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IntroductionChild malnutrition (undernutrition) and adult non-communicable diseases (NCDs) are major global public health problems. While convincing evidence links prenatal malnutrition with increased risk of NCDs, less is known about the long-term sequelae of malnutrition in childhood. We therefore examined evidence of associations between postnatal malnutrition, encompassing documented severe childhood malnutrition in low/middle-income countries (LMICs) or famine exposure, and later-life cardiometabolic NCDs.MethodsOur peer-reviewed search strategy focused on ‘severe childhood malnutrition’, ‘LMICs’, ‘famine’, and ‘cardiometabolic NCDs’ to identify studies in Medline, Embase, Global Health, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. We synthesised results narratively and assessed study quality with the UK National Institute for Health and Care Excellence checklist.ResultsWe identified 57 studies of cardiometabolic NCD outcomes in survivors of documented severe childhood malnutrition in LMICs (n=14) and historical famines (n=43). Exposure to severe malnutrition or famine in childhood was consistently associated with increased risk of cardiovascular disease (7/8 studies), hypertension (8/11), impaired glucose metabolism (15/24) and metabolic syndrome (6/6) in later life. Evidence for effects on lipid metabolism (6/11 null, 5/11 mixed findings), obesity (3/13 null, 5/13 increased risk, 5/13 decreased risk) and other outcomes was less consistent. Sex-specific differences were observed in some cohorts, with women consistently at higher risk of glucose metabolism disorders and metabolic syndrome.ConclusionSevere malnutrition or famine during childhood is associated with increased risk of cardiometabolic NCDs, suggesting that developmental plasticity extends beyond prenatal life. Severe malnutrition in childhood thus has serious implications not only for acute morbidity and mortality but also for survivors’ long-term health. Heterogeneity across studies, confounding by prenatal malnutrition, and age effects in famine studies preclude firm conclusions on causality. Research to improve understanding of mechanisms linking postnatal malnutrition and NCDs is needed to inform policy and programming to improve the lifelong health of severe malnutrition survivors.

In this paper, the stability of the plasma metabolome at −20 °C for up to 30 days was evaluated using liquid chromatography-high resolution mass spectrometric metabolomics analysis. To follow the time-series deterioration of the plasma metabolome, the use of an elastic net regularized regression model for the prediction of storage time at −20 °C based on the plasma metabolomic profile, and the selection and ranking of metabolites with high temporal changes was demonstrated using the glmnet package in R. Out of 1229 (positive mode) and 1483 (negative mode) metabolite features, the elastic net model extracted 32 metabolites of interest in both positive and negative modes. L-gamma-glutamyl-L-(iso)leucine (tentative identification) was found to have the highest time-dependent change and significantly increased proportionally to the storage time of plasma at −20 °C (R 2  = 0.6378 [positive mode], R 2  = 0.7893 [negative mode], p-value < 0.00001). Based on the temporal profiles of the extracted metabolites by the model, results show only minimal deterioration of the plasma metabolome at −20 °C up to 1 month. However, majority of the changes appeared at around 12–15 days of storage. This allows scientists to better plan logistics and storage strategies for samples obtained from low-resource settings, where −80 °C storage is not guaranteed.

Mortality in children with severe malnutrition is strongly related to signs of metabolic dysfunction, such as hypoglycemia. Lower circulating tryptophan levels in children with severe malnutrition suggest a possible disturbance in the tryptophan-nicotinamide adenine dinucleotide (TRP-NAD+) pathway and subsequently in NAD+  dependent metabolism regulator sirtuin1 (SIRT1). Here we show that severe malnutrition in weanling mice, induced by 2-weeks of low protein diet feeding from weaning, leads to an impaired TRP-NAD+  pathway with decreased NAD+ levels and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAD+  pathway with NAD+  precursors improves hepatic mitochondrial and overall metabolic function through SIRT1 modulation. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAD+  pathway can improve liver metabolic function in a mouse model of severe malnutrition. These results could lead to the development of new interventions for children with severe malnutrition. Impaired liver metabolic function is related to mortality in severely malnourished children. Here the authors report a role for the tryptophan-NAD + pathway in reduced hepatic mitochondrial function and liver steatosis in a mouse model of severe malnutrition.

Background Caffeic acid (CA) and its derivative, chlorogenic acid (CGA), have shown promise in preventing and alleviating fatty liver disease. CA, compared to CGA, has much lower production costs and higher bioavailability, making it a potentially superior feed additive. However, the efficacy, mechanistic differences, and comparative impacts of CA and CGA on fatty liver disease in laying hens remain unclear. This study aimed to evaluate and compare the effects of CA and CGA on production performance, egg quality, and fatty liver disease in laying hens. Results A total of 1,440 61-week-old Hyline Brown laying hens were randomly divided into 8 groups and fed diets supplemented with basal diet, 25, 50, 100 and 200 mg/kg of CA, and 100, 200 and 400 mg/kg of CGA (CON, CA25, CA50, CA100, CA200, CGA100, CGA200 and CGA400, respectively) for 12 weeks. Both CA and CGA improved production performance and egg quality, while reducing markers of hepatic damage and lipid accumulation. CA and CGA significantly decreased TG, TC, and LDL-C levels and increased T-SOD activity. Transcriptomic and proteomic analyses revealed that CA and CGA reduced hepatic lipid accumulation through downregulation of lipid biosynthesis-related genes ( ACLY , ACACA , FASN , and SCD1 ) and enhanced lipid transport and oxidation genes ( FABPs , CD36 , CPT1A , ACOX1 , and SCP2 ). Of note, low-dose CA25 exhibited equivalent efficacy to the higher dose CGA100 group in alleviating fatty liver conditions. Mechanistically, CA and CGA alleviated lipid accumulation via activation of the ADPN-AMPK-PPARα signaling pathway. Conclusions This study demonstrates that dietary CA and CGA effectively improve laying performance, egg quality, and hepatic lipid metabolism in laying hens, with CA potentially being more economical and efficient. Transcriptomic and proteomic evidence highlight shared mechanisms between CA25 and CGA100. These findings provide a foundation for CA and CGA as therapeutic agents for fatty liver disease and related metabolic diseases in hens, and also offer insights into the targeted modification of CGA (including the isomer of CGA) into CA, thereby providing novel strategies for the efficient utilization of CGA. Graphical Abstract Highlights (1) Dietary CA and CGA improve fatty liver, laying performance and egg quality. (2) Lower dose of CA25 achieves the equivalent improvement as CGA100 or CGA200. (3) CA and CGA mediate the ADPN-AMPK-PPARα pathway to alleviate fatty liver.

Despite advances in gut health research, the variability of important gut markers within individuals over time remains underexplored. We investigated the intra-individual variation of various faecal gut health markers using an optimised processing protocol aimed at reducing variability. Faecal samples from ten healthy adults over three consecutive days demonstrated marker-specific intra-individual coefficients of variation (CV%), namely: stool consistency (16.5%), water content (5.7%), pH (3.9%), total SCFAs (17.2%), total BCFAs (27.4%), total bacteria and fungi copies (40.6% and 66.7%), calprotectin and myeloperoxidase (63.8% and 106.5%), and untargeted metabolites (on average 40%). For thirteen microbiota genera, including Bifidobacterium and Akkermansia , variability exceeded 30%, whereas microbiota diversity was less variable (Phylogenetic Diversity 3.3%, Inverse Simpson 17.2%). Mill-homogenisation of frozen faeces significantly reduced the replicates CV% for total SCFAs (20.4–7.5%) and total BCFAs (15.9–7.8%), and untargeted metabolites compared to faecal hammering only, without altering mean concentrations. Our results show the potential need for repeated sampling to accurately represent specific gut health markers. We also demonstrated the effectiveness of optimised preprocessing of human stool samples in reducing overall analytical variability.

In sub-Saharan Africa, children with severe malnutrition (SM) and HIV have substantially worse outcomes than children with SM alone, facing higher mortality risk and impaired nutritional recovery post-hospitalisation. Biological mechanisms underpinning this risk remain incompletely understood. This case-control study nested within the CHAIN cohort in Kenya, Uganda, Malawi, and Burkina Faso examined effect of HIV on six months post-discharge growth among children with SM and those at risk of malnutrition, assessed proteomic signatures associated with HIV in these children, and investigated how these systemic processes impact post-discharge growth in children with SM. Using SomaScan TM assay, 7335 human plasma proteins were quantified. Linear mixed models identified HIV-associated biological processes and their associations with post-discharge growth. Using structural equation modelling, we examined directed paths explaining how HIV influences post-discharge growth. Here, we show that at baseline, HIV is associated with lower anthropometry. Additionally, HIV is associated with protein profiles indicating increased complement activation and decreased insulin-like growth factor signalling and bone mineralisation. HIV indirectly affects post-discharge growth by influencing baseline anthropometry and modulating proteins involved in bone mineralisation and humoral immune responses. These findings suggest specific biological pathways linking HIV to poor growth, offering insights for targeted interventions in this vulnerable population. Here the authors show in a case-control study with more than 800 children that HIV indirectly affects early post-discharge growth in children recovering from severe malnutrition by impacting baseline anthropometry and altering proteins key to bone mineralisation, growth signalling, and humoral immune response.

Crohn's disease is a pathological condition of the gastro-intestinal tract, causing severe transmural inflammation in the ileum and/or colon. Cigarette smoking is one of the best known environmental risk factors for the development of Crohn's disease. Nevertheless, very little is known about the effect of prolonged cigarette smoke exposure on inflammatory modulators in the gut. We examined the effect of cigarette smoke on cytokine profiles in the healthy and inflamed gut of human subjects and in the trinitrobenzene sulphonic acid mouse model, which mimics distal Crohn-like colitis. In addition, the effect of cigarette smoke on epithelial expression of transient receptor potential channels and their concurrent increase with cigarette smoke-augmented cytokine production was investigated. Active smoking was associated with increased IL-8 transcription in ileum of controls (p < 0,001; n = 18-20/group). In the ileum, TRPV1 mRNA levels were decreased in never smoking Crohn's disease patients compared to healthy subjects (p <0,001; n = 20/group). In the colon, TRPV1 mRNA levels were decreased (p = 0,046) in smoking healthy controls (n = 20/group). Likewise, healthy mice chronically exposed to cigarette smoke (n = 10/group) showed elevated ileal Cxcl2 (p = 0,0075) and colonic Kc mRNA levels (p = 0,0186), whereas TRPV1 mRNA and protein levels were elevated in the ileum (p = 0,0315). Although cigarette smoke exposure prior to trinitrobenzene sulphonic acid administration did not alter disease activity, increased pro-inflammatory cytokine production was observed in the distal colon (Kc: p = 0,0273; Cxcl2: p = 0,104; Il1-[beta]: p = 0,0796), in parallel with the increase of Trpv1 mRNA (p < 0,001). We infer that CS affects pro-inflammatory cytokine expression in healthy and inflamed gut, and that the simultaneous modulation of TRPV1 may point to a potential involvement of TRPV1 in cigarette smoke-induced production of inflammatory mediators.

HIV infection affects up to 30% of children presenting with severe acute malnutrition (SAM) in Africa and is associated with increased mortality. Children with SAM are treated similarly regardless of HIV status, although mechanisms of nutritional recovery in HIV and/or SAM are not well understood. We performed a secondary analysis of a clinical trial and plasma proteomics data among children with complicated SAM in Kenya and Malawi. Compared to children with SAM without HIV (n = 113), HIV-infected children (n = 54) had evidence (false discovery rate (FDR) corrected p < 0.05) of metabolic stress, including enriched pathways related to inflammation and lipid metabolism. Moreover, we observed reduced plasma levels of zinc-α-2-glycoprotein, butyrylcholinesterase, and increased levels of complement C2 resembling findings in metabolic syndrome, diabetes and other non-communicable diseases. HIV was also associated (FDR corrected p < 0.05) with higher plasma levels of inflammatory chemokines. Considering evidence of biomarkers of metabolic stress, it is of potential concern that our current treatment strategy for SAM regardless of HIV status involves a high-fat therapeutic diet. The results of this study suggest a need for clinical trials of therapeutic foods that meet the specific metabolic needs of children with HIV and SAM.

In vitro techniques are essential in elucidating biochemical mechanisms and for screening a wide range of possible bioactive candidates. The number of papers published reporting in vitro bioavailability and bioactivity of flavonoids and flavonoid-rich plant extracts is numerous and still increasing. However, even with the present knowledge on the bioavailability and metabolism of flavonoids after oral ingestion, certain inaccuracies still persist in the literature, such as the use of plant extracts to study bioactivity towards vascular cells. There is therefore a need to revisit, even question, these approaches in terms of their biological relevance. In this review, the bioavailability of flavonoid glycosides, the use of cell models for intestinal absorption and the use of flavonoid aglycones and flavonoid-rich plant extracts in in vitro bioactivity studies will be discussed. Here, we focus on the limitations of current in vitro systems and revisit the validity of some in vitro approaches, and not on the detailed mechanism of flavonoid absorption and bioactivity. Based on the results in the review, there is an apparent need for stricter guidelines on publishing data on in vitro data relating to the bioavailability and bioactivity of flavonoids and flavonoid-rich plant extracts.