Mycotoxin contamination in the Arab world: Highlighting the main knowledge gaps and the current legislation.

Since the discovery of aflatoxins in the 1960s, knowledge in the mycotoxin research field has increased dramatically. Hundreds of review articles have been published summarizing many different aspects, including mycotoxin contamination per country or region. However, mycotoxin contamination in the Arab world, which includes 22 countries in Africa and Asia, has not yet been specifically reviewed. To this end, the contamination of mycotoxins in the Arab world was reviewed not only to profile the pervasiveness of the problem in this region but also to identify the main knowledge gaps imperiling the safety of food and feed in the future. To the best of our knowledge, 306 (non-)indexed publications in English, Arabic, or French were published from 1977 to 2021, focusing on the natural occurrence of mycotoxins in matrices of 14 different categories. Characteristic factors (e.g., detected mycotoxins, concentrations, and detection methods) were extracted, processed, and visualized. The main results are summarized as follows: (i) research on mycotoxin contamination has increased over the years. However, the accumulated data on their occurrences are scarce to non-existent in some countries; (ii) the state-of-the-art technologies on mycotoxin detection are not broadly implemented neither are contemporary multi-mycotoxin detection strategies, thus showing a need for capacity-building initiatives; and (iii) mycotoxin profiles differ among food and feed categories, as well as between human biofluids. Furthermore, the present work highlights contemporary legislation in the Arab countries and provides future perspectives to mitigate mycotoxins, enhance food and feed safety, and protect the consumer public. Concluding, research initiatives to boost mycotoxin research among Arab countries are strongly recommended.

A study protocol for a pilot randomized controlled trial to evaluate the effectiveness of a gene-based nutrition and lifestyle recommendation for weight management among adults: the MyGeneMyDiet® study.

Introduction: Managing nutrition and lifestyle practices, nutrition phenotypes, and the genome forms the foundation of precision nutrition. Precision nutrition focuses on metabolic variability among individuals, and one approach to achieving its goals is to integrate gene-based nutrition and lifestyle recommendations in nutrition practice. However, scientific evidence proving the effectiveness of such recommendations is limited. This study will examine whether providing nutrition and lifestyle recommendations based on individual genotype can lead to better weight loss, along with reduction in body mass index (BMI), waist circumference, and body fat percentage among overweight and obese adults. Methods and analysis: A parallel group, single-blind, randomized controlled trial will be conducted. Sixty-two overweight/obese individuals aged 19-59 years old will be recruited. Participants will be randomly allocated to either the intervention (n = 31) or the control arm (n = 31). Participants in the intervention group will receive the MyGeneMyDiet® Recommendation for Weight Management, a gene-based nutrition and lifestyle recommendation that was developed based on existing evidence of the effects of FTO rs9939609 on body weight, BMI, and physical activity; UCP1 rs1800592 on calorie intake; and TCF7L2 rs7903146 on dietary fat intake. Participants in the control group will receive the standard recommendations for weight management. The primary outcomes will be the differences in weight, BMI, waist circumference, and body fat percentage between arms in both the active phase (6 months) and inactive phase (last 6 months) of the trial. Participants in both arms will be evaluated at baseline and in months 3, 6, 9, and 12. Discussion: To the best of our knowledge, this will be the first gene-based intervention that will adopt a phase of intensive nutrition counseling, followed by a simulation of a free-living state to determine adherence to a gene-based recommendation. This study will contribute to the future implementation of precision nutrition interventions by providing evidence on the effectiveness of a gene-based nutrition and lifestyle recommendation for weight loss. Clinical trial registration: clinicaltrials.gov, identifier [NCT05098899].

Inflammation: the driver of poor outcomes among children with severe acute malnutrition?

Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition and underlies at least 10% of all deaths among children younger than 5 years in low-income countries. SAM is a complex, multisystem disease, with physiological perturbations observed in conjunction with the loss of lean mass, including structural and functional changes in many organ systems. Despite the high mortality burden, predominantly due to infections, the underlying pathogenic pathways remain poorly understood. Intestinal and systemic inflammation is heightened in children with SAM. Chronic inflammation and its consequent immunomodulation may explain the increased morbidity and mortality from infections in children with SAM, both during hospitalization and in the longer term after discharge. Recognition of the role of inflammation in SAM is critical in considering new therapeutic targets in this disease, which has not seen a transformational approach to treatment for several decades. This review highlights the central role of inflammation in the wide-ranging pathophysiology of SAM, as well as identifying potential interventions that have biological plausibility based on evidence from other inflammatory syndromes.

KDM8 epigenetically controls cardiac metabolism to prevent initiation of dilated cardiomyopathy.

Cardiac metabolism is deranged in heart failure, but underlying mechanisms remain unclear. Here, we show that lysine demethylase 8 (Kdm8) maintains an active mitochondrial gene network by repressing Tbx15, thus preventing dilated cardiomyopathy leading to lethal heart failure. Deletion of Kdm8 in mouse cardiomyocytes increased H3K36me2 with activation of Tbx15 and repression of target genes in the NAD+ pathway before dilated cardiomyopathy initiated. NAD+ supplementation prevented dilated cardiomyopathy in Kdm8 mutant mice, and TBX15 overexpression blunted NAD+-activated cardiomyocyte respiration. Furthermore, KDM8 was downregulated in human hearts affected by dilated cardiomyopathy, and higher TBX15 expression defines a subgroup of affected hearts with the strongest downregulation of genes encoding mitochondrial proteins. Thus, KDM8 represses TBX15 to maintain cardiac metabolism. Our results suggest that epigenetic dysregulation of metabolic gene networks initiates myocardium deterioration toward heart failure and could underlie heterogeneity of dilated cardiomyopathy.

The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction.

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.

Effects of a 12-week whole-grain or refined wheat intervention on plasma acylcarnitines, bile acids and signaling lipids, and association with liver fat: A post-hoc metabolomics study of a randomized controlled trial.

Background: We previously showed that whole-grain wheat (WGW) consumption had beneficial effects on liver fat accumulation, as compared to refined wheat (RW). The mechanisms underlying these effects remain unclear. Objective: In this study, we investigated the effects of WGW vs. RW consumption on plasma metabolite levels to explore potential underlying mechanisms of the preventive effect of WGW consumption on liver fat accumulation. Methods: Targeted metabolomics of plasma obtained from a concluded 12-week double-blind, randomized controlled trial was performed. Fifty overweight or obese men and women aged 45-70 years with mildly elevated levels of plasma cholesterol were randomized to either 98 g/d of WGW or RW products. Before and after the intervention, a total of 89 fasting plasma metabolite concentrations including acylcarnitines, trimethylamine-N-oxide (TMAO), choline, betaine, bile acids, and signaling lipids were quantified by UPLC-MS/MS. Intrahepatic triglycerides (IHTG) were quantified by 1H-MRS, and multiple liver markers, including circulating levels of ß-hydroxybutyrate, alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (γ-GT), serum amyloid A (SAA), and C-reactive protein, were assessed. Results: The WGW intervention increased plasma concentrations of four out of 52 signaling lipids-lysophosphatidic acid C18:2, lysophosphatidylethanolamine C18:1 and C18:2, and platelet-activating factor C18:2-and decreased concentrations of the signaling lipid lysophosphatidylglycerol C20:3 as compared to RW intervention, although these results were no longer statistically significant after false discovery rate (FDR) correction. Plasma concentrations of the other metabolites that we quantified were not affected by WGW or RW intervention. Changes in the above-mentioned metabolites were not correlated to change in IHTG upon the intervention. Conclusion: Plasma acylcarnitines, bile acids, and signaling lipids were not robustly affected by the WGW or RW interventions, which makes them less likely candidates to be directly involved in the mechanisms that underlie the protective effect of WGW consumption or detrimental effect of RW consumption on liver fat accumulation. Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT02385149].

Effect of 5-Hydroxytryptophan on Fatigue in Quiescent Inflammatory Bowel Disease: A Randomized Controlled Trial.

BACKGROUND & AIMS: Fatigue is highly prevalent among patients with inflammatory bowel disease (IBD), and only limited treatment options are available. Based on the hypothetical link between low serum tryptophan concentrations and fatigue, we determined the effect of 5-hydroxytryptophan supplementation on fatigue in patients with inactive IBD. METHODS: A multicenter randomized controlled trial was performed at 13 Belgian hospitals, including 166 patients with IBD in remission but experiencing fatigue, defined by a fatigue visual analog scale (fVAS) score of ≥5. Patients were treated in a crossover manner with 100 mg oral 5-hydroxytryptophan or placebo twice daily for 2 consecutive periods of 8 weeks. The primary end point was the proportion of patients reaching a ≥20% reduction in fVAS after 8 weeks of intervention. Secondary outcomes included changes in serum tryptophan metabolites, Functional Assessment of Chronic Illness Therapy Fatigue scale, and scores for depression, anxiety, and stress. The effect of the intervention on the outcomes was evaluated by linear mixed modeling. RESULTS: During 5-hydroxytryptophan treatment, a significant increase in serum 5-hydroxytryptophan (estimated mean difference, 52.66 ng/mL; 95% confidence interval [CI], 39.34-65.98 ng/mL; P < .001) and serotonin (3.0 ng/mL; 95 CI, 1.97-4.03 ng/mL; P < .001) levels was observed compared with placebo. The proportion of patients reaching ≥20% reduction in fVAS was similar in placebo- (37.6%) and 5-hydroxytryptophan (35.6%)-treated patients (P = .830). The fVAS reduction (-0.18; 95% CI, -0.81 to 0.46; P = .581) and Functional Assessment of Chronic Illness Therapy Fatigue scale increase (0.68; 95% CI, -2.37 to 3.73; P = .660) were both comparable between 5-hydroxytryptophan and placebo treatment as well as changes in depression, anxiety, and stress scores. CONCLUSIONS: Despite a significant increase in serum 5-hydroxytryptophan and serotonin levels, oral 5-hydroxytryptophan did not modulate IBD-related fatigue better than placebo. (Trial Registration: Belgian Federal Agency for Medication and Health Products, EudraCT number: 2017-005059-10 and ClinicalTrials.gov: NCT03574948, https://clinicaltrials.gov/ct2/show/NCT03574948.).

Nutritional Characterization of Street Food in Urban Turkmenistan, Central Asia.

Objective: Describing the availability and nutritional composition of the most commonly available street foods in Ashgabat, Turkmenistan. Methods: One hundred sixty-one street food vending sites (six public markets) were assessed, through a collection of data on vending sites' characteristics and food availability, and samples of commonly available foods (21 homemade; 11 industrial), for chemical analysis. Results: Fruit, beverages, and food other than fruit were available in 6.8, 29.2, and 91.9% of all vending sites, respectively. Regarding the latter, 52.7% of the vending sites sold only homemade products (main dishes, snacks, cakes, biscuits and pastries, bread, ice-cream chocolate and confectionery, savory pastries and sandwiches), 37.2% only industrial (ice-cream, chocolate and confectionery, cakes, biscuits and pastries, snacks, bread and savory pastries) and 10.1% both. Homemade foods presented significantly higher total fat [homemade 11.6 g (range 6.6-19.4 g); industrial 6.2 g (range 4.0-8.6 g), p = 0.001], monounsaturated, polyunsaturated and trans-fat, and sodium and potassium content per serving. Industrial wafers presented the highest mean saturated (11.8 g/serving) and trans-fat (2.32 g/serving) content. Homemade hamburgers presented the highest mean sodium content (1889 mg/serving). Conclusions: Strategies to encourage the production and sales of healthier street foods, especially homemade, are needed to promote healthier urban food environments in urban Turkmenistan.

The Impact of Vedolizumab and Ustekinumab on Articular Extra-Intestinal Manifestations in Inflammatory Bowel Disease Patients: A Real-Life Multicentre Cohort Study.

BACKGROUND AND AIMS: Extra-intestinal manifestations are frequently reported in inflammatory bowel diseases. However, data comparing the effect of vedolizumab and ustekinumab on articular extra-intestinal manifestations are limited. The aim here was to evaluate differences in new-onset and the evolution of pre-existing joint extra-intestinal manifestations during both treatments. METHODS: An international multicentre retrospective study was performed on inflammatory bowel disease patients who started vedolizumab or ustekinumab between May 2010 and December 2020. Extra-intestinal manifestations were assessed at baseline and joint extra-intestinal manifestations were evaluated throughout the 2-year follow-up. Arthropathy was defined by joint inflammation [arthritis/sacroiliitis], diagnosed by a rheumatologist, and arthralgia as articular pain without confirmed inflammation. Additionally, skin, ocular and hepatic extra-intestinal manifestations were assessed at baseline. Uni- and multivariate analyses were performed. RESULTS: In total, 911 patients [vedolizumab: 584; ustekinumab: 327] were included. Deterioration of pre-existing arthropathy and rate of new-onset arthropathy were not significantly associated with vedolizumab over ustekinumab. Arthropathy was used as reason to stop treatment in six vedolizumab and two ustekinumab patients. The odds of developing new arthralgia within 6 months was higher in patients who took vedolizumab compared to ustekinumab (adjusted odds ratio [aOR]: 2.28 [1.01-5.15], p = 0.047). However, this effect was not sustained during the 2-year follow-up (aOR: 1.35 [0.80-2.29], p = 0.259). Deterioration of pre-existing arthralgia was comparable between ustekinumab and vedolizumab-treated patients. In two vedolizumab-treated patients arthralgia was given as the reason to stop treatment. CONCLUSIONS: Vedolizumab and ustekinumab can be used safely in patients with articular extra-intestinal manifestations. Only a temporary increased risk for developing arthralgia has been observed under vedolizumab.

The role of albumin and the extracellular matrix on the pathophysiology of oedema formation in severe malnutrition.

BACKGROUND: While fluid flows in a steady state from plasma, through interstitium, and into the lymph compartment, altered fluid distribution and oedema can result from abnormal Starling's forces, increased endothelial permeability or impaired lymphatic drainage. The mechanism of oedema formation, especially the primary role of hypoalbuminaemia, remains controversial. Here, we explored the roles of albumin and albumin-independent mechanisms in oedema formation among children with severe malnutrition (SM). METHODS: We performed secondary analysis of data obtained from two independent clinical trials in Malawi and Kenya (NCT02246296 and NCT00934492). We then used an unconventional strategy of comparing children with kwashiorkor and marasmus by matching (discovery cohort, n = 144) and normalising (validation cohort, n = 98, 2 time points) for serum albumin. Untargeted proteomics was used in the discovery cohort to determine plausible albumin-independent mechanisms associated with oedema, which was validated using enzyme-linked immunosorbent assay and multiplex assays in the validation cohort. FINDINGS: We demonstrated that low serum albumin is necessary but not sufficient to develop oedema in SM. We further found that markers of extracellular matrix (ECM) degradation rather than markers of EG degradation distinguished oedematous and non-oedematous children with SM. INTERPRETATION: Our results show that oedema formation has both albumin-dependent and independent mechanisms. ECM integrity appears to have a greater role in oedema formation than EG shedding in SM. FUNDING: Research Foundation Flanders (FWO), Thrasher Foundation (15122 and 9403), VLIR-UOS-Ghent University Global Minds Fund, Bill & Melinda Gates Foundation (OPP1131320), MRC/DfID/Wellcome Trust Global Health Trials Scheme (MR/M007367/1), Canadian Institutes of Health Research (156307), Wellcome Trust (WT083579MA).

Systemic inflammation and metabolic disturbances underlie inpatient mortality among ill children with severe malnutrition.

Children admitted to hospital with an acute illness and concurrent severe malnutrition [complicated severe malnutrition (CSM)] have a high risk of dying. The biological processes underlying their mortality are poorly understood. In this case-control study nested within a multicenter randomized controlled trial among children with CSM in Kenya and Malawi, we found that blood metabolomic and proteomic profiles robustly differentiated children who died (n = 92) from those who survived (n = 92). Fatalities were characterized by increased energetic substrates (tricarboxylic acid cycle metabolites), microbial metabolites (e.g., propionate and isobutyrate), acute phase proteins (e.g., calprotectin and C-reactive protein), and inflammatory markers (e.g., interleukin-8 and tumor necrosis factor-α). These perturbations indicated disruptions in mitochondria-related bioenergetic pathways and sepsis-like responses. This study identified specific biomolecular disturbances associated with CSM mortality, revealing that systemic inflammation and bioenergetic deficits are targetable pathophysiological processes for improving survival of this vulnerable population.

Prevalence of Fatigue and Unrecognized Depression in Patients with Inflammatory Bowel Disease in Remission under Immunosuppressants and Biologicals.

BACKGROUND: Although highly prevalent among inflammatory bowel disease (IBD) patients, fatigue remains an unmet clinical need. The aim was to describe the prevalence of fatigue in an IBD population in remission and identify factors associated with fatigue. METHODS: IBD patients in clinical and biochemical remission under treatment with immunomodulators or biologicals were included. Fatigue, physical tiredness and depression were assessed using the fatigue Visual Analogue Scale (fVAS), the Shortened Fatigue Questionnaire (SFQ) and the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), respectively. Relevant clinical and biochemical parameters were included in regression analyses to identify factors associated with physical fatigue. RESULTS: In total, 157 IBD patients were included. Up to 45.9% of patients reported fatigue, physical tiredness was observed in 51% and depression in 10.8%. The majority of patients with subclinical depression were fatigued. Female sex (OR = 4.17 [1.55-6.78], p = 0.002) was independently associated with physical fatigue. Transferrin saturation (OR = -0.11 [-0.22--0.007], p = 0.037) and treatment with adalimumab (compared to infliximab, OR = -3.65 [-7.21--0.08], p = 0.045) entailed a lower risk of fatigue. CONCLUSION: Fatigue is observed in about half of IBD patients in remission and can be a symptom of underlying undetected depression. Sex, transferrin saturation and medication were identified as independent risk factors.

Plasma lipids and growth faltering: A longitudinal cohort study in rural Gambian children.

Growth faltering in children arises from metabolic and endocrine dysfunction driven by complex interactions between poor diet, persistent infections, and immunopathology. Here, we determined the progression of the plasma lipidome among Gambian children (n = 409) and assessed its association with growth faltering during the first 2 years of life using the panel vector autoregression method. We further investigated temporal associations among lipid clusters. We observed that measures of stunting, wasting, and underweight are dynamically associated with each other and that lipid groups containing polyunsaturated fatty acids (PUFAs) and phosphatidylcholines consistently predict future growth outcomes. Linear growth was dynamically associated with the majority of lipids, indicating a higher nutritional demand to improve height compared to weight among growth-restricted children. Our results indicate a critical role for PUFAs and choline in early life dietary interventions to combat the child growth faltering still so prevalent in low-income settings.

Severe malnutrition or famine exposure in childhood and cardiometabolic non-communicable disease later in life: a systematic review.

INTRODUCTION: Child 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. METHODS: Our 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. RESULTS: We 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. CONCLUSION: Severe 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.

Childhood severe acute malnutrition is associated with metabolic changes in adulthood.

BACKGROUNDSevere acute malnutrition (SAM) is a major contributor to global mortality in children under 5 years. Mortality has decreased; however, the long-term cardiometabolic consequences of SAM and its subtypes, severe wasting (SW) and edematous malnutrition (EM), are not well understood. We evaluated the metabolic profiles of adult SAM survivors using targeted metabolomic analyses.METHODSThis cohort study of 122 adult SAM survivors (SW = 69, EM = 53) and 90 age-, sex-, and BMI-matched community participants (CPs) quantified serum metabolites using direct flow injection mass spectrometry combined with reverse-phase liquid chromatography. Univariate and sparse partial least square discriminant analyses (sPLS-DAs) assessed differences in metabolic profiles and identified the most discriminative metabolites.RESULTSSeventy-seven metabolite variables were significant in distinguishing between SAM survivors (28.4 ± 8.8 years, 24.0 ± 6.1 kg/m2) and CPs (28.4 ± 8.9 years, 23.3 ± 4.4 kg/m2) (mean ± SDs) in univariate and sPLS-DA models. Compared with CPs, SAM survivors had less liver fat; higher branched-chain amino acids (BCAAs), urea cycle metabolites, and kynurenine/tryptophan (KT) ratio (P < 0.001); and lower ß-hydroxybutyric acid and acylcarnitine/free carnitine ratio (P < 0.001), which were both associated with hepatic steatosis (P < 0.001). SW and EM survivors had similar metabolic profiles as did stunted and nonstunted SAM survivors.CONCLUSIONAdult SAM survivors have distinct metabolic profiles that suggest reduced ß-oxidation and greater risk of type 2 diabetes (BCAAs, KT ratio, urea cycle metabolites) compared with CPs. This indicates that early childhood SAM exposure has long-term metabolic consequences that may worsen with age and require targeted clinical management.FUNDINGHealth Research Council of New Zealand, Caribbean Public Health Agency, Centre for Global Child Health at the Hospital for Sick Children. DST is an Academic Fellow and a Restracomp Fellow at the Centre for Global Child Health. GBG is a postdoctoral fellow of the Research Foundation Flanders.

Childhood Malnutrition and Association of Lean Mass with Metabolome and Hormone Profile in Later Life.

This study aimed to determine the associations of targeted metabolomics and hormone profiles data with lean mass index (LMI), which were estimated using bioelectrical impedance, in survivors of child severe malnutrition (SM) (n = 69) and controls (n = 77) in Malawi 7 years after being treated. Linear associations between individual metabolite or hormone and LMI were determined, including their interaction with nutrition status 7 years prior. Path analysis was performed to determine structural associations. Lastly, predictive models for LMI were developed using the metabolome and hormone profile by elastic net regularized regression (EN). Metabolites including several lipids, amino acids, and hormones were individually associated (p < 0.05 after false discovery rate correction) with LMI. However, plasma FGF21 (Control: ß = -0.02, p = 0.59; Case: ß = -0.14, p < 0.001) and tryptophan (Control: ß = 0.15, p = 0.26; Case: ß = 0.70, p < 0.001) were associated with LMI among cases but not among controls (both interaction p-values < 0.01). Moreover, path analysis revealed that tryptophan mediates the association between child SM and LMI. EN revealed that most predictors of LMI differed between groups, further indicating altered metabolic mechanisms driving lean mass accretion among SM survivors later in life.

Translational research into the effects of cigarette smoke on inflammatory mediators and epithelial TRPV1 in Crohn's disease.

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-ß: 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.