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Bei der Institutionalisierung des Forschungsdatenmanagements (FDM) stehen Hochschulen für angewandte Wissenschaften (HAW) vor einer Vielzahl von Herausforderungen und müssen die notwendigen Rahmenbedingungen zur Umsetzung des FDM für die Forschenden ihrer Institution schaffen. HAW besitzen einen starken Fokus auf der praxisbezogenen Lehre, wobei Forschung auch einen zunehmend höheren Stellenwert erfährt. Dementsprechend muss neben dem Ausbau der wissenschaftsunterstützenden Infrastruktur auch ein Bewusstsein für die Bedeutung von FDM in der Hochschulleitung geschaffen werden, um zu einem nachhaltigen FDM zu kommen. An der Hochschule für nachhaltige Entwicklung Eberswalde (HNEE) wurde zur strukturierten Planung der Institutionalisierung eine Strategie entlang des RISE-DE Referenzmodells erstellt und verabschiedet. Im Beitrag werden der Strategieprozess und die Rahmenbedingungen dargelegt. Dazu gehören auch die in der Landesinitiative Forschungsdatenmanagement Brandenburg (FDM-BB) bestehenden und in der Entwicklung befindlichen Angebote und Services. Diese betreffen die Bereiche Beratung, Schulung und technische Dienste und werden im Projekt durch Data Stewards abgedeckt. Für diese unterschiedlichen Formen des Data Stewardships wird eine Einordnung vorgenommen und aufgezeigt, wie Data Stewardship an der Eberswalder Hochschule zum Erstellen der Forschungsdatenstrategie mit Hilfe des RISE-DE Referenzmodells zum Einsatz kam. Hier werden insbesondere die personelle Verortung und der Aufbau einer Forschungsdaten-Governance durch den Data Steward entlang des Strategieprozesses beschrieben. Zum Abschluss zeigt der Artikel auf, wie eine kleine Hochschule durch die Zusammenarbeit im Verbund und von den Angeboten in den Bereichen Beratung, Schulung und technische Dienste profitieren und so in der Forschungsdatenstrategie höhere Ziele setzen kann.

Myasthenia Gravis (MG) is mediated by autoantibodies against acetylcholine receptors that cause loss of the receptors in the neuromuscular junction. Eculizumab, a C5-inhibitor, is the only approved treatment for MG that mechanistically addresses complement-mediated loss of nicotinic acetylcholine receptors. It is an expensive drug and was approved despite missing the primary efficacy endpoint in the Phase 3 REGAIN study. There are two observations to highlight. Firstly, further C5 inhibitors are in clinical development, but other terminal pathway proteins, such as C7, have been relatively understudied as therapeutic targets, despite the potential for lower and less frequent dosing. Secondly, given the known heterogenous mechanisms of action of autoantibodies in MG, effective patient stratification in the REGAIN trial may have provided more favorable efficacy readouts. We investigated C7 as a target and assessed the in vitro function, binding epitopes and mechanism of action of three mAbs against C7. We found the mAbs were human, cynomolgus monkey and/or rat cross-reactive and each had a distinct, novel mechanism of C7 inhibition. TPP1820 was effective in preventing experimental MG in rats in both prophylactic and therapeutic dosing regimens. To enable identification of MG patients that are likely to respond to C7 inhibition, we developed a patient stratification assay and showed in a small cohort of MG patients (n=19) that 63% had significant complement activation and C7-dependent loss of AChRs in this in vitro set up. This study provides validation of C7 as a target for treatment of MG and provides a means of identifying patients likely to respond to anti-C7 therapy based on complement-activating properties of patient autoantibodies.

Christensenella minuta DSM 22607 has recently been suggested as a potential microbiome-based therapy for inflammatory bowel disease (IBD) because it displays strong anti-inflammatory effects both in vitro and in vivo. Here, we aimed to decipher the mechanism(s) underlying the DSM 22607-mediated beneficial effects on the host in a mouse model of chemically induced acute colitis. We observed that C. minuta plays a key role in the preservation of the epithelial barrier and the management of DNBS-induced inflammation by inhibiting interleukin (IL)-33 and Tumor necrosis factor receptor superfamily member 8 (Tnfrsf8) gene expression. We also showed that DSM 22607 abundance was positively correlated with Akkermansia sp. and Dubosiella sp. and modulated microbial metabolites in the cecum. These results offer new insights into the biological and molecular mechanisms underlying the beneficial effects of C. minuta DSM 22607 by protecting the intestinal barrier integrity and regulating inflammation., (© 2024. The Author(s).)

Crohn's disease (CD) is characterised by chronic inflammation. We aimed to identify a relationship between plasma inflammatory metabolomic signature and genomic data in CD using blood plasma metabolic profiles. Proton NMR spectroscopy were achieved for 228 paediatric CD patients. Regression (OPLS) modelling and machine learning (ML) approaches were independently applied to establish the metabolic inflammatory signature, which was correlated against gene-level pathogenicity scores generated for all patients and functional enrichment was analysed. OPLS modelling of metabolomic spectra from unfasted patients revealed distinctive shifts in plasma metabolites corresponding to regions of the spectrum assigned to N-acetyl glycoprotein, glycerol and phenylalanine that were highly correlated (R 2  = 0.62) with C-reactive protein levels. The same metabolomic signature was independently identified using ML to predict patient inflammation status. Correlation of the individual peaks comprising this metabolomic signature of inflammation with pathogenic burden across 15,854 unselected genes identified significant enrichment for genes functioning within 'intrinsic component of membrane' (p = 0.003) and 'inflammatory bowel disease (IBD)' (p = 0.003). The seven genes contributing IBD enrichment are critical regulators of pro-inflammatory signaling. Overall, a metabolomic signature of inflammation can be detected from blood plasma in CD. This signal is correlated with pathogenic mutation in pro-inflammatory immune response genes., (© 2022. The Author(s).)

The gut microbial ecosystem is governed by complex microbe-microbe interactions, with most documented as interspecies relationships. In this issue of Cell Host & Microbe, Özçam et al. identified intraspecies competition among related strains of the gut symbiont Limosilactobacillus reuteri that are mediated via the antimicrobial activity of polyketide synthase (PKS)., Competing Interests: Declaration of interests S.P.C. is an employee of Ysopia bioscience with managerial responsibilities., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Microbiome-based therapies for inflammatory bowel diseases offer a novel and promising therapeutic approach. The human commensal bacteria of the species Christensenella minuta (C. minuta) have been reported consistently missing in patients affected by Crohn's disease (CD) and have been documented to induce anti-inflammatory effects in human epithelial cells, supporting their potential as a novel biotherapy. This work aimed at selecting the most promising strain of C. minuta for future development as a clinical candidate for CD therapy. Here, we describe a complete screening process combining in vitro and in vivo assays to conduct a rational selection of a live strain of C. minuta with strong immunomodulatory properties. Starting from a collection of 32 strains, a panel of in vitro screening assays was used to narrow it down to five preclinical candidates that were further screened in vivo in an acute TNBS-induced rat colitis model. The most promising candidate was validated in vivo in two mouse models of colitis. The validated clinical candidate strain, C. minuta DSM 33715, was then fully characterized. Hence, applying a rationally designed screening algorithm, a novel strain of C. minuta was successfully identified as the most promising clinical candidate for CD., (© 2022. The Author(s).)

Objectives: Imbalanced nutrition and obesity are risk factors for depression, a relationship that in rodents can be modeled by depression-like behavior in response to high-fat diet (HFD). In this work, we examined the role of the intestinal microbiota and the adipocytokine leptin as potential mediators of the effects of HFD to induce anhedonia-like behavior and reduce self-care in mice. Methods: Male mice were fed a control diet or HFD (60 kJ% from fat) for a period of 4 weeks, after which behavioral tests and molecular analyses (gut microbiome composition, intestinal metabolome, fecal fatty acids, plasma hormone levels) were performed. The role of the intestinal microbiota was addressed by selective depletion of gut bacteria with a combination of non-absorbable antibiotics, while the implication of leptin was examined by the use of leptin-deficient ob/ob mice. Results: Antibiotic treatment reduced the HFD-induced weight gain and adiposity and prevented HFD-induced anhedonia-like behavior and self-care reduction. These effects were associated with a decrease in fecal fatty acids and intestinal microbiota-related metabolites including short-chain fatty acids, glucose and amino acids. Gut microbiota depletion suppressed the HFD-induced rise of plasma leptin, and the circulating leptin levels correlated with the anhedonia-like behavior and reduced self-care caused by HFD. The anhedonic effect of HFD was absent in leptin-deficient ob/ob mice although these animals gained more weight and adiposity in response to HFD than wild-type mice. Discussion: The results indicate that anhedonia-like behavior induced by HFD in mice depends on the intestinal microbiome and involves leptin as a signaling hormone.

The community of the diverse microorganisms residing in the gastrointestinal tract, known as the gut microbiota, is exceedingly being studied for its impact on health and disease. This community plays a major role in nutrient metabolism, maintenance of the intestinal epithelial barrier but also in local and systemic immunomodulation. A dysbiosis of the gut microbiota, characterized by an unbalanced microbial ecology, often leads to a loss of essential functions that may be associated with proinflammatory conditions. Specifically, some key microbes that are depleted in dysbiotic ecosystems, called keystone species, carry unique functions that are essential for the balance of the microbiota. In this review, we discuss current understanding of reported keystone species and their proposed functions in health. We also elaborate on current and future bioinformatics tools needed to identify missing functions in the gut carried by keystone species. We propose that the identification of such keystone species functions is a major step for the understanding of microbiome dynamics in disease and toward the development of microbiome-based therapeutics., Competing Interests: SC and HT are employees of YSOPIA Bioscience. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tudela, Claus and Saleh.)

During the last decade, a plethora of novel therapies containing live microorganisms as active substance(s) has emerged with the aim to treat, prevent, or cure diseases in human beings. Both the Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines and Health Care (EDQM) codified these biotherapies as Live Biotherapeutic Products (LBPs). While these innovative products offer healthcare opportunities, they also represent a challenge for developers who need to set the most suitable designs for non-clinical and clinical studies in order to demonstrate a positive benefit/risk ratio through relevant quality, safety, and efficacy data that are expected by the drug competent authorities. This article describes how YSOPIA Bioscience, supported by the Pharmabiotic Research Institute (PRI), addressed the regulatory challenges during the early development phase of their single-strain LBP, Xla1, in order to obtain the necessary authorizations to bring this drug to the clinical stage., Competing Interests: JCP, SC, WM, GR, LR, and FE are employees of YSOPIA Bioscience. MC-S and AR are employees of the Pharmabiotic Research Institute., (Copyright © 2021 Paquet, Claus, Cordaillat-Simmons, Mazier, Rawadi, Rinaldi, Elustondo and Rouanet.)

Interactions between diet and gut microbiota are critical regulators of energy metabolism. The effects of fibre intake have been deeply studied but little is known about the impact of proteins. Here, we investigated the effects of high protein supplementation (Investigational Product, IP) in a double blind, randomised placebo-controled intervention study (NCT01755104) where 107 participants received the IP or an isocaloric normoproteic comparator (CP) alongside a mild caloric restriction. Gut microbiota profiles were explored in a patient subset (n = 53) using shotgun metagenomic sequencing. Visceral fat decreased in both groups (IP group: - 20.8 ± 23.2 cm 2 ; CP group: - 14.5 ± 24.3 cm 2 ) with a greater reduction (p < 0.05) with the IP supplementation in the Per Protocol population. Microbial diversity increased in individuals with a baseline low gene count (p < 0.05). The decrease in weight, fat mass and visceral fat mass significantly correlated with the increase in microbial diversity (p < 0.05). Protein supplementation had little effects on bacteria composition but major differences were seen at functional level. Protein supplementation stimulated bacterial amino acid metabolism (90% amino-acid synthesis functions enriched with IP versus 13% in CP group (p < 0.01)). Protein supplementation alongside a mild energy restriction induces visceral fat mass loss and an activation of gut microbiota amino-acid metabolism.Clinical trial registration: NCT01755104 (24/12/2012). https://clinicaltrials.gov/ct2/show/record/NCT01755104?term=NCT01755104&draw=2&rank=1 ., (© 2021. The Author(s).)

Christensenella minuta are human gut dwelling bacteria that have been proposed as key members of the gut microbiome, regulating energy balance and adiposity of their host. We formerly identified that a novel strain of C. minuta (strain DSM33407) boosted microbiota diversity and stimulated deconjugation of the primary bile acid taurocholic acid in human samples. However, there is no description of a bile salt hydrolase (BSH) protein carried in the genome of C. minuta . Here, we identified and cloned a protein from C. minuta's genome that carries a potent BSH activity, which preferentially deconjugates glycine-conjugated bile acids. We then retrieved 14,319 putative BSH sequences from the NCBI database and filtered them using the UHGP database to collect a total of 6701 sequences that were used to build the most comprehensive phylogenetic tree of BSH-related enzymes identified in the human microbiome so far. This phylogenetic tree revealed that C. minuta's BSH amino acid sequence clusters away from others with a threshold of 70% identity. This is therefore the first description of C. minuta's BSH protein, which may be involved in its unique role within the human gut microbial ecosystem.

Christensenellaceae is a family of subdominant commensal bacteria found in humans. It is thought to play an important role in gut health by maintaining microbial symbiosis. Indeed, these bacteria occur at significantly lower levels or are absent in individuals suffering from inflammatory bowel diseases (IBDs). Here, we explored if type species Christensenella minuta (strain: DSM 22607) could have the potential to help treat IBDs. We assessed key properties displayed by the bacterium using a combination of in vitro and in vivo assays. We found that while C. minuta is a strict anaerobe, it is also oxygen tolerant. Additionally, we observed that the species produces high levels of acetate and moderate levels of butyrate. We performed deep phenotyping using Biolog microarrays. Using human intestinal cell lines, we discovered that C. minuta demonstrated strong anti-inflammatory activity, resulting in reduced levels of proinflammatory IL-8 cytokines via the inhibition of the NF-κB signaling pathway. Furthermore, C. minuta protected intestinal epithelial integrity in vitro. Finally, in two distinct animal models of acute colitis, C. minuta prevented intestinal damage, reduced colonic inflammation, and promoted mucosal healing. Together, these results indicate that C. minuta has potent immunomodulatory properties, underscoring its potential use in innovative microbiome-based IBD biotherapies.

Obesity is associated with gut microbiota dysbiosis, characterized by a high Firmicutes/Bacteroidetes ratio. Gut-dwelling bacteria of the Christensenellaceae family have been proposed to act as keystones of the human gut ecosystem and to prevent adipogenesis. The objectives of the present study were to demonstrate the antiobesity potential of a new strain of Christensenella minuta in preclinical models and explore related mechanisms of action. The antiobesity potential of C. minuta DSM33407 was assessed in a diet-induced obesity mouse model. Changes in hepatic lipid metabolism were explored using targeted transcriptomics. Effects on gut microbiota were further assessed in a humanized Simulator of the Human Intestinal Microbial Ecosystem (SHIME ® ) model inoculated with obese fecal samples. Shotgun metagenomics was applied to study microbial community structures in both models. C. minuta DSM33407 protected from diet-induced obesity and regulated associated metabolic markers such as glycemia and leptin. It also regulated hepatic lipid metabolism through a strong inhibition of de novo lipogenesis and maintained gut epithelial integrity. In the humanized SHIME ® model, these effects were associated with modulations of the intestinal microbiota characterized by a decreased Firmicutes/Bacteroidetes ratio. These data indicate that C. minuta DSM33407 is a convincing therapeutic candidate for the management of obesity and associated metabolic disorders.

Background: Cancer cachexia is a multifactorial syndrome characterized by multiple metabolic dysfunctions. Besides the muscle, other organs such as the liver and the gut microbiota may also contribute to this syndrome. Indeed, the gut microbiota, an important regulator of the host metabolism, is altered in the C26 preclinical model of cancer cachexia. Interventions targeting the gut microbiota have shown benefits, but mechanisms underlying the host-microbiota crosstalk in this context are still poorly understood., Methods: To explore this crosstalk, we combined proton nuclear magnetic resonance ( 1 H-NMR) metabolomics in multiple compartments with 16S rDNA sequencing. These analyses were complemented by molecular and biochemical analyses, as well as hepatic transcriptomics., Results: 1 H-NMR revealed major changes between control (CT) and cachectic (C26) mice in the four analysed compartments (i.e. caecal content, portal vein, liver, and vena cava). More specifically, glucose metabolism pathways in the C26 model were altered with a reduction in glycolysis and gluconeogenesis and an activation of the hexosamine pathway, arguing against the existence of a Cori cycle in this model. In parallel, amino acid uptake by the liver, with an up to four-fold accumulation of nine amino acids (q-value <0.05), was mainly used for acute phase response proteins synthesis rather than to fuel the tricarboxylic acid cycle and gluconeogenesis. We also identified a 35% reduction in hepatic carnitine levels (q-value <0.05) and a lower activation of the phosphatidylcholine pathway as potential contributors to the hepatic steatosis present in this model. Our work also reveals a reduction of different beneficial intestinal bacterial activities in cancer cachexia. We found decreased levels of two short-chain fatty acids, acetate and butyrate (72% and 88% reduction in C26 caecal content; q-value <0.001), and a reduction in aromatic amino acid metabolites, which may contribute to the altered intestinal homeostasis in these mice. A member of the Ruminococcaceae family (ASV 2) was identified as the main bacterium responsible for the drop in butyrate. Finally, we report a two-fold intestinal transit acceleration (P-value <0.001) as a key factor shaping the gut microbiota composition and activity in cancer cachexia, which together lead to a faecal loss of proteins and amino acids., Conclusions: Our work highlights new metabolic pathways potentially involved in cancer cachexia and further supports the interest of exploring the gut microbiota composition and activity, as well as intestinal transit, in cancer patients with and without cachexia., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Objective: Increasing evidence indicates that intestinal microbiota play a role in diverse metabolic processes via intestinal butyrate production. Human bariatric surgery data suggest that the gut-brain axis is also involved in this process, but the underlying mechanisms remain unknown., Methods: We compared the effect of fecal microbiota transfer (FMT) from post-Roux-en-Y gastric bypass (RYGB) donors vs oral butyrate supplementation on ( 123 I-FP-CIT-determined) brain dopamine transporter (DAT) and serotonin transporter (SERT) binding as well as stable isotope-determined insulin sensitivity at baseline and after 4 weeks in 24 male and female treatment-naïve metabolic syndrome subjects. Plasma metabolites and fecal microbiota were also determined at these time points., Results: We observed an increase in brain DAT after donor FMT compared to oral butyrate that reduced this binding. However, no effect on body weight and insulin sensitivity was demonstrated after post-RYGB donor feces transfer in humans with metabolic syndrome. Increases in fecal levels of Bacteroides uniformis were significantly associated with an increase in DAT, whereas increases in Prevotella spp. showed an inverse association. Changes in the plasma metabolites glycine, betaine, methionine, and lysine (associated with the S-adenosylmethionine cycle) were also associated with altered striatal DAT expression., Conclusions: Although more and larger studies are needed, our data suggest a potential gut microbiota-driven modulation of brain dopamine and serotonin transporters in human subjects with obese metabolic syndrome. These data also suggest the presence of a gut-brain axis in humans that can be modulated., Ntr Registration: 4488., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Recent developments in the understanding of the relationship between the microbiota and its host have provided evidence regarding the therapeutic potential of selected microorganisms to prevent or treat disease. According to Directive 2001/83/EC, in the European Union (EU), any product intended to prevent or treat disease is defined as a medicinal product and requires a marketing authorization by competent authorities prior to commercialization. Even if the pharmaceutical regulatory framework is harmonized at the EU level, obtaining marketing authorisations for medicinal products remains very challenging for Live Biotherapeutic Products (LBPs). Compared to other medicinal products currently on the market, safety assessment of LBPs represents a real challenge because of their specific characteristics and mode of action. Indeed, LBPs are not intended to reach the systemic circulation targeting distant organs, tissues, or receptors, but rather exert their effect through direct interactions with the complex native microbiota and/or the modulation of complex host-microbiota relation, indirectly leading to distant biological effects within the host. Hence, developers must rely on a thorough risk analysis, and pharmaceutical guidelines for other biological products should be taken into account in order to design relevant non-clinical and clinical development programmes. Here we aim at providing a roadmap for a risk analysis that takes into account the specificities of LBPs. We describe the different risks associated with these products and their interactions with the patient. Then, from that risk assessment, we propose solutions to design non-clinical programmes and First in Human (FIH) early clinical trials appropriate to assess LBP safety., (Copyright © 2020 Rouanet, Bolca, Bru, Claes, Cvejic, Girgis, Harper, Lavergne, Mathys, Pane, Pot, Shortt, Alkema, Bezulowsky, Blanquet-Diot, Chassard, Claus, Hadida, Hemmingsen, Jeune, Lindman, Midzi, Mogna, Movitz, Nasir, Oberreither, Seegers, Sterkman, Valo, Vieville and Cordaillat-Simmons.)

Metabolomics has found numerous applications in the study of liver metabolism in health and disease. Metabolomics studies can be conducted in a variety of biological matrices ranging from easily accessible biofluids such as urine, blood or feces, to organs, tissues or even cells. Sample collection and storage are critical steps for which standard operating procedures must be followed. Inappropriate sample collection or storage can indeed result in high variability, interferences with instrumentation or degradation of metabolites. In this review, we will first highlight important general factors that should be considered when planning sample collection in the study design of metabolomic studies, such as nutritional status and circadian rhythm. Then, we will discuss in more detail the specific procedures that have been described for optimal pre-analytical handling of the most commonly used matrices (urine, blood, feces, tissues and cells).

Background and Purpose: Epidiolex™, a form of highly purified cannabidiol (CBD) derived from Cannabis plants, has demonstrated seizure control activity in patients with Dravet syndrome, without a fully elucidated mechanism of action. We have employed an unbiased approach to investigate this mechanism at a cellular level., Experimental Approach: We use a tractable biomedical model organism, Dictyostelium, to identify a protein controlling the effect of CBD and characterize this mechanism. We then translate these results to a Dravet syndrome mouse model and an acute in vitro seizure model., Key Results: CBD activity is partially dependent upon the mitochondrial glycine cleavage system component, GcvH1 in Dictyostelium, orthologous to the human glycine cleavage system component H protein, which is functionally linked to folate one-carbon metabolism (FOCM). Analysis of FOCM components identified a mechanism for CBD in directly inhibiting methionine synthesis. Analysis of brain tissue from a Dravet syndrome mouse model also showed drastically altered levels of one-carbon components including methionine, and an in vitro rat seizure model showed an elevated level of methionine that is attenuated following CBD treatment., Conclusions and Implications: Our results suggest a novel mechanism for CBD in the regulating methionine levels and identify altered one-carbon metabolism in Dravet syndrome and seizure activity., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objectives: The biological mechanisms linking diet-related obesity and depression remain unclear. Therefore, we examined the impact of high-fat diet (HFD) on murine behaviour, intestinal microbiome, brain metabolome, neuropeptide Y (NPY) expression, and dipeptidyl peptidase-4 (DPP-4) activity. Methods: Male C57Bl/6J mice were fed an HFD (60 kJ% from fat) or control diet (12 kJ% from fat) for 8 weeks, followed by behavioural phenotyping. Caecal microbiome was analysed by 16S rDNA sequencing, brain metabolome by 1 H nuclear magnetic resonance, NPY expression by PCR and immunoassay, and dipeptidyl peptidase-4 (DPP-4) activity by enzymatic assay. The effect of a 4-week treatment with imipramine (7 mg/kg/day) and the DPP-4 inhibitor sitagliptin (50 mg/kg/day) on HFD-induced behavioural changes was also tested. Results: HFD led to a depression-like phenotype as revealed by reduced sociability and sucrose preference. In the caecum, HFD diminished the relative abundance of Bacteroidetes and increased the relative abundance of Firmicutes and Cyanobacteria. In the brain, HFD modified the metabolome of prefrontal cortex and striatum, changing the relative concentrations of molecules involved in energy metabolism (e.g. lactate) and neuronal signalling (e.g. γ-aminobutyric acid). The expression of NPY in hypothalamus and hippocampus was decreased by HFD, whereas plasma NPY and DPP-4-like activity were increased. The HFD-induced anhedonia remained unaltered by imipramine and sitagliptin. Discussion: The depression-like behaviour induced by prolonged HFD in mice is associated with distinct alterations of intestinal microbiome, brain metabolome, NPY system, and DPP-4-like activity. Importantly, the HFD-evoked behavioural disturbance remains unaltered by DPP-4 inhibition and antidepressant treatment with imipramine.

This issue of Cell Host & Microbe highlights the opposite faces of Prevotella copri (P. copri). Tett et al. (2019) and Fehlner-Peach et al. (2019) unravel the complexity of gut dwelling P. copri, whereas Rolhion et al. (2019) explore the P. copri dark side with its ability to potentiate Listeria monocytogenes pathogenicity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The rapid expansion of Type 2 Diabetes (T2D), that currently affects 90% of people suffering from diabetes, urges us to develop a better understanding of the metabolic processes involved in the disease process in order to develop better therapies. The most commonly used model for T2D research is the db/db (BKS.Cg-Dock7 < m > +/+ Lepr < db >/J) mouse model. Yet, a systematic 1 H NMR based metabolomics characterisation of most tissues in this animal model has not been published. Here, we provide a systematic organ-specific metabolomics analysis of this widely employed model using NMR spectroscopy., Objectives: The aim of this study was to characterise the metabolic modulations associated with T2D in db/db mice in 18 relevant biological matrices., Methods: High-resolution 1 H-NMR and 2D-NMR spectroscopy were applied to 18 biological matrices of 12 db/db mice (WT control n = 6, db/db = 6) aged 22 weeks, when diabetes is fully established., Results: 61 metabolites associated with T2D were identified. Kidney, spleen, eye and plasma were the biological matrices carrying the largest metabolomics modulations observed in established T2D, based on the total number of metabolites that showed a statistical difference between the diabetic and control group in each tissue (16 in each case) and the strength of the O-PLS DA model for each tissue. Glucose and glutamate were the most commonly associated metabolites found significantly increased in nine biological matrices. Investigated sections where no increase of glucose was associated with T2D include all intestinal segments (i.e. duodenum, jejunum, ileum and colon). Microbial co-metabolites such as acetate and butyrate, used as carbon sources by the host, were identified in excess in the colonic tissues of diabetic individuals., Conclusions: The metabolic biomarkers identified using 1 H NMR-based metabolomics will represent a useful resource to explore metabolic pathways involved in T2D in the db/db mouse model.

Background & Aims: This review examines to what extent high-protein diets (HPD), which may favor body weight loss and improve metabolic outcomes in overweight and obese individuals, may also impact the gut environment, shaping the microbiota and the host-microbe (co)metabolic pathways and products, possibly affecting large intestine mucosa homeostasis., Methods: PubMed-referenced publications were analyzed with an emphasis on dietary intervention studies involving human volunteers in order to clarify the beneficial vs. deleterious effects of HPD in terms of both metabolic and gut-related health parameters; taking into account the interactions with the gut microbiota., Results: HPD generally decrease body weight and improve blood metabolic parameters, but also modify the fecal and urinary contents in various bacterial metabolites and co-metabolites. The effects of HPD on the intestinal microbiota composition appear rather heterogeneous depending on the type of dietary intervention. Recently, HPD consumption was shown to modify the expression of genes playing key roles in homeostatic processes in the rectal mucosa, without evidence of intestinal inflammation. Importantly, the effects of HPD on the gut were dependent on the protein source (i.e. from plant or animal sources), a result which should be considered for further investigations., Conclusion: Although HPD appear to be efficient for weight loss, the effects of HPD on microbiota-derived metabolites and gene expression in the gut raise new questions on the impact of HPD on the large intestine mucosa homeostasis leading the authors to recommend some caution regarding the utilization of HPD, notably in a recurrent and/or long-term ways., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Introduction: Death is the permanent cessation of the critical functions of the organism as a whole. However, the shutdown of a complex biological organism does not abruptly terminate at time of death. New high-throughput technologies allow the systematic investigation of the biochemical modulations occurring after death. Recent genomics studies have demonstrated that genes remain active after death, triggering upregulation of some genes and initiating feedback loops. These genes were mostly involved in pathways related to immunity, inflammation and cancer. These genetic modulations suggest many biochemical events persist after death, which can be captured using a metabolomics approach., Objectives: This proof of concept work aimed to determine whether NMR spectroscopy could identify metabolomics changes occurring after death, and characterise the nature of these metabolomics modulations., Methods: High-resolution 1 H-NMR spectroscopy was applied to six biological matrices: heart, kidney, liver, spleen, skin and white adipose tissue of ten adult mice at three different type points., Results: Forty-three metabolites were associated with post mortem metabolomics modulations. Kidney, heart and spleen showed the highest metabolic perturbations. Conversely, skin and white adipose tissue were the least altered matrices. Early metabolic modulations were associated with energy metabolism and DNA synthesis, by contrast, late metabolomics modulations were associated with microbial metabolism., Conclusions: NMR has proven potential to determine the time of death based on post-mortem metabolomics modulations. This could be useful in the context of transplants, forensic studies and as internal quality control in metabolomics studies. Further investigations are required to validate these findings in humans in order to determine which compounds robustly reflect post-mortem metabolic fluctuations to accurately determine the time of death.

Background: Infection of the digestive track by gastro-intestinal pathogens results in the development of symptoms ranging from mild diarrhea to more severe clinical signs such as dysentery, severe dehydration and potentially death. Although, antibiotics are efficient to tackle infections, they also trigger dysbiosis that has been suggested to result in variation in weight gain in animal production systems., Results: Here is the first study demonstrating the metabolic impact of infection by a gastro-intestinal pathogen (Brachyspira pilosicoli) and its resolution by antibiotic treatment (tiamulin) on the host (chicken) systemic metabolism and gut microbiota composition using high-resolution 1 H nuclear magnetic resonance (NMR) spectroscopy and 16S rDNA next generation sequencing (NGS). Clear systemic metabolic markers of infections such as glycerol and betaine were identified. Weight loss in untreated animals was in part explained by the observation of a modification of systemic host energy metabolism characterized by the utilization of glycerol as a glucose precursor. However, antibiotic treatment triggered an increased VLDL/HDL ratio in plasma that may contribute to reducing weight loss observed in treated birds. All metabolic responses co-occurred with significant shift of the microbiota upon infection or antibiotic treatment., Conclusion: This study indicates that infection and antibiotic treatment trigger dysbiosis that may impact host systemic energy metabolism and cause phenotypic and health modifications.

The gut microbiota coexists in partnership with the human host through adaptations to environmental and physiological changes that help maintain dynamic homeostatic healthy states. Break-down of this delicate balance under sustained exposure to stressors (e.g. unhealthy diets) can, however, contribute to the onset of disease. Diet is a key modifiable environmental factor that modulates the gut microbiota and its metabolic capacities that, in turn, could impact human physiology. On this basis, the diet and the gut microbiota could act as synergistic forces that provide resilience against disease or that speed the progress from health to disease states. Associations between unhealthy dietary patterns, non-communicable diseases and intestinal dysbiosis can be explained by this hypothesis. Translational studies showing that dietary-induced alterations in microbial communities recapitulate some of the pathological features of the original host further support this notion. In this introductory paper by the European project MyNewGut, we briefly summarize the investigations conducted to better understand the role of dietary patterns and food components in metabolic and mental health and the specificities of the microbiome-mediating mechanisms. We also discuss how advances in the understanding of the microbiome's role in dietary health effects can help to provide acceptable scientific grounds on which to base dietary advice for promoting healthy living., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Competing interests: None declared.

Background: Although high-protein diets (HPDs) are frequently consumed for body-weight control, little is known about the consequences for gut microbiota composition and metabolic activity and for large intestine mucosal homeostasis. Moreover, the effects of HPDs according to the source of protein need to be considered in this context. Objective: The objective of this study was to evaluate the effects of the quantity and source of dietary protein on microbiota composition, bacterial metabolite production, and consequences for the large intestinal mucosa in humans. Design: A randomized, double-blind, parallel-design trial was conducted in 38 overweight individuals who received a 3-wk isocaloric supplementation with casein, soy protein, or maltodextrin as a control. Fecal and rectal biopsy-associated microbiota composition was analyzed by 16S ribosomal DNA sequencing. Fecal, urinary, and plasma metabolomes were assessed by 1 H-nuclear magnetic resonance. Mucosal transcriptome in rectal biopsies was determined with the use of microarrays. Results: HPDs did not alter the microbiota composition, but induced a shift in bacterial metabolism toward amino acid degradation with different metabolite profiles according to the protein source. Correlation analysis identified new potential bacterial taxa involved in amino acid degradation. Fecal water cytotoxicity was not modified by HPDs, but was associated with a specific microbiota and bacterial metabolite profile. Casein and soy protein HPDs did not induce inflammation, but differentially modified the expression of genes playing key roles in homeostatic processes in rectal mucosa, such as cell cycle or cell death. Conclusions: This human intervention study shows that the quantity and source of dietary proteins act as regulators of gut microbiota metabolite production and host gene expression in the rectal mucosa, raising new questions on the impact of HPDs on the large intestine mucosa homeostasis. This trial was registered at clinicaltrials.gov as NCT02351297., (© 2017 American Society for Nutrition.)

Choline is a crucial methyl donor necessary for epigenetic regulation. In this issue of Cell Host & Microbe, Romano et al. (2017) demonstrate that choline-utilizing gut bacteria compete with their host for this essential resource, calling for a systematic consideration of gut microbial composition for personalized diet recommendations., (Copyright © 2017. Published by Elsevier Inc.)

Glucagon-like peptide one (GLP-1)-based therapies for reducing hyperglycemia in type 2 diabetic patients are efficient, though some individuals develop GLP-1 resistance. In a recent issue of Cell Metabolism, Grasset et al. (2017) demonstrated that GLP-1 sensitivity is modulated by gut bacteria through NO signaling in the enteric nervous system., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Pathogenic anaerobes Brachyspira spp. are responsible for an increasing number of Intestinal Spirochaetosis (IS) cases in livestock against which few approved treatments are available. Tiamulin is used to treat swine dysentery caused by Brachyspira spp. and recently has been used to handle avian intestinal spirochaetosis (AIS). The therapeutic dose used in chickens requires further evaluation since cases of bacterial resistance to tiamulin have been reported. In this study, we evaluated the impact of tiamulin at varying concentrations on the metabolism of B. pilosicoli using a 1 H-NMR-based metabonomics approach allowing the capture of the overall bacterial metabolic response to antibiotic treatment. Based on growth curve studies, tiamulin impacted bacterial growth even at very low concentration (0.008 μg/mL) although its metabolic activity was barely affected 72 h post exposure to antibiotic treatment. Only the highest dose of tiamulin tested (0.250 μg/mL) caused a major metabolic shift. Results showed that below this concentration, bacteria could maintain a normal metabolic trajectory despite significant growth inhibition by the antibiotic, which may contribute to disease reemergence post antibiotic treatment. Indeed, we confirmed that B. pilosicoli remained viable even after exposition to the highest antibiotic dose. This paper stresses the need to ensure new evaluation of bacterial viability post bacteriostatic exposure such as tiamulin to guarantee treatment efficacy and decrease antibiotic resistance development., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cancer cachexia is a multifactorial syndrome that includes muscle wasting and inflammation. As gut microbes influence host immunity and metabolism, we investigated the role of the gut microbiota in the therapeutic management of cancer and associated cachexia. A community-wide analysis of the caecal microbiome in two mouse models of cancer cachexia (acute leukaemia or subcutaneous transplantation of colon cancer cells) identified common microbial signatures, including decreased Lactobacillus spp. and increased Enterobacteriaceae and Parabacteroides goldsteinii/ASF 519. Building on this information, we administered a synbiotic containing inulin-type fructans and live Lactobacillus reuteri 100-23 to leukaemic mice. This treatment restored the Lactobacillus population and reduced the Enterobacteriaceae levels. It also reduced hepatic cancer cell proliferation, muscle wasting and morbidity, and prolonged survival. Administration of the synbiotic was associated with restoration of the expression of antimicrobial proteins controlling intestinal barrier function and gut immunity markers, but did not impact the portal metabolomics imprinting of energy demand. In summary, this study provided evidence that the development of cancer outside the gut can impact intestinal homeostasis and the gut microbial ecosystem and that a synbiotic intervention, by targeting some alterations of the gut microbiota, confers benefits to the host, prolonging survival and reducing cancer proliferation and cachexia.

Exposure to environmental chemicals has been linked to various health disorders, including obesity, type 2 diabetes, cancer and dysregulation of the immune and reproductive systems, whereas the gastrointestinal microbiota critically contributes to a variety of host metabolic and immune functions. We aimed to evaluate the bidirectional relationship between gut bacteria and environmental pollutants and to assess the toxicological relevance of the bacteria-xenobiotic interplay for the host. We examined studies using isolated bacteria, faecal or caecal suspensions-germ-free or antibiotic-treated animals-as well as animals reassociated with a microbiota exposed to environmental chemicals. The literature indicates that gut microbes have an extensive capacity to metabolise environmental chemicals that can be classified in five core enzymatic families (azoreductases, nitroreductases, β-glucuronidases, sulfatases and β-lyases) unequivocally involved in the metabolism of >30 environmental contaminants. There is clear evidence that bacteria-dependent metabolism of pollutants modulates the toxicity for the host. Conversely, environmental contaminants from various chemical families have been shown to alter the composition and/or the metabolic activity of the gastrointestinal bacteria, which may be an important factor contributing to shape an individual's microbiotype. The physiological consequences of these alterations have not been studied in details but pollutant-induced alterations of the gut bacteria are likely to contribute to their toxicity. In conclusion, there is a body of evidence suggesting that gut microbiota are a major, yet underestimated element that must be considered to fully evaluate the toxicity of environmental contaminants., Competing Interests: The authors declare no conflict of interest.

Inositol levels, maintained by the biosynthetic enzyme inositol-3-phosphate synthase (Ino1), are altered in a range of disorders, including bipolar disorder and Alzheimer's disease. To date, most inositol studies have focused on the molecular and cellular effects of inositol depletion without considering Ino1 levels. Here we employ a simple eukaryote, Dictyostelium discoideum, to demonstrate distinct effects of loss of Ino1 and inositol depletion. We show that loss of Ino1 results in an inositol auxotrophy that can be rescued only partially by exogenous inositol. Removal of inositol supplementation from the ino1(-) mutant resulted in a rapid 56% reduction in inositol levels, triggering the induction of autophagy, reduced cytokinesis, and substrate adhesion. Inositol depletion also caused a dramatic generalized decrease in phosphoinositide levels that was rescued by inositol supplementation. However, loss of Ino1 triggered broad metabolic changes consistent with the induction of a catabolic state that was not rescued by inositol supplementation. These data suggest a metabolic role for Ino1 that is independent of inositol biosynthesis. To characterize this role, an Ino1 binding partner containing SEL1L1 domains (Q54IX5) and having homology to mammalian macromolecular complex adaptor proteins was identified. Our findings therefore identify a new role for Ino1, independent of inositol biosynthesis, with broad effects on cell metabolism., (Copyright © 2016 Frej et al.)

Introduction: Poultry is one of the most consumed meat in the world and its related industry is always looking for ways to improve animal welfare and productivity. It is therefore essential to understand the metabolic response of the chicken to new feed formulas, various supplements, infections and treatments., Objectives: As a basis for future research investigating the impact of diet and infections on chicken's metabolism, we established a high-resolution proton nuclear magnetic resonance (NMR)-based metabolic atlas of the healthy chicken ( Gallus gallus )., Methods: Metabolic extractions were performed prior to 1 H-NMR and 2D NMR spectra acquisition on twelve biological matrices: liver, kidney, spleen, plasma, egg yolk and white, colon, caecum, faecal water, ileum, pectoral muscle and brain of 6 chickens. Metabolic profiles were then exhaustively characterized., Results: Nearly 80 metabolites were identified. A cross-comparison of these matrices was performed to determine metabolic variations between and within each section and highlighted that only eight core metabolites were systematically found in every matrice., Conclusion: This work constitutes a database for future NMR-based metabolomic investigations in relation to avian production and health., Competing Interests: Caroline I Le Roy, Martin J Woodward, Roberto M La Ragione, Luke J Mappley, Sandrine P Claus declares that they have no conflict of interest. Ethical approval All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Avian intestinal spirochaetosis (AIS) is a common disease occurring in poultry that can be caused by Brachyspira pilosicoli, a Gram-negative bacterium of the order Spirochaetes. During AIS, this opportunistic pathogen colonises the lower gastrointestinal (GI) tract of poultry (principally, the ileum, caeca, and colon), which can cause symptoms such as diarrhoea, reduced growth rate, and reduced egg production and quality. Due to the large increase of bacterial resistance to antibiotic treatment, the European Union banned in 2006 the prophylactic use of antibiotics as growth promoters in livestock. Consequently, the number of outbreaks of AIS has dramatically increased in the UK resulting in significant economic losses. This review summarises the current knowledge about AIS infection caused by B. pilosicoli and discusses various treatments and prevention strategies to control AIS.

Avian intestinal spirochaetosis (AIS) caused by Brachyspira spp., and notably Brachyspira pilosicoli, is common in layer flocks and reportedly of increasing incidence in broilers and broiler breeders. Disease manifests as diarrhoea, increased feed consumption, reduced growth rates and occasional mortality in broilers and these signs are shown in layers also associated with a delayed onset of lay, reduced egg weights, faecal staining of eggshells and non-productive ovaries. Treatment with Denagard® Tiamulin has been used to protect against B. pilosicoli colonisation, persistence and clinical presentation of AIS in commercial layers, but to date there has been no definitive study validating efficacy. Here, we used a poultry model of B. pilosicoli infection of layers to compare the impact of three doses of Denagard® Tiamulin. Four groups of thirty 17 week old commercial pre-lay birds were all challenged with B. pilosicoli strain B2904 with three oral doses two days apart. All birds were colonised within 2 days after the final oral challenge and mild onset of clinical signs were observed thereafter. A fifth group that was unchallenged and untreated was also included for comparison as healthy birds. Five days after the final oral Brachypira challenge three groups were given Denagard® Tiamulin in drinking water made up following the manufacturer's recommendations with doses verified as 58.7 ppm, 113 ppm and 225 ppm. Weight gain body condition and the level of diarrhoea of birds infected with B. pilosicoli were improved and shedding of the organism reduced significantly (p=0.001) following treatment with Denagard® Tiamulin irrespective of dose given. The level and duration of colonisation of organs of birds infected with B. pilosicoli was also reduced. Confirming previous findings we showed that the ileum, caeca, colon, and both liver and spleen were colonised and here we demonstrated that treatment with Denagard® Tiamulin resulted in significant reduction in the numbers of Brachyspira found in each of these sites and dramatic reduction in faecal shedding (p<0.001) to approaching zero as assessed by culture of cloacal swabs. Although the number of eggs produced per bird and the level of eggshell staining appeared unaffected, egg weights of treated birds were greater than those of untreated birds for a period of approximately two weeks following treatment. These data conclusively demonstrate the effectiveness of Denagard® Tiamulin in reducing B. pilosicoli infection in laying hens., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We aimed at evaluating the association between intestinal Lactobacillus sp. composition and their metabolic activity with the host metabolism in adult and elderly individuals. Faecal and plasma metabolites were measured and correlated to the Lactobacillus species distribution in healthy Estonian cohorts of adult (n = 16; < 48 y) and elderly (n = 33; > 65 y). Total cholesterol, LDL, C-reactive protein and glycated hemoglobin were statistically higher in elderly, while platelets, white blood cells and urinary creatinine were higher in adults. Aging was associated with the presence of L. paracasei and L. plantarum and the absence of L. salivarius and L. helveticus. High levels of intestinal Lactobacillus sp. were positively associated with increased concentrations of faecal short chain fatty acids, lactate and essential amino acids. In adults, high red blood cell distribution width was positively associated with presence of L. helveticus and absence of L. ruminis. L. helveticus was correlated to lactate and butyrate in faecal waters. This indicates a strong relationship between the composition of the gut Lactobacillus sp. and host metabolism. Our results confirm that aging is associated with modulations of blood biomarkers and intestinal Lactobacillus species composition. We identified specific Lactobacillus contributions to gut metabolic environment and related those to blood biomarkers. Such associations may prove useful to decipher the biological mechanisms underlying host-gut microbial metabolic interactions in an ageing population.

It is recognised that ageing induces various changes to the human colonic microbiota. Most relevant is a reduction in bifidobacteria, which is a health-positive genus. Prebiotics, such as galacto-oligosaccharides (GOS), are dietary ingredients that selectively fortify beneficial gut microbial groups. Therefore, they have the potential to reverse the age-related decline in bifidobacteria and modulate associated health parameters. We assessed the effect of GOS mixture (Bimuno (B-GOS)) on gut microbiota, markers of immune function and metabolites in forty elderly (age 65-80 years) volunteers in a randomised, double-blind, placebo (maltodextrin)-controlled, cross-over study. The intervention periods consisted of 10 weeks with daily doses of 5·5 g/d with a 4-week washout period in between. Blood and faecal samples were collected for the analyses of faecal bacterial populations and immune and metabolic biomarkers. B-GOS consumption led to significant increases in bacteroides and bifidobacteria, the latter correlating with increased lactic acid in faecal waters. Higher IL-10, IL-8, natural killer cell activity and C-reactive protein and lower IL-1β were also observed. Administration of B-GOS to elderly volunteers may be useful in positively affecting the microbiota and some markers of immune function associated with ageing.

A novel automated algorithm is proposed to approximate the seizure onset zone (SOZ), while providing reproducible output. The SOZ, a surrogate marker for the epileptogenic zone (EZ), was approximated from intracranial electroencephalograms (iEEG) of nine people with temporal lobe epilepsy (TLE), using three methods: (1) Total ripple length (TRL): Manually segmented high-frequency oscillations, (2) Rippleness (R): Area under the curve (AUC) of the autocorrelation functions envelope, and (3) Autoregressive model residual variation (ARR, novel algorithm): Time-variation of residuals from autoregressive models of iEEG windows. TRL, R, and ARR results were compared in terms of separability, using Kolmogorov-Smirnov tests, and performance, using receiver operating characteristic (ROC) curves, to the gold standard for SOZ delineation: visual observation of ictal video-iEEGs. TRL, R, and ARR can distinguish signals from iEEG channels located within the SOZ from those outside it (p < 0.01). The ROC AUC was 0.82 for ARR, while it was 0.79 for TRL, and 0.64 for R. ARR outperforms TRL and R, and may be applied to identify channels in the SOZ automatically in interictal iEEGs of people with TLE. ARR, interpreted as evidence for nonharmonicity of high-frequency EEG components, could provide a new way to delineate the EZ, thus contributing to presurgical workup.

γ-butyrobetaine has long been known as the precursor of endogenous L-carnitine synthesis. In this issue, Koeth et al. (2014) demonstrate that it is also a major metabolite of L-carnitine degradation by gut bacteria that precedes the enteric production of trimethylamine and trimethylamine-N-oxide., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose of Review: There is growing interest in applying metabolic profiling technologies to food science as this approach is now embedded into the foodomics toolbox. This review aims at exploring how metabolic profiling can be applied to the development of functional foods., Recent Findings: One of the biggest challenges of modern nutrition is to propose a healthy diet to populations worldwide that must suit high inter-individual variability driven by complex gene-nutrient-environment interactions. Although a number of functional foods are now proposed in support of a healthy diet, a one-size-fits-all approach to nutrition is inappropriate and new personalized functional foods are necessary. Metabolic profiling technologies can assist at various levels of the development of functional foods, from screening for food composition to identification of new biomarkers of food intake to support diet intervention and epidemiological studies., Summary: Modern 'omics' technologies, including metabolic profiling, will support the development of new personalized functional foods of high relevance to 21st century medical challenges, such as controlling the worldwide spread of metabolic disorders and ensuring healthy ageing.

A variety of foods have been implicated in symptoms of patients with Irritable Bowel Syndrome (IBS) but wheat products are most frequently cited by patients as a trigger. Our aim was to investigate the effects of breads, which were fermented for different lengths of time, on the colonic microbiota using in vitro batch culture experiments. A set of in vitro anaerobic culture systems were run over a period of 24 h using faeces from 3 different IBS donors (Rome Criteria-mainly constipated) and 3 healthy donors. Changes in gut microbiota during a time course were identified by fluorescence in situ hybridisation (FISH), whilst the small-molecular weight metabolomic profile was determined by NMR analysis. Gas production was separately investigated in non pH-controlled, 36 h batch culture experiments. Numbers of bifidobacteria were higher in healthy subjects compared to IBS donors. In addition, the healthy donors showed a significant increase in bifidobacteria (P<0.005) after 8 h of fermentation of a bread produced using a sourdough process (type C) compared to breads produced with commercial yeasted dough (type B) and no time fermentation (Chorleywood Breadmaking process) (type A). A significant decrease of δ-Proteobacteria and most Gemmatimonadetes species was observed after 24 h fermentation of type C bread in both IBS and healthy donors. In general, IBS donors showed higher rates of gas production compared to healthy donors. Rates of gas production for type A and conventional long fermentation (type B) breads were almost identical in IBS and healthy donors. Sourdough bread produced significantly lower cumulative gas after 15 h fermentation as compared to type A and B breads in IBS donors but not in the healthy controls. In conclusion, breads fermented by the traditional long fermentation and sourdough are less likely to lead to IBS symptoms compared to bread made using the Chorleywood Breadmaking Process.

An individual's metabolic phenotype, and ultimately health, is significantly influenced by complex interactions between their genes and the diet. Studying these associations and their downstream biochemical consequences has proven extremely challenging using traditional hypothesis-led strategies. Metabonomics, a systems biology approach, allows the global metabolic response of biological systems to stimuli to be characterised. Through the application of this approach to nutritional-based research, nutrimetabonomics, the biochemical response to dietary inputs is being investigated at greater levels of resolution. This has allowed novel insights to be gained regarding intricate diet-gene interactions and their consequences for health and disease. In this review, we present some of the latest research exploring how nutrimetabonomics can assist in the elucidation of novel biomarkers of dietary behaviour and provide new perspectives on diet-health relationships. The use of this approach to study the metabolic interplay between the gut microbiota and the host is also explored.

Objective: Proper interactions between the intestinal mucosa, gut microbiota and nutrient flow are required to establish homoeostasis of the host. Since the proximal part of the small intestine is the first region where these interactions occur, and since most of the nutrient absorption occurs in the jejunum, it is important to understand the dynamics of metabolic responses of the mucosa in this intestinal region., Design: Germ-free mice aged 8-10 weeks were conventionalised with faecal microbiota, and responses of the jejunal mucosa to bacterial colonisation were followed over a 30-day time course. Combined transcriptome, histology, (1)H NMR metabonomics and microbiota phylogenetic profiling analyses were used., Results: The jejunal mucosa showed a two-phase response to the colonising microbiota. The acute-phase response, which had already started 1 day after conventionalisation, involved repression of the cell cycle and parts of the basal metabolism. The secondary-phase response, which was consolidated during conventionalisation (days 4-30), was characterised by a metabolic shift from an oxidative energy supply to anabolic metabolism, as inferred from the tissue transcriptome and metabonome changes. Detailed transcriptome analysis identified tissue transcriptional signatures for the dynamic control of the metabolic reorientation in the jejunum. The molecular components identified in the response signatures have known roles in human metabolic disorders, including insulin sensitivity and type 2 diabetes mellitus., Conclusion: This study elucidates the dynamic jejunal response to the microbiota and supports a prominent role for the jejunum in metabolic control, including glucose and energy homoeostasis. The molecular signatures of this process may help to find risk markers in the declining insulin sensitivity seen in human type 2 diabetes mellitus, for instance.

Objective: To highlight the contribution of the gut microbiota to the modulation of host metabolism by dietary inulin-type fructans (ITF prebiotics) in obese women., Methods: A double blind, placebo controlled, intervention study was performed with 30 obese women treated with ITF prebiotics (inulin/oligofructose 50/50 mix; n=15) or placebo (maltodextrin; n=15) for 3 months (16 g/day). Blood, faeces and urine sampling, oral glucose tolerance test, homeostasis model assessment and impedancemetry were performed before and after treatment. The gut microbial composition in faeces was analysed by phylogenetic microarray and qPCR analysis of 16S rDNA. Plasma and urine metabolic profiles were analysed by 1H-NMR spectroscopy., Results: Treatment with ITF prebiotics, but not the placebo, led to an increase in Bifidobacterium and Faecalibacterium prausnitzii; both bacteria negatively correlated with serum lipopolysaccharide levels. ITF prebiotics also decreased Bacteroides intestinalis, Bacteroides vulgatus and Propionibacterium, an effect associated with a slight decrease in fat mass and with plasma lactate and phosphatidylcholine levels. No clear treatment clustering could be detected for gut microbial analysis or plasma and urine metabolomic profile analyses. However, ITF prebiotics led to subtle changes in the gut microbiota that may importantly impact on several key metabolites implicated in obesity and/or diabetes., Conclusions: ITF prebiotics selectively changed the gut microbiota composition in obese women, leading to modest changes in host metabolism, as suggested by the correlation between some bacterial species and metabolic endotoxaemia or metabolomic signatures.

Modeling aging and age-related pathologies presents a substantial analytical challenge given the complexity of gene-environment influences and interactions operating on an individual. A top-down systems approach is used to model the effects of lifelong caloric restriction, which is known to extend life span in several animal models. The metabolic phenotypes of caloric-restricted (CR; n = 24) and pair-housed control-fed (CF; n = 24) Labrador Retriever dogs were investigated by use of orthogonal projection to latent structures discriminant analysis (OPLS-DA) to model both generic and age-specific responses to caloric restriction from the ¹H NMR blood serum profiles of young and older dogs. Three aging metabolic phenotypes were resolved: (i) an aging metabolic phenotype independent of diet, characterized by high levels of glutamine, creatinine, methylamine, dimethylamine, trimethylamine N-oxide, and glycerophosphocholine and decreasing levels of glycine, aspartate, creatine and citrate indicative of metabolic changes associated largely with muscle mass; (ii) an aging metabolic phenotype specific to CR dogs that consisted of relatively lower levels of glucose, acetate, choline, and tyrosine and relatively higher serum levels of phosphocholine with increased age in the CR population; (iii) an aging metabolic phenotype specific to CF dogs including lower levels of liproprotein fatty acyl groups and allantoin and relatively higher levels of formate with increased age in the CF population. There was no diet metabotype that consistently differentiated the CF and CR dogs irrespective of age. Glucose consistently discriminated between feeding regimes in dogs (≥312 weeks), being relatively lower in the CR group. However, it was observed that creatine and amino acids (valine, leucine, isoleucine, lysine, and phenylalanine) were lower in the CR dogs (<312 weeks), suggestive of differences in energy source utilization. ¹H NMR spectroscopic analysis of longitudinal serum profiles enabled an unbiased evaluation of the metabolic markers modulated by a lifetime of caloric restriction and showed differences in the metabolic phenotype of aging due to caloric restriction, which contributes to longevity studies in caloric-restricted animals. Furthermore, OPLS-DA provided a framework such that significant metabolites relating to life extension could be differentiated and integrated with aging processes.

Background: The process of weaning causes a major shift in intestinal microbiota and is a critical period for developing appropriate immune responses in young mammals., Objective: To use a new systems approach to provide an overview of host metabolism and the developing immune system in response to nutritional intervention around the weaning period., Design: Piglets (n=14) were weaned onto either an egg-based or soya-based diet at 3 weeks until 7 weeks, when all piglets were switched onto a fish-based diet. Half the animals on each weaning diet received Bifidobacterium lactis NCC2818 supplementation from weaning onwards. Immunoglobulin production from immunologically relevant intestinal sites was quantified and the urinary (1)H NMR metabolic profile was obtained from each animal at post mortem (11 weeks)., Results: Different weaning diets induced divergent and sustained shifts in the metabolic phenotype, which resulted in the alteration of urinary gut microbial co-metabolites, even after 4 weeks of dietary standardisation. B lactis NCC2818 supplementation affected the systemic metabolism of the different weaning diet groups over and above the effects of diet. Additionally, production of gut mucosa-associated IgA and IgM was found to depend upon the weaning diet and on B lactis NCC2818 supplementation., Conclusion: The correlation of urinary (1)H NMR metabolic profile with mucosal immunoglobulin production was demonstrated, thus confirming the value of this multi-platform approach in uncovering non-invasive biomarkers of immunity. This has clear potential for translation into human healthcare with the development of urine testing as a means of assessing mucosal immune status. This might lead to early diagnosis of intestinal dysbiosis and with subsequent intervention, arrest disease development. This system enhances our overall understanding of pathologies under supra-organismal control.