Characterizing the metabolic phenotype of intestinal villus blunting in Zambian children with severe acute malnutrition and persistent diarrhea

Background: Environmental enteric dysfunction (EED) is widespread throughout the tropics and in children is associated with stunting and other adverse health outcomes. One of the hallmarks of EED is villus damage. In children with severe acute malnutrition (SAM) the severity of enteropathy is greater and short term mortality is high, but the metabolic consequences of enteropathy are unknown. Here, we characterize the urinary metabolic alterations associated with villus health, classic enteropathy biomarkers and anthropometric measurements in severely malnourished children in Zambia. Methods/Principal findings: We analysed 20 hospitalised children with acute malnutrition aged 6 to 23 months in Zambia. Small intestinal biopsies were assessed histologically (n = 15), anthropometric and gut function measurements were collected and the metabolic phenotypes were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy. Endoscopy could not be performed on community controls children. Growth parameters were inversely correlated with enteropathy biomarkers (p = 0.011) and parameters of villus health were inversely correlated with translocation and permeability biomarkers (p = 0.000 and p = 0.015). Shorter villus height was associated with reduced abundance of metabolites related to gut microbial metabolism, energy and muscle metabolism (p = 0.034). Villus blunting was also related to increased sucrose excretion (p = 0.013). Conclusions/Significance: Intestinal villus blunting is associated with several metabolic perturbations in hospitalized children with severe undernutrition. Such alterations include altered muscle metabolism, reinforcing the link between EED and growth faltering, and a disruption in the biochemical exchange between the gut microbiota and host. These findings extend our understanding on the downstream consequences of villus blunting and provide novel non-invasive biomarkers of enteropathy dysfunction. The major limitations of this study are the lack of comparative control group and gut microbiota characterization

Association between urinary metabolic profile and the intestinal effects of cocoa in rats

The aim of this study was to elucidate the relationship between the urinary metabolic fingerprint and the effects of cocoa and cocoa fibre on body weight, hormone metabolism, intestinal immunity and microbiota composition. To this effect, Wistar rats were fed, for 3 weeks, a diet containing 10 % cocoa (C10) or two other diets with same the proportion of fibres: one based on cocoa fibre (CF) and another containing inulin as a reference (REF) diet. The rats' 24 h urine samples were analysed by an untargeted 1H NMR spectroscopy-based metabonomic approach. Concentrations of faecal IgA and plasma metabolic hormones were also quantified. The C10 diet decreased the intestinal IgA, plasma glucagon-like peptide-1 and glucagon concentrations and increased ghrelin levels compared with those in the REF group. Clear differences were observed between the metabolic profiles from the C10 group and those from the CF group. Urine metabolites derived from cocoa correlated with the cocoa effects on body weight, immunity and the gut microbiota. Overall, cocoa intake alters the host and bacterial metabolism concerning energy and amino acid pathways, leading to a metabolic signature that can be used as a marker for consumption. This metabolic profile correlates with body weight, metabolic hormones, intestinal immunity and microbiota composition.</p

Association between urinary metabolic profile and the intestinal effects of cocoa in rats

The aim of this study was to elucidate the relationship between the urinary metabolic fingerprint and the effects of cocoa and cocoa fibre on body weight, hormone metabolism, intestinal immunity and microbiota composition. To this effect, Wistar rats were fed, for 3 weeks, a diet containing 10% cocoa (C10) or two other diets with same the proportion of fibres: one based on cocoa fibre (CF) and another containing inulin as a reference (REF) diet. The rats' 24 h urine samples were analysed by an untargeted 1H NMR spectroscopy-based metabonomic approach. Concentrations of faecal IgA and plasma metabolic hormones were also quantified. The C10 diet decreased the intestinal IgA, plasma glucagon-like peptide-1 and glucagon concentrations and increased ghrelin levels compared with those in the REF group. Clear differences were observed between the metabolic profiles from the C10 group and those from the CF group. Urine metabolites derived from cocoa correlated with the cocoa effects on body weight, immunity and the gut microbiota. Overall, cocoa intake alters the host and bacterial metabolism concerning energy and amino acid pathways, leading to a metabolic signature that can be used as a marker for consumption. This metabolic profile correlates with body weight, metabolic hormones, intestinal immunity and microbiota composition

Tryptophan, glutamine, leucine, and micronutrient supplementation improves environmental enteropathy in Zambian adults: a randomized controlled trial.

BACKGROUND: Environmental enteropathy (EE) refers to villus blunting, reduced absorption, and microbial translocation in children and adults in tropical or deprived residential areas. In previous work we observed an effect of micronutrients on villus height (VH). OBJECTIVE: We aimed to determine, in a randomized controlled trial, if amino acid (AA) or multiple micronutrient (MM) supplementation can improve intestinal structure or barrier dysfunction in Zambian adults with EE. METHODS: AA (tryptophan, leucine, and glutamine) and/or MM supplements were given for 16 wk in a 2 × 2 factorial comparison against placebo. Primary outcomes were changes in VH, in vivo small intestinal barrier dysfunction assessed by confocal laser endomicroscopy (CLE), and mechanistic (or mammalian) target of rapamycin complex 1 (MTORC1) nutrient responsiveness in lamina propria CD4+ lymphocytes. RESULTS: Over 16 wk AA, but not MM, supplementation increased VH by 16% (34.5 μm) compared with placebo (P = 0.04). Fluorescein leak, measured by CLE, improved only in those allocated to both AA and MM supplementation. No effect was seen on MTORC1 activation, but posttreatment MTORC1 and VH were correlated (ρ = 0.51; P = 0.001), and change in MTORC1 was correlated with change in VH in the placebo group (ρ = 0.63; P = 0.03). In secondary analyses no effect was observed on biomarkers of microbial translocation. Metabolomic analyses suggest alterations in a number of microbial- and host-derived metabolites including the leucine metabolite β-hydroxy-β-methylbutyrate, which was increased by AA supplementation and correlated with VH. CONCLUSIONS: In this phase 2 trial, AA supplementation protected against a decline in VH over the supplementation period, and improved barrier function when combined with micronutrients. Leucine and MTORC1 metabolism may be involved in the mechanism of effect. This trial was registered at www.pactr.org as PACTR201505001104412

Microbiota alterations in proline metabolism impact depression

Aminoàcids; Depressió; MicrobiotaAminoácidos; Depresión; MicrobiotaAmino acids; Depression; MicrobiotaThe microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not addressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including patients with mild depression. Microbial functions and metabolites converging onto glutamate/GABA metabolism, particularly proline, were linked to depression. High proline consumption was the dietary factor with the strongest impact on depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotionally impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related prefrontal cortex genes. RNAi-mediated knockdown of proline and GABA transporters in Drosophila and mono-association with L. plantarum, a high GABA producer, conferred protection against depression-like states. Targeting the microbiome and dietary proline may open new windows for efficient depression treatment.This work was partially supported by Instituto de Salud Carlos III (Madrid, Spain) through the research grants PI15/01934, PI18/01022, and PI21/01361 to J.M.F.-R. and PI20/01090 (co-funded by the European Regional Development Fund. “A way to make Europe”) to J.M.-P.; the Catalan Government (AGAUR, #SGR2017-0734, ICREA Academia Award 2021) to J.M.F.-R.; the Spanish Ministry of Science, Innovation and Universities (PID2019-105969GB-I00); Generalitat Valenciana (Prometeo/2018/133), Spain; and Fondo Europeo de Desarrollo Regional (FEDER) funds to A.M. This work was also supported by the European Commission (FP7, NeuroPain #2013-602891); the Catalan Government (AGAUR, #SGR2017-669, ICREA Academia Award 2020) to R.M.; the Spanish Instituto de Salud Carlos III (RTA, #RD16/0017/0020) to R.M.; Ministry of Science and Innovation and State Research Agency (#PID2020- 120029GB-I00/MICIN/AEI/10.13039/501100011033) to R.M.; the European Regional Development Fund (project no. 01.2.2-LMT-K-718-02-0014) under grant agreement with the Research Council of Lithuania (LMTLT); and the Project ThinkGut (EFA345/19), 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra program (POCTEFA, 2014–2020). We also acknowledge funding from the Spanish Ministry of Science, Innovation and Universities (RTI2018-099200-B-I00) and the Generalitat of Catalonia (Agency for Management of University and Research Grants [2017SGR696] and Department of Health [SLT002/16/00250]) to R.P. M.A.-R. is funded by Instituto de Salud Carlos III, Río Hortega (CM19/00190). J.M.-P. is funded by a Miguel Servet contract (CP18/00009) from the Instituto de Salud Carlos III. J.S. is funded by a predoctoral PERIS contract (SLT002/16/00250) from the Catalan Government. M.J. is a professor under “Serra Hunter” program (Generalitat de Catalunya)

The APOA1BP-SREBF-NOTCH axis is associated with reduced atherosclerosis risk in morbidly obese patients

Background and Aims: Atherosclerosis is characterized by an inflammatory disease linked to excessive lipid accumulation in the artery wall. The Notch signalling pathway has been shown to play a key regulatory role in the regulation of inflammation. Recently, in vitro and pre-clinical studies have shown that apolipoprotein A-I binding protein (AIBP) regulates cholesterol metabolism (SREBP) and NOTCH signalling (haematopoiesis) and may be protective against atherosclerosis, but the evidence in humans is scarce. Methods: We evaluated the APOA1BP-SREBF-NOTCH axis in association with atherosclerosis in two well-characterized cohorts of morbidly obese patients (n = 78) within the FLORINASH study, including liver transcriptomics, 1H-NMR plasma metabolomics, high-resolution ultrasonography evaluating carotid intima-media thickness (cIMT), and haematological parameters. Results: The liver expression levels of APOA1BP were associated with lower cIMT and leukocyte counts, a better plasma lipid profile and higher circulating levels of metabolites associated with lower risk of atherosclerosis (glycine, histidine and asparagine). Conversely, liver SREBF and NOTCH mRNAs were positively associated with atherosclerosis, liver steatosis, an unfavourable lipid profile, higher leukocytes and increased levels of metabolites linked to inflammation and CVD such as branched-chain amino acids and glycoproteins. APOA1BP and NOTCH signalling also had a strong association, as revealed by the negative correlations among APOA1BP expression levels and those of all NOTCH receptors and jagged ligands. Conclusions: We here provide the first evidence in human liver of the putative APOA1BP-SREBF-NOTCH axis signalling pathway and its association with atherosclerosis and inflammation

Immunomodulatory and Prebiotic Effects of 2'-Fucosyllactose in Suckling Rats

Human milk oligosaccharides are unconjugated complex glycans present in high concentration in human milk that serve as pre-biotics and immunomodulators. They are not primarily absorbed or metabolized by the infant and reach the lower part of the intestinal tract unaltered. One of the main oligosaccharides found in human milk is 2'-fucosyllactose (2'-FL). This study aimed to investigate the effects of daily oral administration of 2'-FL in healthy suckling rats. From days 2 to 16 of life, rats were daily given the oligosaccharide (2'-FL) or vehicle (REF), weighed and their stool characteristics were assessed. On days 8 and 16 of life the morphometry, intestinal architecture, and cytokine release, mesenteric lymph nodes cell composition, plasma immunoglobulin concentrations, fecal microbiota composition, cecal short-chain fatty acids content, and the urinary metabolic profile were assessed. Animals given 2'-FL showed higher plasma IgG and IgA and more T cell subsets in the mesenteric lymph nodes on day 16. Moreover, at intestinal level, villus heights, and areas were increased on day 8. Cecal samples displayed a higher Lactobacillus proportion and a different urinary metabolic profile was observed on day 8, and a higher proportion of butyrate on day 16. In conclusion, supplementation of 2'-FL in early life has a pre-biotic and intestinal trophic effect and promotes maturation of the immune system

Relation between plasma antioxidant vitamin levels, adiposity and cardio-metabolic profile in adolescents: Effects of a multidisciplinary obesity programme

Background & aims In vivo and in vitro evidence suggests that antioxidant vitamins and carotenoids may be key factors in the treatment and prevention of obesity and obesity-associated disorders. Hence, the objective of the present study was to determine the relationship between plasma lipid-soluble antioxidant vitamin and carotenoid levels and adiposity and cardio-metabolic risk markers in overweight and obese adolescents participating in a multidisciplinary weight loss programme. Methods A therapeutic programme was conducted with 103 adolescents aged 12–17 years old and diagnosed with overweight or obesity. Plasma concentrations of a-tocopherol, retinol, ß-carotene and lycopene, anthropometric indicators of general and central adiposity, blood pressure and biochemical parameters were analysed at baseline and at 2 and 6 months of treatment. Results Lipid-corrected retinol (P < 0.05), ß-carotene (P = 0.001) and a-tocopherol (P < 0.001) plasma levels increased significantly, whereas lipid-corrected lycopene levels remained unaltered during the treatment. Anthropometric indicators of adiposity (P < 0.001), blood pressure (P < 0.01) and biochemical parameters (P < 0.05) decreased significantly, whereas fat free mass increased significantly (P < 0.001). These clinical and biochemical improvements were related to changes in plasma lipid-corrected antioxidant vitamin and carotenoid levels. The adolescents who experienced the greatest weight loss also showed the largest decrease in anthropometric indicators of adiposity and biochemical parameters and the highest increase in fat free mass. Weight loss in these adolescents was related to an increase in plasma levels of lipid-corrected a-tocopherol (P = 0.001), ß-carotene (P = 0.034) and lycopene (P = 0.019). Conclusions Plasma lipid-soluble antioxidant vitamin and carotenoid levels are associated with reduced adiposity, greater weight loss and an improved cardio-metabolic profile in overweight and obese adolescents

Subjects with detectable Saccharomyces cerevisiae in the gut microbiota show deficits in attention and executive function

This work was partially supported by research grants FIS (PI15/01934 and PI18/01022) from the Instituto de Salud Carlos III from Spain, SAF2015-65878-R and RTI2018-099200-B-I00 from the Ministerio de Economía y Competitividad, Prometeo/2018/A/133 from Generalitat Valenciana, Spain, and also by Fondo Europeo de Desarrollo Regional (FEDER) funds, European Commission (FP7, NeuroPain #2013-602891), the Generalitat of Catalunya (AGAUR, #SGR2017-669, #SGR2017-696, Department of Health SLT002/16/00250; ICREA Academia Award 2015), the Instituto de Salud Carlos III from Spain (RTA, #RD16/0017/0020) and the Fondo Europeo de Desarrollo Regional (No. 01.2.2-LMT-K-718-02-0014); and by Project ThinkGut (EFA345/19), 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra programme (POCTEFA 2014-2020). María Arnoriaga-Rodríguez is funded by Instituto de Salud Calos III, Río Hortega (CP19/00190). Jordi Mayneris-Perxachs is funded by the Miguel Servet Program from the Instituto de Salud Carlos III (ISCIII CP18/00009), co-funded by the European Social Fund “Investing in your future”. Mariona Jové is a professor under the Serra Hunter programme (Generalitat de Catalunya).Peer reviewe