Publications
48 results found
Belluomo I, Whitlock SE, Myridakis A, et al., 2024, Combining Thermal Desorption with Selected Ion Flow Tube Mass Spectrometry for Analyses of Breath Volatile Organic Compounds., Anal Chem, Vol: 96, Pages: 1397-1401
An instrument integrating thermal desorption (TD) to selected ion flow tube mass spectrometry (SIFT-MS) is presented, and its application to analyze volatile organic compounds (VOCs) in human breath is demonstrated for the first time. The rationale behind this development is the need to analyze breath samples in large-scale multicenter clinical projects involving thousands of patients recruited in different hospitals. Following adapted guidelines for validating analytical techniques, we developed and validated a targeted analytical method for 21 compounds of diverse chemical class, chosen for their clinical and biological relevance. Validation has been carried out by two independent laboratories, using calibration standards and real breath samples from healthy volunteers. The merging of SIFT-MS and TD integrates the rapid analytical capabilities of SIFT-MS with the capacity to collect breath samples across multiple hospitals. Thanks to these features, the novel instrument has the potential to be easily employed in clinical practice.
Myridakis A, Wen Q, Boshier PR, et al., 2023, Global urinary volatolomics with (GC×)GC-TOF-MS, Analytical Chemistry, Vol: 95, Pages: 17170-17176, ISSN: 0003-2700
Urinary volatolomics offers a noninvasive approach for disease detection and monitoring. Herein we present an improved methodology for global volatolomic profiling. Wide coverage was achieved by utilizing a multiphase sorbent for volatile organic compound (VOC) extraction. A single, midpolar column gas chromatography (GC) assay yielded substantially higher numbers of monitored VOCs compared to our previously reported single-sorbent method. Multidimensional GC (GC×GC) enhanced further biomarker discovery while data analysis was simplified by using a tile-based approach. At the same time, the required urine volume was reduced 5-fold from 2 to 0.4 mL. The applicability of the methodology was demonstrated in a pancreatic ductal adenocarcinoma cohort where previous findings were confirmed while a series of additional VOCs with diagnostic potential were discovered.
Andrikopoulos P, Aron-Wisnewsky J, Chakaroun R, et al., 2023, Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide, Nature Communications, Vol: 14, Pages: 1-18, ISSN: 2041-1723
The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied “explainable” machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk.
Wen Q, Myridakis A, Boshier PR, et al., 2023, A complete pipeline for untargeted urinary volatolomic profiling with sorptive extraction and dual polar and nonpolar column methodologies coupled with gas chromatography time-of-flight mass spectrometry., Analytical Chemistry, Vol: 95, Pages: 758-765, ISSN: 0003-2700
Volatolomics offers an opportunity for noninvasive detection and monitoring of human disease. While gas chromatography-mass spectrometry (GC-MS) remains the technique of choice for analyzing volatile organic compounds (VOCs), barriers to wider adoption in clinical practice still exist, including: sample preparation and introduction techniques, VOC extraction, throughput, volatolome coverage, biological interpretation, and quality control (QC). Therefore, we developed a complete pipeline for untargeted urinary volatolomic profiling. We optimized a novel extraction technique using HiSorb sorptive extraction, which exhibited high analytical performance and throughput. We achieved a broader VOC coverage by using HiSorb coupled with a set of complementary chromatographic methods and time-of-flight mass spectrometry. Furthermore, we developed a data preprocessing strategy by evaluating internal standard normalization, batch correction, and we adopted strict QC measures including removal of nonlinearly responding, irreproducible, or contaminated metabolic features, ensuring the acquisition of high-quality data. The applicability of this pipeline was evaluated in a clinical cohort consisting of pancreatic ductal adenocarcinoma (PDAC) patients (n = 28) and controls (n = 33), identifying four urinary candidate biomarkers (2-pentanone, hexanal, 3-hexanone, and p-cymene), which can successfully discriminate the cancer and noncancer subjects. This study presents an optimized, high-throughput, and quality-controlled pipeline for untargeted urinary volatolomic profiling. Use of the pipeline to discriminate PDAC from control subjects provides proof of principal of its clinical utility and potential for application in future biomarker discovery studies.
Belda E, Voland L, Tremaroli V, et al., 2022, Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism, Gut, Vol: 71, Pages: 2463-2480, ISSN: 0017-5749
Objectives Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome’s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation.Design We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice.Results Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration.Conclusion Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity.Trial registration number NCT02059538.
Woodfield G, Belluomo I, Laponogov I, et al., 2022, Diagnostic performance of a non-invasive breath test for colorectal cancer: COBRA1 study, Gastroenterology, Vol: 163, Pages: 1447-1449.e8, ISSN: 0016-5085
Hewitt M, Belluomo I, Zuffa S, et al., 2022, Variation of volatile organic compound levels within ambient room air and its impact upon the standardisation of breath sampling, Scientific Reports, Vol: 12, Pages: 1-7, ISSN: 2045-2322
INTRODUCTION: The interest around analysis of volatile organic compounds (VOCs) within breath has increased in the last two decades. Uncertainty remains around standardisation of sampling and whether VOCs within room air can influence breath VOC profiles.OBJECTIVES: To assess the abundance of VOCs within room air in common breath sampling locations within a hospital setting and whether this influences the composition of breath. A secondary objective is to investigate diurnal variation in room air VOCs.METHODS: Room air was collected using a sampling pump and thermal desorption (TD) tubes in the morning and afternoon from five locations. Breath samples were collected in the morning only. TD tubes were analysed using gas chromatography coupled with time-of-flight mass spectrometry (GC-TOF-MS).RESULTS: A total of 113 VOCs were identified from the collected samples. Multivariate analysis demonstrated clear separation between breath and room air. Room air composition changed throughout the day and different locations were characterized by specific VOCs, which were not influencing breath profiles.CONCLUSIONS: Breath did not demonstrate separation based on location, suggesting that sampling can be performed across different locations without affecting results.
Serger E, Luengo-Gutierrez L, Chadwick JS, et al., 2022, The gut metabolite indole-3 propionate promotes nerve regeneration and repair, Nature, Vol: 607, Pages: 585-592, ISSN: 0028-0836
The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate1. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms2. Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration3. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and the release of neurotrophins, can be activated by intermittent fasting (IF)4,5. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by Clostridium sporogenes is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating the recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis. Our results demonstrate the ability of a microbiome-derived metabolite, such as IPA, to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.
Fromentin S, Forslund SK, Chechi K, et al., 2022, Microbiome and metabolome features of the cardiometabolic disease spectrum, Nature Medicine, Vol: 28, Pages: 303-+, ISSN: 1078-8956
Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages—acute coronary syndrome, chronic IHD and IHD with heart failure—and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.
Forslund SK, Chakaroun R, Zimmermann-Kogadeeva M, et al., 2021, Combinatorial, additive and dose-dependent drug-microbiome associations, Nature, Vol: 600, Pages: 500-505, ISSN: 0028-0836
During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1,2,3,4,5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.
Nuzzo A, Guedj K, Curac S, et al., 2021, Accuracy of citrulline, I-FABP and d-lactate in the diagnosis of acute mesenteric ischemia, Scientific Reports, Vol: 11, Pages: 1-10, ISSN: 2045-2322
Early diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMI—citrulline, intestinal fatty acid-binding protein (I-FABP), and D-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patients—50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 μmol/L (12.0–26.0) vs. 23.3 μmol/L (18.3–29.8), p = 0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence interval = 0.58–0.78). No statistical difference was found in plasma I-FABP and plasma D-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and D-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers.
Bermudez-Martin P, Becker JAJ, Caramello N, et al., 2021, The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota, Microbiome, Vol: 9, Pages: 1-23, ISSN: 2049-2618
BackgroundAutism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice.ResultsMice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice.ConclusionsThe microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.
Drabinska N, Flynn C, Ratcliffe N, et al., 2021, A literature survey of all volatiles from healthy human breath and bodily fluids: the human volatilome, JOURNAL OF BREATH RESEARCH, Vol: 15, ISSN: 1752-7155
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- Citations: 63
Belluomo I, Boshier PR, Myridakis A, et al., 2021, Selected ion flow tube mass spectrometry for targeted analysis of volatile organic compounds in human breath, NATURE PROTOCOLS, Vol: 16, Pages: 3419-3438, ISSN: 1754-2189
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- Citations: 22
Letertre MPM, Myridakis A, Whiley L, et al., 2021, A targeted ultra performance liquid chromatography - Tandem mass spectrometric assay for tyrosine and metabolites in urine and plasma: Application to the effects of antibiotics on mice, JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, Vol: 1164, ISSN: 1570-0232
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- Citations: 5
Wen Q, Boshier P, Myridakis A, et al., 2020, Urinary volatile organic compound analysis for the diagnosis of cancer: a systematic literature review and quality assessment, Metabolites, Vol: 11, Pages: 17-17, ISSN: 2218-1989
The analysis of urinary volatile organic compounds (VOCs) is a promising field of research with the potential to discover new biomarkers for cancer early detection. This systematic review aims to summarise the published literature concerning cancer-associated urinary VOCs. A systematic online literature search was conducted to identify studies reporting urinary VOC biomarkers of cancers in accordance with the recommendations of the Cochrane Library and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Thirteen studies comprising 1266 participants in total were included in the review. Studies reported urinary VOC profiles of five cancer subtypes: prostate cancer, gastrointestinal cancer, leukaemia/lymphoma, lung cancer, and bladder cancer. Forty-eight urinary VOCs belonging to eleven chemical classes were identified with high diagnostic performance. VOC profiles were distinctive for each cancer type with limited cross-over. The metabolic analysis suggested distinctive phenotypes for prostate and gastrointestinal cancers. The heterogenicity of study design, methodological and reporting quality may have contributed to inconsistencies between studies. Urinary VOC analysis has shown promising performance for non-invasive diagnosis of cancer. However, limitations in study design have resulted in inconsistencies between studies. These limitations are summarised and discussed in order to support future studies.
Giovanni SD, serger E, Chadwick J, et al., 2020, The intermittent fasting-dependent gut microbial metabolite indole-3 propionate promotes nerve regeneration and recovery after injury
<jats:title>Abstract</jats:title> <jats:p>The regenerative potential of mammalian peripheral nervous system (PNS) neurons after injury is critically limited by their slow axonal regenerative rate<jats:sup>1</jats:sup>. Since a delayed target re-innervation leads to irreversible loss of function of target organs<jats:sup>2</jats:sup>, accelerated axonal regeneration is required to enhance functional outcomes following injury. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms<jats:sup>3</jats:sup>. Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration<jats:sup>4</jats:sup>. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and release of neurotrophins, can be activated by intermittent fasting (IF)<jats:sup>5,6</jats:sup>. IF has in turn been shown to increase synaptic plasticity<jats:sup>7,8</jats:sup> and neurogenesis<jats:sup>9</jats:sup>, partially sharing molecular mechanisms with axonal regeneration. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in the mouse via an unexpected mechanism that relies upon the gram + gut microbiome and an increase of the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by <jats:italic>Clostridium sporogenes</jats:italic> is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-d
Pean N, Le Lay A, Brial F, et al., 2020, Dominant gut Prevotella copri in gastrectomised non-obese diabetic Goto-Kakizaki rats improves glucose homeostasis through enhanced FXR signalling, Diabetologia, Vol: 63, Pages: 1223-1235, ISSN: 0012-186X
Aims/hypothesisDrug and surgical-based therapies in type 2 diabetes are associated with altered gut microbiota architecture. Here we investigated the role of the gut microbiome in improved glucose homeostasis following bariatric surgery.MethodsWe carried out gut microbiome analyses in gastrectomised (by vertical sleeve gastrectomy [VSG]) rats of the Goto–Kakizaki (GK) non-obese model of spontaneously occurring type 2 diabetes, followed by physiological studies in the GK rat.ResultsVSG in the GK rat led to permanent improvement of glucose tolerance associated with minor changes in the gut microbiome, mostly characterised by significant enrichment of caecal Prevotella copri. Gut microbiota enrichment with P. copri in GK rats through permissive antibiotic treatment, inoculation of gut microbiota isolated from gastrectomised GK rats, and direct inoculation of P. copri, resulted in significant improvement of glucose tolerance, independent of changes in body weight. Plasma bile acids were increased in GK rats following inoculation with P. copri and P. copri-enriched microbiota from VSG-treated rats; the inoculated GK rats then showed increased liver glycogen and upregulated expression of Fxr (also known as Nr1h4), Srebf1c, Chrebp (also known as Mlxipl) and Il10 and downregulated expression of Cyp7a1.ConclusionsOur data underline the impact of intestinal P. copri on improved glucose homeostasis through enhanced bile acid metabolism and farnesoid X receptor (FXR) signalling, which may represent a promising opportunity for novel type 2 diabetes therapeutics.
Georgiadis P, Gavriil M, Rantakokko P, et al., 2019, DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia, Environment International, Vol: 126, Pages: 24-36, ISSN: 0160-4120
OBJECTIVES: To characterize the impact of PCB exposure on DNA methylation in peripheral blood leucocytes and to evaluate the corresponding changes in relation to possible health effects, with a focus on B-cell lymphoma. METHODS: We conducted an epigenome-wide association study on 611 adults free of diagnosed disease, living in Italy and Sweden, in whom we also measured plasma concentrations of 6 PCB congeners, DDE and hexachlorobenzene. RESULTS: We identified 650 CpG sites whose methylation correlates strongly (FDR < 0.01) with plasma concentrations of at least one PCB congener. Stronger effects were observed in males and in Sweden. This epigenetic exposure profile shows extensive and highly statistically significant overlaps with published profiles associated with the risk of future B-cell chronic lymphocytic leukemia (CLL) as well as with clinical CLL (38 and 28 CpG sites, respectively). For all these sites, the methylation changes were in the same direction for increasing exposure and for higher disease risk or clinical disease status, suggesting an etiological link between exposure and CLL. Mediation analysis reinforced the suggestion of a causal link between exposure, changes in DNA methylation and disease. Disease connectivity analysis identified multiple additional diseases associated with differentially methylated genes, including melanoma for which an etiological link with PCB exposure is established, as well as developmental and neurological diseases for which there is corresponding epidemiological evidence. Differentially methylated genes include many homeobox genes, suggesting that PCBs target stem cells. Furthermore, numerous polycomb protein target genes were hypermethylated with increasing exposure, an effect known to constitute an early marker of carcinogenesis. CONCLUSIONS: This study provides mechanistic evidence in support of a link between exposure to PCBs and the etiology of CLL and underlines the utility of omic profiling in the evaluation o
Abdul Rahim MBH, Chilloux J, Martinez-Gili L, et al., 2019, Diet-induced metabolic changes of the human gut microbiome: importance of short-chain fatty acids, methylamines and indoles, Acta Diabetologica, Vol: 56, Pages: 493-500, ISSN: 0940-5429
The human gut is a home for more than 100 trillion bacteria, far more than all other microbial populations resident on the body's surface. The human gut microbiome is considered as a microbial organ symbiotically operating within the host. It is a collection of different cell lineages that are capable of communicating with each other and the host and has an ability to undergo self-replication for its repair and maintenance. As the gut microbiota is involved in many host processes including growth and development, an imbalance in its ecological composition may lead to disease and dysfunction in the human. Gut microbial degradation of nutrients produces bioactive metabolites that bind target receptors, activating signalling cascades, and modulating host metabolism. This review covers current findings on the nutritional and pharmacological roles of selective gut microbial metabolites, short-chain fatty acids, methylamines and indoles, as well as discussing nutritional interventions to modulate the microbiome.
Vafeiadi M, Myridakis A, Roumeliotaki T, et al., 2018, Association of Early Life Exposure to Phthalates With Obesity and Cardiometabolic Traits in Childhood: Sex Specific Associations, FRONTIERS IN PUBLIC HEALTH, Vol: 6
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- Citations: 61
Dumas M-E, Chilloux J, Myridakis A, et al., 2018, Microbiome inhibition of IRAK-4 by trimethylamine mediates metabolic and immune benefits in high fat diet-induced insulin resistance, 54th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S267-S268, ISSN: 0012-186X
Hoyles L, Fernandez-Real J-M, Federici M, et al., 2018, Publisher Correction: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women, Nature Medicine, Vol: 24, Pages: 1628-1628, ISSN: 1078-8956
In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.
Vermeulen R, Saberi Hosnijeh F, Bodinier B, et al., 2018, Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma; univariate and functionally-informed multivariate analyses, International Journal of Cancer, Vol: 143, Pages: 1335-1347, ISSN: 0020-7136
Recent prospective studies have shown that dysregulation of the immune system may precede the development of B-cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case-control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years prior to diagnosis (range, 2.01-15.97) in 268 incident cases of BCL (including multiple myeloma) and matched controls. Linear mixed models, and Partial Least Square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes, and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed modelIrrespective of the model, our analyses identified associations linking blood lower immune markerslevels of and BCL incidence. In particular, we identified growth factors, and within that family, fibroblast growth factor-2 (FGF-2,p=7.2x10-4), ) and transforming growth factor alpha (TGF-α, p=6.5x10-5) and BCL incidence.Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF-2 (p=7.8x10-7), TGF-α (p=4.08x10-5),fractalkine (p=1.12x10-3), monocyte chemotactic protein-3 (p=1.36x10-4), macrophage inflammatory protein 1-alpha (p=4.6x10-4), and vascular endothelial growth factor (p=4.23x10-5). , and vascular endothelial growth factor (VEGF), to be consistently (and inversely) associated with MM incidence. Our results also provided marginal support for already reported associations between chemokines and diffuse large B-Cell lymphoma (DLBCL), and cytokines and chronic lymphocytic leukemia (CLL). Case-only analyses showed that GM-CSF levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression.In conclusion, our study suggests a role of gr
Berger E, Delpierre C, Hosnijeh FS, et al., 2018, Association between low-grade inflammation and Breast cancer and B-cell Myeloma and Non-Hodgkin Lymphoma: findings from two prospective cohorts, Scientific Reports, Vol: 8, ISSN: 2045-2322
Chronic inflammation may be involved in cancer development and progression. Using 28 inflammatory-related proteins collected from prospective blood samples from two case-control studies nested in the Italian component of the European Prospective Investigation into Cancer and nutrition (n = 261) and in the Northern Sweden Health and Disease Study (n = 402), we tested the hypothesis that an inflammatory score is associated with breast cancer (BC) and Β-cell Non-Hodgkin Lymphoma (B-cell NHL, including 68 multiple myeloma cases) onset. We modelled the relationship between this inflammatory score and the two cancers studied: (BC and B-cell NHL) using generalised linear models, and assessed, through adjustments the role of behaviours and lifestyle factors. Analyses were performed by cancer types pooling both populations, and stratified by cohorts, and time to diagnosis. Our results suggested a lower inflammatory score in B-cell NHL cases (β = −1.28, p = 0.012), and, to lesser, extent with BC (β = −0.96, p = 0.33) compared to controls, mainly driven by cancer cases diagnosed less than 6 years after enrolment. These associations were not affected by subsequent adjustments for potential intermediate confounders, notably behaviours. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated. These observations call for further studies involving larger populations, larger variety of cancer types and repeated measures of larger panel of inflammatory markers.
Hoyles L, Fernández-Real JM, Federici M, et al., 2018, Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women, Nature Medicine, Vol: 24, Pages: 1-17, ISSN: 1078-8956
Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.
Hoyles L, Jiménez-Pranteda MJ, Chilloux J, et al., 2018, Metabolic retroconversion of trimethylamine N-oxide and the gut microbiota, Microbiome, Vol: 6, ISSN: 2049-2618
Background:The dietary methylamines choline, carnitine, and phosphatidylcholine are used by the gut microbiota to produce a range of metabolites, including trimethylamine (TMA). However, little is known about the use of trimethylamine N-oxide (TMAO) by this consortium of microbes.Results:A feeding study using deuterated TMAO in C57BL6/J mice demonstrated microbial conversion of TMAO to TMA, with uptake of TMA into the bloodstream and its conversion to TMAO. Microbial activity necessary to convert TMAO to TMA was suppressed in antibiotic-treated mice, with deuterated TMAO being taken up directly into the bloodstream. In batch-culture fermentation systems inoculated with human faeces, growth of Enterobacteriaceae was stimulated in the presence of TMAO. Human-derived faecal and caecal bacteria (n = 66 isolates) were screened on solid and liquid media for their ability to use TMAO, with metabolites in spent media analysed by 1H-NMR. As with the in vitro fermentation experiments, TMAO stimulated the growth of Enterobacteriaceae; these bacteria produced most TMA from TMAO. Caecal/small intestinal isolates of Escherichia coli produced more TMA from TMAO than their faecal counterparts. Lactic acid bacteria produced increased amounts of lactate when grown in the presence of TMAO but did not produce large amounts of TMA. Clostridia (sensu stricto), bifidobacteria, and coriobacteria were significantly correlated with TMA production in the mixed fermentation system but did not produce notable quantities of TMA from TMAO in pure culture.Conclusions:Reduction of TMAO by the gut microbiota (predominantly Enterobacteriaceae) to TMA followed by host uptake of TMA into the bloodstream from the intestine and its conversion back to TMAO by host hepatic enzymes is an example of metabolic retroconversion. TMAO influences microbial metabolism depending on isolation source and taxon of gut bacterium. Correlation of metabolomic and abundance data from mixed microbiota fermenta
Loukopoulou AN, Vardavas CI, Farmakides G, et al., 2018, Counselling for smoking cessation during pregnancy reduces tobacco-specific nitrosamine (NNAL) concentrations: A randomized controlled trial., Eur J Midwifery, Vol: 2
INTRODUCTION: Smoking cessation during pregnancy is beneficial to both the mother and child. Our objective was to assess if an intensive smoking cessation intervention for pregnant women increases: a) rates of smoking cessation, and b) reduces exposure to tobacco-specific carcinogens during pregnancy. METHODS: A two-group single-blinded parallel randomized controlled trial (RCT) was conducted involving 84 pregnant smokers in either a high intensity (n=42) or minimal contact control group (n=42). Women assigned to the high intensity smoking cessation intervention group received a single 30-minute behavioural counselling session and a tailored self-help booklet. The primary outcome measures were: 7-day point prevalence abstinence measured by selfreport and urine cotinine levels, and maternal tobacco specific carcinogens nitrosamine (NNAL) urine concentrations assessed at 32 weeks of gestation. RESULTS: A significantly greater percentage of pregnant smokers quit smoking in the high intensity group compared to the low intensity control group (45.2% vs 21.4%; p=0.001). A significant decrease in urine cotinine concentrations was documented in the experimental group (-140.74 ± 361.70 ng/mL; p=0.004), with no significant decrease documented in the control group. A significant decrease in NNAL levels was also documented in the experimental group (158.17 ± 145.03 pg/mL before, 86.43 ± 112.54 pg/mL after; p=0.032) with no significant changes in the control group. CONCLUSIONS: The high intensity intervention tested resulted in significantly greater cessation rates. Intensive smoking cessation interventions can be effective in reducing fetal exposure to NNAL. This is the first trial to report on NNAL tobacco-specific carcinogen concentrations before and after an intervention for smoking cessation during pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01210118. ABBREVIATIONS: 5Αs: ask, advise, asses, assist, arrange; GHQ: general health
Hoyles L, Jiménez-Pranteda ML, Chilloux J, et al., 2017, Metabolic retroconversion of trimethylamine <i>N</i>-oxide and the gut microbiota
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>BACKGROUND</jats:title><jats:p>The dietary methylamines choline, carnitine and phosphatidylcholine are used by the gut microbiota to produce a range of metabolites, including trimethylamine (TMA). However, little is known about the use of trimethylamine <jats:italic>N</jats:italic>-oxide (TMAO) by this consortium of microbes.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>A feeding study using deuterated TMAO in C57BL6/J mice demonstrated microbial conversion of TMAO to TMA, with uptake of TMA into the bloodstream and its conversion to TMAO. Microbial activity necessary to convert TMAO to TMA was suppressed in antibiotic-treated mice, with deuterated TMAO being taken up directly into the bloodstream. In batch-culture fermentation systems inoculated with human faeces, growth of <jats:italic>Enterobacteriaceae</jats:italic> was stimulated in the presence of TMAO. Human-derived faecal and caecal bacteria (<jats:italic>n</jats:italic> = 66 isolates) were screened on solid and liquid media for their ability to use TMAO, with metabolites in spent media analysed by <jats:sup>1</jats:sup>H-NMR. As with the <jats:italic>in vitro</jats:italic> fermentation experiments, TMAO stimulated the growth of <jats:italic>Enterobacteriaceae</jats:italic>; these bacteria produced most TMA from TMAO. Caecal/small intestinal isolates of <jats:italic>Escherichia coli</jats:italic> produced more TMA from TMAO than their faecal counterparts. Lactic acid bacteria produced increased amounts of lactate when grown in the presence of TMAO, but did not produce large amounts of TMA. Clostridia (<jats:italic>sensu stricto</jats:italic>), bifidobacteria and coriobacteria were significantly correlated with TMA production in the mixed fermentation system but did
Georgiadis P, Liampa I, Hebels DG, et al., 2017, Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis., BMC Genomics, Vol: 18, ISSN: 1471-2164
BACKGROUND: B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance. RESULTS: We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0-15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while
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