99 results found
Giallourou N, Urbaniak C, Puebla-Barragan S, et al., 2021, Characterizing the breast cancer lipidome and its interaction with the tissue microbiota, Communications Biology, Vol: 4, ISSN: 2399-3642
Breast cancer is the most diagnosed cancer amongst women worldwide. We have previously shown that there is a breast microbiota which differs between women who have breast cancer and those who are disease-free. To better understand the local biochemical perturbations occurring with disease and the potential contribution of the breast microbiome, lipid profiling was performed on non-tumor breast tissue collected from 19 healthy women and 42 with breast cancer. Here we identified unique lipid signatures between the two groups with greater amounts of lysophosphatidylcholines and oxidized cholesteryl esters in the tissue from women with breast cancer and lower amounts of ceramides, diacylglycerols, phosphatidylcholines, and phosphatidylethanolamines. By integrating these lipid signatures with the breast bacterial profiles, we observed that Gammaproteobacteria and those from the class Bacillus, were negatively correlated with ceramides, lipids with antiproliferative properties. In the healthy tissues, diacylglyerols were positively associated with Acinetobacter, Lactococcus, Corynebacterium, Prevotella and Streptococcus. These bacterial groups were found to possess the genetic potential to synthesize these lipids. The cause-effect relationships of these observations and their contribution to disease patho-mechanisms warrants further investigation for a disease afflicting millions of women around the world.
Osman A, Zuffa S, Walton G, et al., 2021, Post-weaning A1/A2 β-casein milk intake modulates depressive-like behavior, brain μ-opioid receptors, and the metabolome of rats, iScience, Vol: 24, ISSN: 2589-0042
The postnatal period is critical for brain and behavioral development and is sensitive to environmental stimuli, such as nutrition. Prevention of weaning from maternal milk was previously shown to cause depressive-like behavior in rats. Additionally, loss of dietary casein was found to act as a developmental trigger for a population of brain opioid receptors. Here, we explore the effect of exposure to milk containing A1 and A2 β-casein beyond weaning. A1 but not A2 β-casein milk significantly increased stress-induced immobility in rats, concomitant with an increased abundance of Clostridium histolyticum bacterial group in the caecum and colon of A1 β-casein fed animals, brain region-specific alterations of μ-opioid and oxytocin receptors, and modifications in urinary biochemical profiles. Moreover, urinary gut microbial metabolites strongly correlated with altered brain metabolites. These findings suggest that consumption of milk containing A1 β-casein beyond weaning age may affect mood via a possible gut-brain axis mechanism.
Salminen S, Collado MC, Endo A, et al., 2021, Publisher Correction: The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics, Nature Reviews Gastroenterology & Hepatology, Vol: 18, Pages: 671-671, ISSN: 1759-5045
Caspani G, Turecki G, Lam R, et al., 2021, Metabolomic signatures associated with depression and predictors of antidepressant response in humans: A CAN-BIND-1 report, Communications Biology, Vol: 4, ISSN: 2399-3642
One of the biggest challenges in treating depression is the heterogeneous and qualitative nature of its clinical presentations. This highlights the need to find quantitative molecular markers to tailor existing treatment strategies to the individual’s biological system. In this study, high-resolution metabolic phenotyping of urine and plasma samples from the CAN-BIND study collected before treatment with two common pharmacological strategies, escitalopram and aripiprazole, was performed. Here we show that a panel of LDL and HDL subfractions were negatively correlated with depression in males. For treatment response, lower baseline concentrations of apolipoprotein A1 and HDL were predictive of escitalopram response in males, while higher baseline concentrations of apolipoprotein A2, HDL and VLDL subfractions were predictive of aripiprazole response in females. These findings support the potential of metabolomics in precision medicine and the possibility of identifying personalized interventions for depression.
Caspani G, Sebok V, Sultana N, et al., 2021, Metabolic phenotyping of opioid and psychostimulant addiction: A novel approach for biomarker discovery and biochemical understanding of the disorder, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 179, Pages: 1578-1606, ISSN: 0007-1188
Guerrant RL, Bolick DT, Swann JR, 2021, Modeling enteropathy or diarrhea with the top bacterial and protozoal pathogens: differential determinants of outcomes, ACS Infectious Diseases, Vol: 7, Pages: 1020-1031, ISSN: 2373-8227
Developing effective therapeutics or preventive interventions for important health threats is greatly enhanced whenever accessible models can enable the assessment of clinically important outcomes. While no non-human model is ever perfect, inexpensive in vivo small animal models in such as mice are often of great help in assessing the relevant efficacy of potential interventions. In addition to acute diarrhea, the long-term growth and developmental effects of enteric infections, with or without overt diarrhea, are increasingly recognized. To address these diverse effects, inexpensive animal models are proving to be very helpful. Herein, we review the major clinical concerns with enteric parasitic and bacterial infections that are extremely common worldwide, especially in vulnerable young children living in impoverished areas, and the recently published murine models of these infections and their outcomes. We find that common dietary deficiencies seen in children in developing areas have striking effects on diarrhea and enteropathy outcomes in mice. However, these effects differ with different pathogens. Specifically, the effects of protein or zinc deficiency differ considerably with different major protozoal and bacterial pathogens, suggesting different pathogenetic pathways and intervention effects. The pathogens reviewed are the seven top parasitic and bacterial pathogens seen in children, namely, Cryptosporidium, Giardia, Campylobacter, Shigella, enterotoxigenic Escherichia coli (ETEC), enteroaggregative E. coli (EAEC), and enteropathogenic E. coli (EPEC).
Mutasa K, Ntozini R, Mbuya MNN, et al., 2021, Biomarkers of environmental enteric dysfunction are not consistently associated with linear growth velocity in rural Zimbabwean infants, The American Journal of Clinical Nutrition, Vol: 113, Pages: 1185-1198, ISSN: 0002-9165
BackgroundChild stunting remains a poorly understood, prevalent public health problem. Environmental enteric dysfunction (EED) is hypothesized to be an important underlying cause.ObjectivesWithin a subgroup of 1169 children enrolled in the SHINE (Sanitation Hygiene Infant Nutrition Efficacy) trial in rural Zimbabwe, followed longitudinally from birth to 18 mo of age, we evaluated associations between the concentration of 11 EED biomarkers and linear growth velocity.MethodsAt infant ages 1, 3, 6, 12, and 18 mo, nurses measured child length and collected stool and blood; the lactulose-mannitol urine test was also conducted at all visits except at 1 mo. Stool neopterin, α-1 antitrypsin, myeloperoxidase, and regenerating gene 1β protein; urinary lactulose and mannitol; and plasma kynurenine, tryptophan, C-reactive protein, insulin-like growth factor-1 (IGF-1), soluble CD14, intestinal fatty acid binding protein, and citrulline were measured. We analyzed the change in relative [∆ length-for-age z score (LAZ)/mo] and absolute (∆ length/mo) growth velocity during 4 age intervals (1–3 mo; 3–6 mo; 6–12 mo; and 12–18 mo) per SD increase in biomarker concentration at the start of each age interval.ResultsIn fully adjusted models, we observed only 3 small, statistically significant associations: kynurenine:tryptophan ratio at 12 mo was associated with decreased mean LAZ velocity during the 12–18 mo interval (−0.015 LAZ/mo; 95% CI: −0.029, −0.001 LAZ/mo); mannitol excretion at 6 mo was associated with increased LAZ velocity during the 6–12 mo interval (0.013 LAZ/mo; 95% CI: 0.001, 0.025 LAZ/mo), and plasma IGF-1 at 1 mo was associated with increased LAZ velocity during the 1–3 mo interval (0.118 LAZ/mo; 95% CI: 0.024, 0.211 LAZ/mo). Results for absolute growth velocity were similar, except IGF-1 was also associated with growth during the 12–18 mo interval. We found no other associations between any EED
Jordi M-P, Wellington A, Lubach G, et al., 2021, Gut microbial and metabolic profiling reveal the lingering effects of infantile iron deficiency unless treated with iron, Molecular Nutrition and Food Research, Vol: 65, ISSN: 1613-4125
ScopeIron deficiency (ID) compromises the health of infants worldwide. Although readily treated with iron, concerns remain about the persistence of some effects. Metabolic and gut microbial consequences of infantile ID were investigated in juvenile monkeys after natural recovery (pID) from iron deficiency or post‐treatment with iron dextran and B vitamins (pID+Fe).Methods and ResultsMetabolomic profiling of urine and plasma is conducted with 1H nuclear magnetic resonance (NMR) spectroscopy. Gut microbiota are characterized from rectal swabs by amplicon sequencing of the 16S rRNA gene. Urinary metabolic profiles of pID monkeys significantly differed from pID+Fe and continuously iron‐sufficient controls (IS) with higher maltose and lower amounts of microbial‐derived metabolites. Persistent differences in energy metabolism are apparent from the plasma metabolic phenotypes with greater reliance on anaerobic glycolysis in pID monkeys. Microbial profiling indicated higher abundances of Methanobrevibacter, Lachnobacterium, and Ruminococcus in pID monkeys and any history of ID resulted in a lower Prevotella abundance compared to the IS controls.ConclusionsLingering metabolic and microbial effects are found after natural recovery from ID. These long‐term biochemical derangements are not present in the pID+Fe animals emphasizing the importance of the early detection and treatment of early‐life ID to ameliorate its chronic metabolic effects.
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
Whiley L, Chappell KE, D'Hondt E, et al., 2021, Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer's disease, Alzheimers Research & Therapy, Vol: 13, Pages: 1-18, ISSN: 1758-9193
BackgroundBoth serotonergic signalling disruption and systemic inflammation have been associated with the pathogenesis of Alzheimer’s disease (AD). The common denominator linking the two is the catabolism of the essential amino acid, tryptophan. Metabolism via tryptophan hydroxylase results in serotonin synthesis, whilst metabolism via indoleamine 2,3-dioxygenase (IDO) results in kynurenine and its downstream derivatives. IDO is reported to be activated in times of host systemic inflammation and therefore is thought to influence both pathways. To investigate metabolic alterations in AD, a large-scale metabolic phenotyping study was conducted on both urine and serum samples collected from a multi-centre clinical cohort, consisting of individuals clinically diagnosed with AD, mild cognitive impairment (MCI) and age-matched controls.MethodsMetabolic phenotyping was applied to both urine (n = 560) and serum (n = 354) from the European-wide AddNeuroMed/Dementia Case Register (DCR) biobank repositories. Metabolite data were subsequently interrogated for inter-group differences; influence of gender and age; comparisons between two subgroups of MCI - versus those who remained cognitively stable at follow-up visits (sMCI); and those who underwent further cognitive decline (cMCI); and the impact of selective serotonin reuptake inhibitor (SSRI) medication on metabolite concentrations.ResultsResults revealed significantly lower metabolite concentrations of tryptophan pathway metabolites in the AD group: serotonin (urine, serum), 5-hydroxyindoleacetic acid (urine), kynurenine (serum), kynurenic acid (urine), tryptophan (urine, serum), xanthurenic acid (urine, serum), and kynurenine/tryptophan ratio (urine). For each listed metabolite, a decreasing trend in concentrations was observed in-line with clinical diagnosis: control > MCI > AD. There were no significant differences in the two MCI subgroups whilst SSRI medication status influenced o
Swann JR, Rajilic-Stojanovic M, Salonen A, et al., 2020, Considerations for the design and conduct of human gut microbiota intervention studies relating to foods, European Journal of Nutrition, Vol: 59, Pages: 3347-3368, ISSN: 0044-264X
With the growing appreciation for the influence of the intestinal microbiota on human health, there is increasing motivation to design and refine interventions to promote favorable shifts in the microbiota and their interactions with the host. Technological advances have improved our understanding and ability to measure this indigenous population and the impact of such interventions. However, the rapid growth and evolution of the field, as well as the diversity of methods used, parameters measured and populations studied, make it difficult to interpret the significance of the findings and translate their outcomes to the wider population. This can prevent comparisons across studies and hinder the drawing of appropriate conclusions. This review outlines considerations to facilitate the design, implementation and interpretation of human gut microbiota intervention studies relating to foods based upon our current understanding of the intestinal microbiota, its functionality and interactions with the human host. This includes parameters associated with study design, eligibility criteria, statistical considerations, characterization of products and the measurement of compliance. Methodologies and markers to assess compositional and functional changes in the microbiota, following interventions are discussed in addition to approaches to assess changes in microbiota-host interactions and host responses. Last, EU legislative aspects in relation to foods and health claims are presented. While it is appreciated that the field of gastrointestinal microbiology is rapidly evolving, such guidance will assist in the design and interpretation of human gut microbiota interventional studies relating to foods.
Mars RAT, Yang Y, Ward T, et al., 2020, Longitudinal multi-omics reveals subset-specific mechanisms underlying irritable bowel syndrome (vol 182, pg 1460, 2020), Cell, Vol: 183, Pages: 1137-1140, ISSN: 0092-8674
Moore SR, Quinn LA, Maier EA, et al., 2020, Intervention and mechanisms of alanyl-glutamine for inflammation, nutrition, and enteropathy: a randomized controlled trial, Journal of Pediatric Gastroenterology and Nutrition, Vol: 71, Pages: 393-400, ISSN: 0277-2116
Objective: Determine the minimum dosage of alanyl-glutamine (Ala-Gln) required to improve gut integrity and growth in children at risk of environmental enteropathy (EE).Methods: This was a double-blinded randomized placebo-controlled dose-response trial. We enrolled 140 children residing in a low-income community in Fortaleza, Brazil. Participants were 2 to 60 months old and had weight-for-age (WAZ), height-for-age (HAZ), or weight-for-height (WHZ) z-scores less than −1. We randomized children to 10 days of nutritional supplementation: Ala-Gln at 3 g/day, Ala-Gln at 6 g/day, Ala-Gln at 12 g/day, or an isonitrogenous dose of glycine (Gly) placebo at 12.5 g/day. Our primary outcome was urinary lactulose-mannitol excretion testing. Secondary outcomes were anthropometry, fecal markers of inflammation, urine metabolic profiles, and malabsorption (spot fecal energy).Results: Of 140 children, 103 completed 120 days of follow-up (24% dropout). In the group receiving the highest dose of Ala-Gln, we detected a modest improvement in urinary lactulose excretion from 0.19% on day 1 to 0.17% on day 10 (P = 0.05). We observed significant but transient improvements in WHZ at day 10 in 2 Ala-Gln groups, and in WHZ and WAZ in all Ala-Gln groups at day 30. We detected no effects on fecal inflammatory markers, diarrheal morbidity, or urine metabolic profiles; but did observe modest reductions in fecal energy and fecal lactoferrin in participants receiving Ala-Gln.Conclusions: Intermediate dose Ala-Gln promotes short-term improvement in gut integrity and ponderal growth in children at risk of EE. Lower doses produced improvements in ponderal growth in the absence of enhanced gut integrity.
Kroll JS, Hall L, Kiu R, et al., 2020, Microbiota supplementation with Bifidobacterium and Lactobacillus modifies the preterm infant gut microbiota and metabolome: an observational study, Cell Reports Medicine, Vol: 1, ISSN: 2666-3791
Supplementation with members of the early-life microbiota as “probiotics” is increasingly used in attempts to beneficially manipulate the preterm infant gut microbiota. We performed a large observational longitudinal study comprising two preterm groups: 101 infants orally supplemented with Bifidobacterium and Lactobacillus (Bif/Lacto) and 133 infants non-supplemented (control) matched by age, sex, and delivery method. 16S rRNA gene profiling on fecal samples (n = 592) showed a predominance of Bifidobacterium and a lower abundance of pathobionts in the Bif/Lacto group. Metabolomic analysis showed higher fecal acetate and lactate and a lower fecal pH in the Bif/Lacto group compared to the control group. Fecal acetate positively correlated with relative abundance of Bifidobacterium, consistent with the ability of the supplemented Bifidobacterium strain to metabolize human milk oligosaccharides into acetate. This study demonstrates that microbiota supplementation is associated with a Bifidobacterium-dominated preterm microbiota and gastrointestinal environment more closely resembling that of full-term infants.
Burgess SL, Leslie JL, Uddin J, et al., 2020, Gut microbiome communication with bone marrow regulates susceptibility to amebiasis., J Clin Invest, Vol: 130, Pages: 4019-4024
The microbiome provides resistance to infection. However, the underlying mechanisms are poorly understood. We demonstrate that colonization with the intestinal bacterium Clostridium scindens protects from Entamoeba histolytica colitis via innate immunity. Introduction of C. scindens into the gut microbiota epigenetically altered and expanded bone marrow granulocyte-monocyte progenitors (GMPs) and resulted in increased intestinal neutrophils with subsequent challenge with E. histolytica. Introduction of C. scindens alone was sufficient to expand GMPs in gnotobiotic mice. Adoptive transfer of bone marrow from C. scindens-colonized mice into naive mice protected against amebic colitis and increased intestinal neutrophils. Children without E. histolytica diarrhea also had a higher abundance of Lachnoclostridia. Lachnoclostridia C. scindens can metabolize the bile salt cholate, so we measured deoxycholate and discovered that it was increased in the sera of C. scindens-colonized specific pathogen-free and gnotobiotic mice, as well as in children protected from amebiasis. Administration of deoxycholate alone increased GMPs and provided protection from amebiasis. We elucidated a mechanism by which C. scindens and the microbially metabolized bile salt deoxycholic acid alter hematopoietic precursors and provide innate protection from later infection with E. histolytica.
Breton J, Giallourou N, Nobis S, et al., 2020, Characterizing the metabolic perturbations induced by activity-based anorexia in the C57Bl/6 mouse using H-1 NMR spectroscopy, CLINICAL NUTRITION, Vol: 39, Pages: 2428-2434, ISSN: 0261-5614
Johanson SM, Swann JR, Umu ÖCO, et al., 2020, Maternal exposure to a human relevant mixture of persistent organic pollutants reduces colorectal carcinogenesis in A/J Min/+ mice, Chemosphere, Vol: 252, ISSN: 0045-6535
An increased risk of developing colorectal cancer has been associated with exposure to persistent organic pollutants (POPs) and alteration in the gut bacterial community. However, there is limited understanding about the impact of maternal exposure to POPs on colorectal cancer and gut microbiota. This study characterized the influence of exposure to a human relevant mixture of POPs during gestation and lactation on colorectal cancer, intestinal metabolite composition and microbiota in the A/J Min/+ mouse model. Surprisingly, the maternal POP exposure decreased colonic tumor burden, as shown by light microscopy and histopathological evaluation, indicating a restriction of colorectal carcinogenesis. 1H nuclear magnetic resonance spectroscopy-based metabolomic analysis identified alterations in the metabolism of amino acids, lipids, glycerophospholipids and energy in intestinal tissue. In addition, 16S rRNA sequencing of gut microbiota indicated that maternal exposure modified fecal bacterial composition. In conclusion, the results showed that early-life exposure to a mixture of POPs reduced colorectal cancer initiation and promotion, possibly through modulation of the microbial and biochemical environment. Further studies should focus on the development of colorectal cancer after combined maternal and dietary exposures to environmentally relevant low-dose POP mixtures.
Letertre M, Munjoma NC, Slade SE, et al., 2020, Metabolic phenotyping using UPLC–MS and rapid microbore UPLC–IM–MS: determination of the effect of different dietary regimes on the urinary metabolome of the rat, Chromatographia, Vol: 83, Pages: 853-861, ISSN: 0009-5893
A rapid reversed-phase gradient method employing a 50 mm × 1 mm i.d., C18 microbore column, combined with ion mobility and high-resolution mass spectrometry, was applied to the metabolic phenotyping of urine samples obtained from rats receiving different diets. This method was directly compared to a “conventional” method employing a 150 × 2.1 mm i.d. column packed with the same C18 bonded phase using the same samples. Multivariate statistical analysis of the resulting data showed similar class discrimination for both microbore and conventional methods, despite the detection of fewer mass/retention time features by the former. Multivariate statistical analysis highlighted a number of ions that represented diet-specific markers in the samples. Several of these were then identified using the combination of mass, ion-mobility-derived collision cross section and retention time including N-acetylglutamate, urocanic acid, and xanthurenic acid. Kynurenic acid was tentatively identified based on mass and ion mobility data.
Letertre MPM, Munjoma NC, Wolfer K, et al., 2020, A two-way interaction between methotrexate and the gut microbiota of male Sprague Dawley rats, Journal of Proteome Research, Vol: 19, Pages: 3326-3339, ISSN: 1535-3893
Methotrexate (MTX) is a chemotherapeutic agent that cancause a range of toxic side effects including gastrointestinal damage,hepatotoxicity, myelosuppression, and nephrotoxicity and has potentiallycomplex interactions with the gut microbiome. Following untargeted UPLCqtof-MS analysis of urine and fecal samples from male Sprague−Dawley ratsadministered at either 0, 10, 40, or 100 mg/kg of MTX, dose-dependentchanges in the endogenous metabolite profiles were detected. Semiquantitativetargeted UPLC-MS detected MTX excreted in urine as well as MTX and twometabolites, 2,4-diamino-N-10-methylpteroic acid (DAMPA) and 7-hydroxyMTX, in the feces. DAMPA is produced by the bacterial enzymecarboxypeptidase glutamate 2 (CPDG2) in the gut. Microbiota profiling(16S rRNA gene amplicon sequencing) of fecal samples showed an increase inthe relative abundance of Firmicutes over the Bacteroidetes at low doses ofMTX but the reverse at high doses. Firmicutes relative abundance was positively correlated with DAMPA excretion in feces at 48 h,which were both lower at 100 mg/kg compared to that seen at 40 mg/kg. Overall, chronic exposure to MTX appears to inducecommunity and functionality changes in the intestinal microbiota, inducing downstream perturbations in CPDG2 activity, and thusmay delay MTX detoxication to DAMPA. This reduction in metabolic clearance might be associated with increased gastrointestinaltoxicity.
Giallourou N, Fardus-Reid F, Panic G, et al., 2020, Metabolic maturation in the first 2 years of life in resource-constrained settings and its association with postnatal growths, Science Advances, Vol: 6, Pages: 1-10, ISSN: 2375-2548
Malnutrition continues to affect the growth and development of millions of children worldwide, and chronic undernutrition has proven to be largely refractory to interventions. Improved understanding of metabolic development in infancy and how it differs in growth-constrained children may provide insights to inform more timely, targeted, and effective interventions. Here, the metabolome of healthy infants was compared to that of growth-constrained infants from three continents over the first 2 years of life to identify metabolic signatures of aging. Predictive models demonstrated that growth-constrained children lag in their metabolic maturity relative to their healthier peers and that metabolic maturity can predict growth 6 months into the future. Our results provide a metabolic framework from which future nutritional programs may be more precisely constructed and evaluated.
Bhatt AP, Pellock SJ, Biernat KA, et al., 2020, Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy, Proceedings of the National Academy of Sciences, Vol: https://www.pnas.org/content/117/13/7374, Pages: 7374-7381, ISSN: 0027-8424
Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immune-deficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan’s effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage.
Rasmussen TS, Mentzel CMJ, Kot W, et al., 2020, Faecal virome transplantation decreases symptoms of type 2 diabetes and obesity in a murine model, Gut, ISSN: 0017-5749
Objective Development of obesity and type 2 diabetes (T2D) are associated with gut microbiota (GM) changes. The gut viral community is predominated by bacteriophages (phages), which are viruses that attack bacteria in a host-specific manner. The antagonistic behaviour of phages has the potential to alter the GM. As a proof-of-concept, we demonstrate the efficacy of faecal virome transplantation (FVT) from lean donors for shifting the phenotype of obese mice into closer resemblance of lean mice.Design The FVT consisted of viromes with distinct profiles extracted from the caecal content of mice from different vendors that were fed a low-fat (LF) diet for 14 weeks. Male C57BL/6NTac mice were divided into five groups: LF (as diet control), high-fat (HF) diet, HF+ampicillin (Amp), HF+Amp+FVT and HF+FVT. At weeks 6 and 7 of the study, the HF+FVT and HF+Amp+FVT mice were treated with FVT by oral gavage. The Amp groups were treated with Amp 24 hours prior to first FVT treatment.Results Six weeks after first FVT, the HF+FVT mice showed a significant decrease in weight gain compared with the HF group. Further, glucose tolerance was comparable between the LF and HF+FVT mice, while the other HF groups all had impaired glucose tolerance. These observations were supported by significant shifts in GM composition, blood plasma metabolome and expression levels of genes associated with obesity and T2D development.Conclusions Transfer of caecal viral communities from mice with a lean phenotype into mice with an obese phenotype led to reduced weight gain and normalised blood glucose parameters relative to lean mice. We hypothesise that this effect is mediated via FVT-induced GM changes.
Gough EK, Moulton LH, Mutasa K, et al., 2020, Effects of improved water, sanitation, and hygiene and improved complementary feeding on environmental enteric dysfunction in children in rural Zimbabwe: A cluster-randomized controlled trial., PLoS Neglected Tropical Diseases, Vol: 14, Pages: 1-29, ISSN: 1935-2727
BACKGROUND: Environmental enteric dysfunction (EED) may be an important modifiable cause of child stunting. We described the evolution of EED biomarkers from birth to 18 months in rural Zimbabwe and tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF), on EED. METHODOLOGY AND FINDINGS: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial was a 2x2 factorial cluster-randomised trial of improved IYCF and improved WASH on child stunting and anaemia at 18 months of age. 1169 infants born to HIV-negative mothers provided plasma and faecal specimens at 1, 3, 6, 12, and 18 months of age. We measured EED biomarkers that reflect all domains of the hypothesized pathological pathway. Markers of intestinal permeability and intestinal inflammation declined over time, while markers of microbial translocation and systemic inflammation increased between 1-18 months. Markers of intestinal damage (I-FABP) and repair (REG-1β) mirrored each other, and citrulline (a marker of intestinal epithelial mass) increased from 6 months of age, suggesting dynamic epithelial turnover and regeneration in response to enteric insults. We observed few effects of IYCF and WASH on EED after adjustment for multiple comparisons. The WASH intervention decreased plasma IGF-1 at 3 months (β:0.89, 95%CI:0.81,0.98) and plasma kynurenine at 12 months (β: 0.92, 95%CI:0.87,0.97), and increased plasma IGF-1 at 18 months (β:1.15, 95%CI:1.05,1.25), but these small WASH effects did not translate into improved growth. CONCLUSIONS: Overall, we observed dynamic trends in EED but few effects of IYCF or WASH on biomarkers during the first 18 months after birth, suggesting that these interventions did not impact EED. Transformative WASH interventions are required to prevent or ameliorate EED in low-income settings.
Colston JM, Peñataro Yori P, Moulton LH, et al., 2019, Penalized regression models to select biomarkers of environmental enteric dysfunction associated with linear growth acquisition in a Peruvian birth cohort, PLoS Neglected Tropical Diseases, Vol: 13, ISSN: 1935-2727
Environmental enteric dysfunction (EED) is associated with chronic undernutrition. Effortsto identify minimally invasive biomarkers of EED reveal an expanding number of candidateanalytes. An analytic strategy is reported to select among candidate biomarkers and systematically express the strength of each marker’s association with linear growth in infancyand early childhood. 180 analytes were quantified in fecal, urine and plasma samples takenat 7, 15 and 24 months of age from 258 subjects in a birth cohort in Peru. Treating the subjects’ length-for-age Z-score (LAZ-score) over a 2-month lag as the outcome, penalized linear regression models with different shrinkage methods were fitted to determine the bestfitting subset. These were then included with covariates in linear regression models to obtainestimates of each biomarker’s adjusted effect on growth. Transferrin had the largest andmost statistically significant adjusted effect on short-term linear growth as measured byLAZ-score–a coefficient value of 0.50 (0.24, 0.75) for each log2 increase in plasma transferrin concentration. Other biomarkers with large effect size estimates included adiponectin,arginine, growth hormone, proline and serum amyloid P-component. The selected subsetexplained up to 23.0% of the variability in LAZ-score. Penalized regression modelingapproaches can be used to select subsets from large panels of candidate biomarkers ofEED. There is a need to systematically express the strength of association of biomarkerswith linear growth or other outcomes to compare results across studies.
Caspani G, Kennedy S, Foster JA, et al., 2019, Gut microbial metabolites in depression: understanding the biochemical mechanisms, Microbial Cell, Vol: 6, Pages: 454-481, ISSN: 2311-2638
Gastrointestinal and central function are intrinsically connected by the gut microbiota, an ecosystem that has co-evolved with the host to expand its biotransformational capabilities and interact with host physiological processes by means of its metabolic products. Abnormalities in this microbiota-gut-brain axis have emerged as a key component in the pathophysiology of depression, leading to more research attempting to understand the neuroactive potential of the products of gut microbial metabolism. This review explores the potential for the gut microbiota to contribute to depression and focuses on the role that microbially-derived molecules – neurotransmitters, short-chain fatty acids, indoles, bile acids, choline metabolites, lactate and vitamins – play in the context of emotional behavior. The future of gut-brain axis research lies is moving away from association, towards the mechanisms underlying the relationship between the gut bacteria and depressive behavior. We propose that direct and indirect mechanisms exist through which gut microbial metabolites affect depressive behavior: these include (i) direct stimulation of central receptors, (ii) peripheral stimulation of neural, endocrine, and immune mediators, and (iii) epigenetic regulation of histone acetylation and DNA methylation. Elucidating these mechanisms is essential to expand our understanding of the etiology of depression, and to develop new strategies to harness the beneficial psychotropic effects of these molecules. Overall, the review highlights the potential for dietary interventions to represent such novel therapeutic strategies for major depressive disorder.
Caspani G, Swann J, 2019, Small talk: microbial metabolites involved in the signaling from microbiota to brain, Current Opinion in Pharmacology, Vol: 48, Pages: 99-106, ISSN: 1471-4892
The wealth of biotransformational capabilities encoded in the microbiome expose the host to an array of bioactive xenobiotic products. Several of these metabolites participate in the communication between the gastrointestinal tract and the central nervous system and have potential to modulate central physiological and pathological processes. This biochemical interplay can occur through various direct and indirect mechanisms. These include binding to host receptors in the brain, stimulation of the vagus nerve in the gut, alteration of central neurotransmission, and modulation of neuroinflammation. Here, the potential for short chain fatty acids, bile acids, neurotransmitters and other bioactive products of the microbiome to participate in the gut-brain axis will be reviewed.
Nye LC, Williams JP, Munjoma NC, et al., 2019, A comparison of collision cross section values obtained via travelling wave ion mobility-mass spectrometry and ultra high performance liquid chromatography-ion mobility-mass spectrometry: Application to the characterisation of metabolites in rat urine, Journal of Chromatography A, Vol: 1602, Pages: 386-396, ISSN: 0021-9673
A comprehensive Collision Cross Section (CCS) library was obtained via Travelling Wave Ion Guide mobility measurements through direct infusion (DI). The library consists of CCS and Mass Spectral (MS) data in negative and positive ElectroSpray Ionisation (ESI) mode for 463 and 479 endogenous metabolites, respectively. For both ionisation modes combined, TWCCSN2 data were obtained for 542 non-redundant metabolites. These data were acquired on two different ion mobility enabled orthogonal acceleration QToF MS systems in two different laboratories, with the majority of the resulting TWCCSN2 values (from detected compounds) found to be within 1% of one another. Validation of these results against two independent, external TWCCSN2 data sources and predicted TWCCSN2 values indicated to be within 1–2% of these other values. The same metabolites were then analysed using a rapid reversed-phase ultra (high) performance liquid chromatographic (U(H)PLC) separation combined with IM and MS (IM-MS) thus providing retention time (tr), m/z and TWCCSN2 values (with the latter compared with the DI-IM-MS data). Analytes for which TWCCSN2 values were obtained by U(H)PLC-IM-MS showed good agreement with the results obtained from DI-IM-MS. The repeatability of the TWCCSN2 values obtained for these metabolites on the different ion mobility QToF systems, using either DI or LC, encouraged the further evaluation of the U(H)PLC-IM-MS approach via the analysis of samples of rat urine, from control and methotrexate-treated animals, in order to assess the potential of the approach for metabolite identification and profiling in metabolic phenotyping studies. Based on the database derived from the standards 63 metabolites were identified in rat urine, using positive ESI, based on the combination of tr, TWCCSN2 and MS data.
Bailey, Breton, Panic, et al., 2019, The mycotoxin deoxynivalenol significantly alters the function and metabolism of bovine kidney epithelial cells in vitro, Toxins, Vol: 11, Pages: 1-13, ISSN: 2072-6651
Bovine mycotoxicosis is a disorder caused by the ingestion of fungal toxins. It is associated with chronic signs, such as reduced growth rate and milk yield, and causes significant economic cost to the dairy industry. The mycotoxins deoxynivalenol (DON), zearalenone (ZEN), and fumonisin B1 (FB1) are commonly found in grain fed to cattle. Patulin (PA) is a common grass silage contaminant but is also found in grain. The effects of these mycotoxins on cellular function at low concentrations are not well understood. Using Madin–Darby bovine kidney cells we evaluated the cellular response to these mycotoxins, measuring cytotoxicity, de novo protein synthesis, cell proliferation, cell cycle analysis, and also metabolic profiling by 1H NMR spectroscopy. DON, ZEN, and PA induced cytotoxicity, and PA and FB1 induced a decrease in metabolic activity in surviving cells. DON was the only mycotoxin found to have a significant effect on the metabolic profile, with exposed cells showing increased cellular amino acids, lactate, 2-oxoglutarate, 3-hydroxybutyrate, and UDP-N-acetylglucosamine and decreased β-alanine, choline, creatine, taurine, and myo-inositol. Cells exposed to DON also showed reductions in protein synthesis. DON has previously been documented as being a ribotoxin; the results here suggest that exposure of bovine cells to DON causes a decrease in protein synthesis with corresponding cellular accumulation of precursors. Cell proliferation was also arrested without causing apoptosis. It is likely that exposure triggers hypoxic, hypertonic, and ribotoxic responses in bovine cells, and that these responses contribute to reduced productivity in exposed cattle. View Full-Text
McBain AJ, O'Neill CA, Amezquita A, et al., 2019, Consumer safety considerations of skin and oral microbiome perturbation., Clinical Microbiology Reviews, Vol: 32, Pages: 1-23, ISSN: 0893-8512
Microbiomes associated with human skin and the oral cavity are uniquely exposed to personal care regimes. Changes in the composition and activities of the microbial communities in these environments can be utilized to promote consumer health benefits, for example, by reducing the numbers, composition, or activities of microbes implicated in conditions such as acne, axillary odor, dandruff, and oral diseases. It is, however, important to ensure that innovative approaches for microbiome manipulation do not unsafely disrupt the microbiome or compromise health, and where major changes in the composition or activities of the microbiome may occur, these require evaluation to ensure that critical biological functions are unaffected. This article is based on a 2-day workshop held at SEAC Unilever, Sharnbrook, United Kingdom, involving 31 specialists in microbial risk assessment, skin and oral microbiome research, microbial ecology, bioinformatics, mathematical modeling, and immunology. The first day focused on understanding the potential implications of skin and oral microbiome perturbation, while approaches to characterize those perturbations were discussed during the second day. This article discusses the factors that the panel recommends be considered for personal care products that target the microbiomes of the skin and the oral cavity.
Randall DW, Kieswich J, Swann J, et al., 2019, Batch effect exerts a bigger influence on the rat urinary metabolome and gut microbiota than uraemia: a cautionary tale, Microbiome, Vol: 7, Pages: 1-10, ISSN: 2049-2618
BackgroundRodent models are invaluable for studying biological processes in the context of whole organisms. The reproducibility of such research is based on an assumption of metabolic similarity between experimental animals, controlled for by breeding and housing strategies that minimise genetic and environmental variation. Here, we set out to demonstrate the effect of experimental uraemia on the rat urinary metabolome and gut microbiome but found instead that the effect of vendor shipment batch was larger in both areas than that of uraemia.ResultsTwenty four Wistar rats obtained from the same commercial supplier in two separate shipment batches underwent either subtotal nephrectomy or sham procedures. All animals undergoing subtotal nephrectomy developed an expected uraemic phenotype. The urinary metabolome was studied using 1H-NMR spectroscopy and found to vary significantly between animals from different batches, with substantial differences in concentrations of a broad range of substances including lactate, acetate, glucose, amino acids, amines and benzoate derivatives. In animals from one batch, there was a complete absence of the microbiome-associated urinary metabolite hippurate, which was present in significant concentrations in animals from the other batch. These differences were so prominent that we would have drawn quite different conclusions about the effect of uraemia on urinary phenotype depending on which batch of animals we had used. Corresponding differences were seen in the gut microbiota between animals in different batches when assessed by the sequencing of 16S rRNA gene amplicons, with higher alpha diversity and different distributions of Proteobacteria subtaxa and short-chain fatty acid producing bacteria in the second batch compared to the first. Whilst we also demonstrated differences in both the urinary metabolome and gut microbiota associated with uraemia, these effects were smaller in size than those associated with shipment batch.Conclusi
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