.
Abstract:
A new generation of plant-based meat alternatives—formulated to mimic the taste and nutritional composition of red meat—have attracted considerable consumer interest, research attention, and media coverage. This has raised questions of whether plant-based meat alternatives represent proper nutritional replacements to animal meat. The goal of our study was to use untargeted metabolomics to provide an in-depth comparison of the metabolite profiles a popular plant-based meat alternative (n = 18) and grass-fed ground beef (n = 18) matched for serving size (113 g) and fat content (14 g). Despite apparent similarities based on Nutrition Facts panels, our metabolomics analysis found that metabolite abundances between the plant-based meat alternative and grass-fed ground beef differed by 90% (171 out of 190 profiled metabolites; false discovery rate adjusted p < 0.05). Several metabolites were found either exclusively (22 metabolites) or in greater quantities in beef (51 metabolites) (all, p < 0.05). Nutrients such as docosahexaenoic acid (ω-3), niacinamide (vitamin B3), glucosamine, hydroxyproline and the anti-oxidants allantoin, anserine, cysteamine, spermine, and squalene were amongst those only found in beef. Several other metabolites were found exclusively (31 metabolites) or in greater quantities (67 metabolites) in the plant-based meat alternative (all, p
Published:
July 5, 2021
Title:
Amino acid and nucleotide metabolism shape the selection of trophic levels in animals
Authors:
Yu, Rosemary; Wang, Hao; Nielsen, Jens
Abstract:
Abstract
What an animal eats determines its trophic level (TL) in the food web. The diet of high-TL animals is thought to contain more energy because it contains higher levels of lipids. This however has not been systematically examined in the context of comprehensive metabolic networks of different animals. Here, we reconstruct species-specific genome-scale metabolic models (GEMs) of 32 animals, and calculate the maximum ATP production per unit of food for each animal. Surprisingly, we find that ATP production is closely associated with metabolic flux through central carbon metabolism and amino acid metabolism, while correlation with lipid metabolism is low. Further, metabolism of specific amino acids and nucleotides underlie maximum ATP production from food. Our analyses indicate that amino acid and nucleotide metabolism, rather than lipid metabolism, are major contributors to the selection of animal trophic levels, demonstrating that species-level metabolic flux plays key roles in trophic interactions and evolution.
Published:
July 3, 2021
Title:
Amino acid and nucleotide metabolism shape the selection of trophic levels in animals
Authors:
Yu, Rosemary; Wang, Hao; Nielsen, Jens
Abstract:
What an animal eats determines its trophic level (TL) in the food web. The diet of high-TL animals is thought to contain more energy because it contains higher levels of lipids. This however has not been systematically examined in the context of comprehensive metabolic networks of different animals. Here, we reconstruct species-specific genome-scale metabolic models (GEMs) of 32 animals, and calculate the maximum ATP production per unit of food for each animal. Surprisingly, we find that ATP production is closely associated with metabolic flux through central carbon metabolism and amino acid metabolism, while correlation with lipid metabolism is low. Further, metabolism of specific amino acids and nucleotides underlie maximum ATP production from food. Our analyses indicate that amino acid and nucleotide metabolism, rather than lipid metabolism, are major contributors to the selection of animal trophic levels, demonstrating that species-level metabolic flux plays key roles in trophic interactions and evolution.
Published:
July 3, 2021
Title:
Amino acid and nucleotide metabolism shape the selection of trophic levels in animals
Authors:
Yu, Rosemary; Wang, Hao; Nielsen, Jens
Abstract:
What an animal eats determines its trophic level (TL) in the food web. The diet of high-TL animals is thought to contain more energy because it contains higher levels of lipids. This however has not been systematically examined in the context of comprehensive metabolic networks of different animals. Here, we reconstruct species-specific genome-scale metabolic models (GEMs) of 32 animals, and calculate the maximum ATP production per unit of food for each animal. Surprisingly, we find that ATP production is closely associated with metabolic flux through central carbon metabolism and amino acid metabolism, while correlation with lipid metabolism is low. Further, metabolism of specific amino acids and nucleotides underlie maximum ATP production from food. Our analyses indicate that amino acid and nucleotide metabolism, rather than lipid metabolism, are major contributors to the selection of animal trophic levels, demonstrating that species-level metabolic flux plays key roles in trophic interactions and evolution.
Published:
July 3, 2021
Title:
A Metabolic Intervention for Improving Human Cognitive Performance During Hypoxia
Authors:
Coleman, Kody; Phillips, Jeff; Sciarini, Michelle; Stubbs, Brianna; Jackson, Olivia; Kernagis, Dawn
Abstract:
BACKGROUND: During hypoxia an operators cognitive performance may decline. This decline is linked to altered brain metabolism, resulting in decreased adenosine triphosphate (ATP) production. Ketone bodies are an alternative substrate to glucose for brain metabolic requirements; previous studies have shown that the presence of elevated ketone bodies in the blood maintains brain ATP levels and reduces cerebral glycolysis during hypoxia. Thus, ketones may be a strategy to mitigate cognitive decline in hypoxia. Ketone ester (KE) consumption allows rapid elevation of blood ketone levels; therefore, we investigated the effects of consuming a KE drink on cognitive performance during hypoxia. Here, we report results of a pilot study.METHODS: There were 11 subjects who completed a cognitive performance test battery under conditions of normoxia and hypoxia following consumption of a KE drink and a placebo control drink.RESULTS: Significant hypoxia effects (O₂ saturation minimum was found to range between 63 and 88 in subjects) were found for blink duration (Ph2 0.665) and blink rate (Ph2 0.626), indicating that the hypoxia condition was associated with longer blink durations and lower blink rates. Significant hypoxia effects were likewise observed for a code substitution task (Ph2 0.487), indicating that performance on the task was significantly disrupted by the hypoxia stressor. KE consumption had a significant effect on blink duration (Ph2 0.270) and the code substitution task (Ph2 0.309).DISCUSSION: These finding suggest that some effects of acute hypoxia can be mitigated by nutritional ketosis.Coleman K, Phillips J, Sciarini M, Stubbs B, Jackson O, Kernagis D. A metabolic intervention for improving human cognitive performance during hypoxia. Aerosp Med Hum Perform. 2021; 92(7):556562.
Published:
July 1, 2021
Title:
Dietary evidence from Central Asian Neanderthals: A combined isotope and plant microremains approach at Chagyrskaya Cave (Altai, Russia)
Authors:
Salazar-García, Domingo C.; Power, Robert C.; Rudaya, Natalia; Kolobova, Ksenya; Markin, Sergey; Krivoshapkin, Andrey; Henry, Amanda G.; Richards, Michael P.; Viola, Bence
Abstract:
Neanderthals are known primarily from their habitation of Western Eurasia, but they also populated large expanses of Northern Asia for thousands of years. Owing to a sparse archaeological record, relatively little is known about these eastern Neanderthal populations. Unlike in their western range, there are limited zooarchaeological and paleobotanical studies that inform us about the nature of their subsistence. Here, we perform a combined analysis of carbon and nitrogen stable isotopes on bone collagen and microbotanical remains in dental calculus to reconstruct the diet of eastern Neanderthals at Chagyrskaya Cave in the Altai Mountains of Southern Siberia, Russia. Stable isotopes identify one individual as possessing a high trophic level due to the hunting of large- and medium-sized ungulates, while the analysis of dental calculus also indicates the presence of plants in the diet of this individual and others from the site. These findings indicate eastern Neanderthals may have had broadly similar subsistence patterns to those elsewhere in their range.
Published:
July 1, 2021
Title:
Dietary evidence from Central Asian Neanderthals: A combined isotope and plant microremains approach at Chagyrskaya Cave (Altai, Russia)
Authors:
Salazar-García, Domingo C.; Power, Robert C.; Rudaya, Natalia; Kolobova, Ksenya; Markin, Sergey; Krivoshapkin, Andrey; Henry, Amanda G.; Richards, Michael P.; Viola, Bence
Abstract:
Neanderthals are known primarily from their habitation of Western Eurasia, but they also populated large expanses of Northern Asia for thousands of years. Owing to a sparse archaeological record, relatively little is known about these eastern Neanderthal populations. Unlike in their western range, there are limited zooarchaeological and paleobotanical studies that inform us about the nature of their subsistence. Here, we perform a combined analysis of carbon and nitrogen stable isotopes on bone collagen and microbotanical remains in dental calculus to reconstruct the diet of eastern Neanderthals at Chagyrskaya Cave in the Altai Mountains of Southern Siberia, Russia. Stable isotopes identify one individual as possessing a high trophic level due to the hunting of large- and medium-sized ungulates, while the analysis of dental calculus also indicates the presence of plants in the diet of this individual and others from the site. These findings indicate eastern Neanderthals may have had broadly similar subsistence patterns to those elsewhere in their range.
Published:
July 1, 2021
Title:
Echocardiographic evaluation of the effect of poor blood glucose control on left ventricular function and ascending aorta elasticity
Authors:
Song, Xiang-Ting; Fan, Li; Yan, Zi-Ning; Rui, Yi-Fei
Abstract:
Background and aims Type 2 diabetes mellitus (T2DM) is associated with high cardiovascular risk. Preclinical left ventricular (LV) dysfunction and subclinical arterial stiffness have been documented in patients with T2DM. The aims of this study were to investigate whether there were any differences in LV function and ascending aorta elasticity between T2DM patients with controlled [defined as glycosylated hemoglobin (HbA1c)
Published:
July 1, 2021
Title:
Impact of the Swank and Wahls elimination dietary interventions on fatigue and quality of life in relapsing-remitting multiple sclerosis: The WAVES randomized parallel-arm clinical trial
Authors:
Wahls, Terry L; Titcomb, Tyler J; Bisht, Babita; Eyck, Patrick Ten; Rubenstein, Linda M; Carr, Lucas J; Darling, Warren G; Hoth, Karin F; Kamholz, John; Snetselaar, Linda G
Abstract:
ObjectiveTo compare the effect of the modified Paleolithic elimination (Wahls) and low-saturated fat (Swank) diets in relapsing-remitting MS (RRMS).MethodsIndividuals (n?=?87) with RRMS were randomized to the Swank or Wahls diets in a parallel group clinical trial consisting of four timepoints: 1) run-in, 2) baseline, 3) 12-weeks, and 4) 24-weeks.Results77 participants completed 12?weeks and 72 completed 24?weeks. The 12-week change from baseline in fatigue was -0.94?±?0.18 (FSS) and -9.87?±?1.93 (MFIS; both p?
Published:
July 1, 2021
Title:
Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer
Authors:
Luu, Maik; Riester, Zeno; Baldrich, Adrian; Reichardt, Nicole; Yuille, Samantha; Busetti, Alessandro; Klein, Matthias; Wempe, Anne; Leister, Hanna; Raifer, Hartmann; Picard, Felix; Muhammad, Khalid; Ohl, Kim; Romero, Rossana; Fischer, Florence; Bauer, Christian A.; Huber, Magdalena; Gress, Thomas M.; Lauth, Matthias; Danhof, Sophia; Bopp, Tobias; Nerreter, Thomas; Mulder, Imke E.; Steinhoff, Ulrich; Hudecek, Michael; Visekruna, Alexander
Abstract:
Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.
Published:
July 1, 2021
Title:
Polyunsaturated fatty acids, specialized pro-resolving mediators, and targeting inflammation resolution in the age of precision nutrition
Authors:
Al-Shaer, Abrar E.; Buddenbaum, Nicole; Shaikh, Saame Raza
Abstract:
Chronic inflammation contributes toward the pathogenesis of numerous diseases including, but not limited to, obesity, autoimmunity, cardiovascular diseases, and cancers. The discovery of specialized pro-resolving mediators (SPMs), which are critical for resolving inflammation, has commenced investigation into targeting pathways of inflammation resolution to improve physiological outcomes. SPMs are predominately synthesized from the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Therefore, one viable strategy to promote inflammation resolution would be to increase dietary intake of EPA/DHA, which are deficient in select populations. However, there are inconsistencies between the use of EPA/DHA as dietary or pharmacological supplements and improved inflammatory status. Herein, we review the literature on the relationship between the high n-6/n-3 PUFA ratio, downstream SPM biosynthesis, and inflammatory endpoints. We highlight key studies that have investigated how dietary intake of EPA/DHA increase tissue SPMs and their effects on inflammation. We also discuss the biochemical pathways by which EPA/DHA drive SPM biosynthesis and underscore mechanistic gaps in knowledge about these pathways which include a neglect for host genetics/ethnic differences in SPM metabolism, sexual dimorphism in SPM levels, and potential competition from select dietary n-6 PUFAs for enzymes of SPM synthesis. Altogether, establishing how dietary PUFAs control SPM biosynthesis in a genetic- and sex-dependent manner will drive new precision nutrition studies with EPA/DHA to prevent chronic inflammation in select populations.
Published:
July 1, 2021
Title:
Inhibition of cancer cells in culture. The effects of treatment with ketone bodies and/or rapamycin treatment
Authors:
Miller, Anna; Lin, Bo; Pincus, Matthew R.; Fine, Eugene J.; Feinman, Richard D.
Abstract:
Background: The potential for ketogenic diets or administration of exogenous ketone bodies to treat or prevent to cancer remains encouraging. Of particular interest is the possibility that, whatever the effect of a nutritional intervention alone, the diet might enhance the effect of existing cancer drugs, thereby requiring lower doses and a reduction in toxicity and side effects. Methods: SW480, a human cell line derived from colon, was treated with ketone bodies (sodium 3-hydroxy butyrate (common name, β-hydroxy butyrate) or with sodium acetoacetate in the presence or absence of rapamycin. Cells were incubated for 96 hours in DMEM with 10 mM glucose medium. HSF2617, a human epithelial fibroblast line served as control and cells were subjected to similar treatment as the SW480 cells. Cell proliferation and glucose consumption were determined with standard reagents. Results: The ketone bodies inhibited proliferation of SW480 cells in culture. Rapamycin also inhibited proliferation and its action was enhanced by the ketone bodies although there was little synergistic effect under these conditions. Human fibroblast controls were not inhibited by the ketone bodies. Both SW480 and control lines showed consumption of glucose during a 96 hour incubation period, suggesting that normal controls can switch to ketogenic metabolism while the cancer cells, which proliferate poorly, cannot. Results are consistent with recent reports of a mouse model showing the synergy of rapamycin and a ketogenic diet (Zou Y, et al. (2020) PLoS ONE 15 (5)) as well as earlier publications describing additive or synergistic effects of ketogenic diets with other modalities of cancer treatment. Conclusions: The results show that the growth of a cancer cell line in culture can be inhibited by the addition of ketone bodies or rapamycin to the growth medium. The combination of treatments was found to be additive, consistent with results from a previously published mouse model. The data demonstrate the potential for a strategy whereby doses of anti-cancer agents that have detrimental or toxic side-effects can be reduced if coupled to an appropriate source of ketone bodies.
Published:
June 28, 2021
Title:
Ketogenic diets and the nervous system: a scoping review of neurological outcomes from nutritional ketosis in animal studies
Authors:
Field, Rowena; Field, Tara; Pourkazemi, Fereshteh; Rooney, Kieron
Abstract:
OBJECTIVES: Ketogenic diets have reported efficacy for neurological dysfunctions; however, there are limited published human clinical trials elucidating the mechanisms by which nutritional ketosis produces therapeutic effects. The purpose of this present study was to investigate animal models that report variations in nervous system function by changing from a standard animal diet to a ketogenic diet, synthesise these into broad themes, and compare these with mechanisms reported as targets in pain neuroscience to inform human chronic pain trials. METHODS: An electronic search of seven databases was conducted in July 2020. Two independent reviewers screened studies for eligibility, and descriptive outcomes relating to nervous system function were extracted for a thematic analysis, then synthesised into broad themes. RESULTS: In total, 170 studies from eighteen different disease models were identified and grouped into fourteen broad themes: alterations in cellular energetics and metabolism, biochemical, cortical excitability, epigenetic regulation, mitochondrial function, neuroinflammation, neuroplasticity, neuroprotection, neurotransmitter function, nociception, redox balance, signalling pathways, synaptic transmission and vascular supply. DISCUSSION: The mechanisms presented centred around the reduction of inflammation and oxidative stress as well as a reduction in nervous system excitability. Given the multiple potential mechanisms presented, it is likely that many of these are involved synergistically and undergo adaptive processes within the human body, and controlled animal models that limit the investigation to a particular pathway in isolation may reach differing conclusions. Attention is required when translating this information to human chronic pain populations owing to the limitations outlined from the animal research.
Published:
June 28, 2021
Title:
A Middle Pleistocene Homo from Nesher Ramla, Israel
Authors:
Hershkovitz, Israel; May, Hila; Sarig, Rachel; Pokhojaev, Ariel; Grimaud-Hervé, Dominique; Bruner, Emiliano; Fornai, Cinzia; Quam, Rolf; Arsuaga, Juan Luis; Krenn, Viktoria A.; Martinón-Torres, Maria; Castro, José María Bermúdez de; Martín-Francés, Laura; Slon, Viviane; Albessard-Ball, Lou; Vialet, Amélie; Schüler, Tim; Manzi, Giorgio; Profico, Antonio; Vincenzo, Fabio Di; Weber, Gerhard W.; Zaidner, Yossi
Abstract:
It has long been believed that Neanderthals originated and flourished on the European continent. However, recent morphological and genetic studies have suggested that they may have received a genetic contribution from a yet unknown non-European group. Here we report on the recent discovery of archaic Homo fossils from the site of Nesher Ramla, Israel, which we dated to 140,000 to 120,000 years ago. Comprehensive qualitative and quantitative analyses of the parietal bones, mandible, and lower second molar revealed that this Homo group presents a distinctive combination of Neanderthal and archaic features. We suggest that these specimens represent the late survivors of a Levantine Middle Pleistocene paleodeme that was most likely involved in the evolution of the Middle Pleistocene Homo in Europe and East Asia.
Published:
June 25, 2021
Title:
Middle Pleistocene Homo behavior and culture at 140,000 to 120,000 years ago and interactions with Homo sapiens
Authors:
Zaidner, Yossi; Centi, Laura; Prévost, Marion; Mercier, Norbert; Falguères, Christophe; Guérin, Gilles; Valladas, Hélène; Richard, Maïlys; Galy, Asmodée; Pécheyran, Christophe; Tombret, Olivier; Pons-Branchu, Edwige; Porat, Naomi; Shahack-Gross, Ruth; Friesem, David E.; Yeshurun, Reuven; Turgeman-Yaffe, Zohar; Frumkin, Amos; Herzlinger, Gadi; Ekshtain, Ravid; Shemer, Maayan; Varoner, Oz; Sarig, Rachel; May, Hila; Hershkovitz, Israel
Abstract:
Fossils of a Middle Pleistocene (MP) Homo within a well-defined archaeological context at the open-air site of Nesher Ramla, Israel, shed light on MP Homo culture and behavior. Radiometric ages, along with cultural and stratigraphic considerations, suggest that the fossils are 140,000 to 120,000 years old, chronologically overlapping with H. sapiens in western Asia. Lithic analysis reveals that MP Homo mastered stone-tool production technologies, previously known only among H. sapiens and Neanderthals. The Levallois knapping methods they used are indistinguishable from that of concurrent H. sapiens in western Asia. The most parsimonious explanation for such a close similarity is the cultural interactions between these two populations. These findings constitute evidence of contacts and interactions between H. sapiens and MP Homo.
Published:
June 25, 2021
Title:
Effect of 2-year caloric restriction on organ and tissue size in nonobese 21- to 50-year-old adults in a randomized clinical trial: the CALERIE study
Authors:
Shen, Wei; Chen, Jun; Zhou, Jane; Martin, Corby K; Ravussin, Eric; Redman, Leanne M
Abstract:
Sustained calorie restriction (CR) promises to extend the lifespan. The effect of CR on changes in body mass across tissues and organs is unclear.We used whole-body MRI to evaluate the effect of 2 y of CR on changes in body composition.In an ancillary study of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, 43 healthy adults [25–50 y; BMI (kg/m2): 22–28] randomly assigned to 25% CR (n = 28) or ad libitum (AL) eating (n = 15) underwent whole-body MRI at baseline and month 24 to measure adipose tissue in subcutaneous, visceral, and intermuscular depots (SAT, VAT, and IMAT, respectively); skeletal muscle; and organs including brain, liver, spleen, and kidneys but not heart.The CR group lost more adipose tissue and lean tissue than controls (P < 0.05). In the CR group, at baseline, total tissue volume comprised 32.1%, 1.9%, and 1.0% of SAT, VAT, and IMAT, respectively. The loss of total tissue volume over 24 mo comprised 68.4%, 7.4%, and 2.2% of SAT, VAT, and IMAT, respectively, demonstrating preferential loss of fat vs. lean tissue. Although there is more muscle loss in CR than AL (P < 0.05), the loss of muscle over 24 mo in the CR group comprised only 17.2% of the loss of total tissue volume. Changes in organ volumes were not different between CR and AL. The degree of CR (% decrease in energy intake vs. baseline) significantly (P < 0.05) affected changes in VAT, IMAT, muscle, and liver volume (standardized regression coefficient ± standard error of estimates: 0.43 ± 0.15 L, 0.40 ± 0.19 L, 0.55 ± 0.17 L, and 0.45 ± 0.18 L, respectively).Twenty-four months of CR (intended, 25%; actual, 13.7%) in young individuals without obesity had effects on body composition, including a preferential loss of adipose tissue, especially VAT, over the loss of muscle and organ tissue. This trial was registered at www.clinicaltrials.gov as NCT02695511.
Published:
June 22, 2021
Title:
Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
Authors:
Ryu, Seungjin; Shchukina, Irina; Youm, Yun-Hee; Qing, Hua; Hilliard, Brandon; Dlugos, Tamara; Zhang, Xinbo; Yasumoto, Yuki; Booth, Carmen J; Fernández-Hernando, Carlos; Suárez, Yajaira; Khanna, Kamal; Horvath, Tamas L; Dietrich, Marcelo O; Artyomov, Maxim N; Wang, Andrew; Dixit, Vishwa Deep
Abstract:
Increasing age is the strongest predictor of risk of COVID-19 severity and mortality. Immunometabolic switch from glycolysis to ketolysis protects against inflammatory damage and influenza infection in adults. To investigate how age compromises defense against coronavirus infection, and whether a pro-longevity ketogenic-diet (KD) impacts immune-surveillance, we developed an aging model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain-A59 (MHV-A59). When inoculated intranasally, mCoV is pneumotropic and recapitulates several clinical hallmarks of COVID-19 infection. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective γδ T cells, deactivates the NLRP3 inflammasome and decreases pathogenic monocytes in lungs of infected aged mice. These data establish harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against coronavirus infection in the aged.
Published:
June 21, 2021
Title:
Types of carbohydrate intake and breast cancer survival
Authors:
Farvid, Maryam S.; Barnett, Junaidah B.; Spence, Nicholas D.; Rosner, Bernard A.; Holmes, Michelle D.
Abstract:
OBJECTIVE: To investigate the associations of different types of carbohydrate intake after breast cancer diagnosis with breast cancer-specific and all-cause mortality. METHODS: We prospectively assessed post-diagnostic intake of total sugar, added sugar, and natural sugar as well as carbohydrate from different sources, among 8932 women with stage I-III breast cancer that were identified in the Nurses' Health Study from 1980 to 2010 and Nurses' Health Study II from 1991 to 2011. Participants completed a validated food frequency questionnaire every four years after diagnosis and were followed up for death. RESULTS: We prospectively documented 1071 deaths due to breast cancer and 2532 all-cause deaths, over a mean of 11.5 years of follow-up. After adjustment for confounding variables, greater post-diagnostic total sugar intake was suggestively associated with greater risk of breast cancer-specific mortality [hazard ratio (HR)Q5vsQ1 = 1.16, 95% confidence interval (CI ) = 0.95-1.41; Ptrend = 0.02] and significantly associated with greater risk of all-cause mortality (HRQ5vsQ1 = 1.23, 95% CI = 1.08-1.41; Ptrend = 0.0001). Greater post-diagnostic added sugar intake was significantly associated with greater risk of all-cause mortality (HRQ5vsQ1 = 1.20, 95% CI = 1.06-1.36; Ptrend = 0.001). Post-diagnostic natural sugar (occurring in foods and not added as an ingredient) intake was not associated with mortality risk. Greater post-diagnostic fructose intake was significantly associated with greater risk of breast cancer-specific mortality (HRQ5vsQ1 = 1.34, 95% CI = 1.10-1.64; Ptrend = 0.005) and all-cause mortality (HRQ5vsQ1 = 1.16, 95% CI = 1.02-1.32; Ptrend = 0.01). High post-diagnostic intake of sucrose was associated with higher risk of breast cancer-specific and all-cause mortality. Increased post-diagnostic intake of carbohydrate from fruit juice was significantly associated with higher risk of breast cancer-specific and all-cause mortality and carbohydrate from vegetables was significantly associated with lower risk of all-cause mortality. High post-diagnostic intake of carbohydrate from potatoes was suggestively associated with higher risk of breast cancer-specific mortality and carbohydrate from refined grains was suggestively associated with higher risk of all-cause mortality. CONCLUSIONS: We found that higher total sugar intake, especially added sugar, sucrose, and fructose, as well as carbohydrate from fruit juice after a breast cancer diagnosis were associated with poorer prognosis. High post-diagnostic intake of carbohydrate from vegetables was associated with reduced risk of mortality.
Published:
June 21, 2021
Title:
Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming
Authors:
Hirschberger, Simon; Strauß, Gabriele; Effinger, David; Marstaller, Xaver; Ferstl, Alicia; Müller, Martin B; Wu, Tingting; Hübner, Max; Rahmel, Tim; Mascolo, Hannah; Exner, Nicole; Heß, Julia; Kreth, Friedrich W; Unger, Kristian; Kreth, Simone
Abstract:
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.
Published:
June 21, 2021
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