Publications
148 results found
Ling C, Versloot CJ, Arvidsson Kvissberg ME, et al., 2023, Rebalancing of mitochondrial homeostasis through an NAD<sup>+</sup>-SIRT1 pathway preserves intestinal barrier function in severe malnutrition, eBioMedicine, Vol: 96
Background: The intestine of children with severe malnutrition (SM) shows structural and functional changes that are linked to increased infection and mortality. SM dysregulates the tryptophan-kynurenine pathway, which may impact processes such as SIRT1- and mTORC1-mediated autophagy and mitochondrial homeostasis. Using a mouse and organoid model of SM, we studied the repercussions of these dysregulations on malnutrition enteropathy and the protective capacity of maintaining autophagy activity and mitochondrial health. Methods: SM was induced through feeding male weanling C57BL/6 mice a low protein diet (LPD) for 14-days. Mice were either treated with the NAD+-precursor, nicotinamide; an mTORC1-inhibitor, rapamycin; a SIRT1-activator, resveratrol; or SIRT1-inhibitor, EX-527. Malnutrition enteropathy was induced in enteric organoids through amino-acid deprivation. Features of and pathways to malnutrition enteropathy were examined, including paracellular permeability, nutrient absorption, and autophagic, mitochondrial, and reactive-oxygen-species (ROS) abnormalities. Findings: LPD-feeding and ensuing low-tryptophan availability led to villus atrophy, nutrient malabsorption, and intestinal barrier dysfunction. In LPD-fed mice, nicotinamide-supplementation was linked to SIRT1-mediated activation of mitophagy, which reduced damaged mitochondria, and improved intestinal barrier function. Inhibition of mTORC1 reduced intestinal barrier dysfunction and nutrient malabsorption. Findings were validated and extended using an organoid model, demonstrating that resolution of mitochondrial ROS resolved barrier dysfunction. Interpretation: Malnutrition enteropathy arises from a dysregulation of the SIRT1 and mTORC1 pathways, leading to disrupted autophagy, mitochondrial homeostasis, and ROS. Whether nicotinamide-supplementation in children with SM could ameliorate malnutrition enteropathy should be explored in clinical trials. Funding: This work was supported by the Bill and Melind
Jones HJ, Bourke CD, Swann JR, et al., 2023, Malnourished Microbes: Host-Microbiome Interactions in Child Undernutrition., Annu Rev Nutr, Vol: 43, Pages: 327-353
Childhood undernutrition is a major global health burden that is only partially resolved by nutritional interventions. Both chronic and acute forms of child undernutrition are characterized by derangements in multiple biological systems including metabolism, immunity, and endocrine systems. A growing body of evidence supports a role of the gut microbiome in mediating these pathways influencing early life growth. Observational studies report alterations in the gut microbiome of undernourished children, while preclinical studies suggest that this can trigger intestinal enteropathy, alter host metabolism, and disrupt immune-mediated resistance against enteropathogens, each of which contribute to poor early life growth. Here, we compile evidence from preclinical and clinical studies and describe the emerging pathophysiological pathways by which the early life gut microbiome influences host metabolism, immunity, intestinal function, endocrine regulation, and other pathways contributing to child undernutrition. We discuss emerging microbiome-directed therapies and consider future research directions to identify and target microbiome-sensitive pathways in child undernutrition.
Swann JR, Diaz Heijtz R, Mayneris-Perxachs J, et al., 2023, Characterizing the metabolomic signature of attention-deficit hyperactivity disorder in twins., Neuropharmacology, Vol: 234
Emerging evidence implicate the gut microbiota as a potential susceptibility factor in attention-deficit hyperactivity disorder (ADHD), a common multifactorial neurodevelopmental condition. However, little is known about the biochemical signature of ADHD, including the metabolic contribution of the microbiota via the gut-brain axis, and the relative contribution of genetics and environmental factors. Here, we perform unbiased metabolomic profiling of urine and fecal samples collected from a well-characterized Swedish twin cohort enriched for ADHD (33 ADHD, 79 non-ADHD), using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. Our results highlight sex-specific patterns in the metabolic phenotype of individuals with ADHD. Specifically, the urine profile of males, but not females, with ADHD was characterized by greater excretion of hippurate, a product of microbial-host co-metabolism that can cross the blood-brain-barrier with bioactivity of potential relevance to ADHD. This trans-genomic metabolite was also negatively correlated with IQ in males and was significantly correlated with fecal metabolites associated with gut microbial metabolism. The fecal profile of ADHD individuals was characterized by increased excretion of stearoyl-linoleoyl-glycerol, 3,7-dimethylurate, and FAD and lower amounts of glycerol 3-phosphate, thymine, 2(1H)-quinolinone, aspartate, xanthine, hypoxanthine, and orotate. These changes were independent of ADHD medication, age, and BMI. Furthermore, our specific twins' models revealed that many of these gut metabolites had a stronger genetic influence than environmental. These findings suggest that metabolic disturbances in ADHD, involving combined gut microbial and host metabolic processes, may largely derive from gene variants previously linked to behavioral symptoms in this disorder. This article is part of the Special Issue on "Microbiome & the Brain: Mechanisms & Maladies".
Warren CA, Shin JH, Bansal EN, et al., 2023, Alanyl-glutamine supplementation for Clostridioides difficile infection treatment (ACT): a double-blind randomised controlled trial study protocol., BMJ Open, Vol: 13
INTRODUCTION: Clostridioides difficile is the leading cause of healthcare-associated infections in the USA, with an estimated 1 billion dollars in excess cost to the healthcare system annually. C. difficile infection (CDI) has high recurrence rate, up to 25% after first episode and up to 60% for succeeding episodes. Preliminary in vitro and in vivo studies indicate that alanyl-glutamine (AQ) may be beneficial in treating CDI by its effect on restoring intestinal integrity in the epithelial barrier, ameliorating inflammation and decreasing relapse. METHODS AND ANALYSIS: This study is a randomised, placebo-controlled, double-blind, phase II clinical trial. The trial is designed to determine optimal dose and safety of oral AQ at 4, 24 and 44 g doses administered daily for 10 days concurrent with standard treatment of non-severe or severe uncomplicated CDI in persons age 18 and older. The primary outcome of interest is CDI recurrence during 60 days post-treatment follow-up, with the secondary outcome of mortality during 60 days post-treatment follow-up. Exploratory analysis will be done to determine the impact of AQ supplementation on intestinal and systemic inflammation, as well as intestinal microbial and metabolic profiles. ETHICS AND DISSEMINATION: The study has received University of Virginia Institutional Review Board approval (HSR200046, Protocol v9, April 2023). Findings will be disseminated via conference presentations, lectures and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04305769.
Zuffa S, Schimmel P, Gonzalez-Santana A, et al., 2023, Early-life differences in the gut microbiota composition and functionality of infants at elevated likelihood of developing autism spectrum disorder., Transl Psychiatry, Vol: 13
Evidence from cross-sectional human studies, and preliminary microbial-based intervention studies, have implicated the microbiota-gut-brain axis in the neurobiology of autism spectrum disorder (ASD). Using a prospective longitudinal study design, we investigated the developmental profile of the fecal microbiota and metabolome in infants with (n = 16) and without (n = 19) a family history of ASD across the first 36 months of life. In addition, the general developmental levels of infants were evaluated using the Mullen Scales of Early Learning (MSEL) test at 5 and 36 months of age, and with ADOS-2 at 36 months of age. At 5 months of age, infants at elevated-likelihood of ASD (EL) harbored less Bifidobacterium and more Clostridium and Klebsiella species compared to the low-likelihood infants (LL). Untargeted metabolic profiling highlighted that LL infants excreted a greater amount of fecal γ-aminobutyric acid (GABA) at 5 months, which progressively declined with age. Similar age-dependent patterns were not observed in the EL group, with GABA being consistently low across all timepoints. Integrated microbiome-metabolome analysis showed a positive correlation between GABA and Bifidobacterium species and negative associations with Clostridium species. In vitro experiments supported these observations demonstrating that bifidobacteria can produce GABA while clostridia can consume it. At the behavioral level, there were no significant differences between the EL and LL groups at 5 months. However, at 36 months of age, the EL group had significantly lower MSEL and ADOS-2 scores compared to the LL group. Taken together, the present results reveal early life alterations in gut microbiota composition and functionality in infants at elevated-likelihood of ASD. These changes occur before any behavioral impairments can be detected, supporting a possible role for the gut microbiota in emerging behavioral variability later in life.
Deane CS, Swann JR, 2023, Harnessing metabolomics to better understand exercise-mediated substrate metabolism., Exp Physiol, Vol: 108, Pages: 797-798
Giallourou N, Arnold J, McQuade ETR, et al., 2023, Giardia hinders growth by disrupting nutrient metabolism independent of inflammatory enteropathy., Nat Commun, Vol: 14
Giardia lamblia (Giardia) is among the most common intestinal pathogens in children in low- and middle-income countries (LMICs). Although Giardia associates with early-life linear growth restriction, mechanistic explanations for Giardia-associated growth impairments remain elusive. Unlike other intestinal pathogens associated with constrained linear growth that cause intestinal or systemic inflammation or both, Giardia seldom associates with chronic inflammation in these children. Here we leverage the MAL-ED longitudinal birth cohort and a model of Giardia mono-association in gnotobiotic and immunodeficient mice to propose an alternative pathogenesis of this parasite. In children, Giardia results in linear growth deficits and gut permeability that are dose-dependent and independent of intestinal markers of inflammation. The estimates of these findings vary between children in different MAL-ED sites. In a representative site, where Giardia associates with growth restriction, infected children demonstrate broad amino acid deficiencies, and overproduction of specific phenolic acids, byproducts of intestinal bacterial amino acid metabolism. Gnotobiotic mice require specific nutritional and environmental conditions to recapitulate these findings, and immunodeficient mice confirm a pathway independent of chronic T/B cell inflammation. Taken together, we propose a new paradigm that Giardia-mediated growth faltering is contingent upon a convergence of this intestinal protozoa with nutritional and intestinal bacterial factors.
Hodge SH, Krauss MZ, Kaymak I, et al., 2022, Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 220, ISSN: 0022-1007
Hu G, Ling C, Chi L, et al., 2022, The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction., Nat Commun, Vol: 13
Mortality in children with severe malnutrition is strongly related to signs of metabolic dysfunction, such as hypoglycemia. Lower circulating tryptophan levels in children with severe malnutrition suggest a possible disturbance in the tryptophan-nicotinamide adenine dinucleotide (TRP-NAD+) pathway and subsequently in NAD+ dependent metabolism regulator sirtuin1 (SIRT1). Here we show that severe malnutrition in weanling mice, induced by 2-weeks of low protein diet feeding from weaning, leads to an impaired TRP-NAD+ pathway with decreased NAD+ levels and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAD+ pathway with NAD+ precursors improves hepatic mitochondrial and overall metabolic function through SIRT1 modulation. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAD+ pathway can improve liver metabolic function in a mouse model of severe malnutrition. These results could lead to the development of new interventions for children with severe malnutrition.
Smith LE, Chagwena DT, Bourke C, et al., 2022, Child Health, Agriculture and Integrated Nutrition (CHAIN): protocol for a randomised controlled trial of improved infant and young child feeding in rural Zimbabwe, BMJ OPEN, Vol: 12, ISSN: 2044-6055
Marino LV, Paulson S, Ashton JJ, et al., 2022, A scoping review: urinary markers of metabolic maturation in infants with CHD and the relationship to growth., Cardiol Young, Pages: 1-10
BACKGROUND: Growth failure in infants born with CHD is a persistent problem, even in those provided with adequate nutrition. OBJECTIVE: To summarise the published data describing the change in urinary metabolites during metabolic maturation in infants with CHD and identify pathways amenable to therapeutic intervention. DESIGN: Scoping review. ELIGIBILITY CRITERIA: Studies using qualitative or quantitative methods to describe urinary metabolites pre- and post-cardiac surgery and the relationship with growth in infants with CHD. SOURCES OF EVIDENCE: NICE Healthcare Databases website was used as a tool for multiple searches. RESULTS: 347 records were identified, of which 37 were duplicates. Following the removal of duplicate records, 310 record abstracts and titles were screened for inclusion. The full texts of eight articles were reviewed for eligibility, of which only two related to infants with CHD. The studies included in the scoping review described urinary metabolites in 42 infants. A content analysis identified two overarching themes of metabolic variation predictive of neurodevelopmental abnormalities associated with anaerobic metabolism and metabolic signature associated with the impact on gut microbiota, inflammation, energy, and lipid digestion. CONCLUSION: The results of this scoping review suggest that there are considerable gaps in our knowledge relating to metabolic maturation of infants with CHD, especially with respect to growth. Surgery is a key early life feature for CHD infants and has an impact on the developing biochemical phenotype with implications for metabolic pathways involved in immunomodulation, energy, gut microbial, and lipid metabolism. These early life fingerprints may predict those individuals at risk for neurodevelopmental abnormalities.
Letertre M, Bhatt A, Harvey M, et al., 2022, Characterizing the metabolic effects of the selective inhibition of gut microbial β-glucuronidases in mice, Scientific Reports, Vol: 12, ISSN: 2045-2322
The hydrolysis of xenobiotic glucuronides by gut bacterial glucuronidases reactivates previously detoxified compounds resulting in severe gut toxicity for the host. Selective bacterial β-glucuronidase inhibitors can mitigate this toxicity but their impact on wider host metabolic processes has not been studied. To investigate this the inhibitor 4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4′,5′:4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine (UNC10201652, Inh 9) was administered to mice to selectively inhibit a narrow range of bacterial β-glucuronidases in the gut. The metabolomic profiles of the intestinal contents, biofluids, and several tissues involved in the enterohepatic circulation were measured and compared to control animals. No biochemical perturbations were observed in the plasma, liver or gall bladder. In contrast, the metabolite profiles of urine, colon contents, feces and gut wall were altered compared to the controls. Changes were largely restricted to compounds derived from gut microbial metabolism. This work establishes that inhibitors targeted towards bacterial β-glucuronidases modulate the functionality of the intestinal microbiota without adversely impacting the host metabolic system.
Marino L, Paulson S, Ashton JJ, et al., 2022, A Scoping Review: Urinary Markers of Metabolic Maturation in Preterm Infants and Future Interventions to Improve Growth, NUTRIENTS, Vol: 14
Farras M, Swann JR, Rowland I, et al., 2022, Impact of Phenol-Enriched Olive Oils on Serum Metabonome and Its Relationship with Cardiometabolic Parameters: A Randomized, Double-Blind, Cross-Over, Controlled Trial, ANTIOXIDANTS, Vol: 11
Penny HA, Domingues RG, Krauss MZ, et al., 2022, Rhythmicity of intestinal IgA responses confers oscillatory commensal microbiota mutualism, SCIENCE IMMUNOLOGY, Vol: 7, ISSN: 2470-9468
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- Citations: 6
Vaitkute G, Panic G, Alber DG, et al., 2022, Linking gastrointestinal microbiota and metabolome dynamics to clinical outcomes in paediatric haematopoietic stem cell transplantation, MICROBIOME, Vol: 10, ISSN: 2049-2618
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- Citations: 1
Salminen S, Collado MC, Endo A, et al., 2022, The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics (vol 123, pg 1561, 2017), NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, Vol: 19, Pages: 551-551, ISSN: 1759-5045
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- Citations: 2
Salminen S, Collado MC, Endo A, et al., 2022, Reply to: Postbiotics - when simplification fails to clarify (Mar, 10.1038/s41575-022-00596-9, 2022), NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, Vol: 19, Pages: 275-275, ISSN: 1759-5045
Caspani G, Green M, Swann JR, et al., 2022, Microbe-Immune Crosstalk: Evidence That T Cells Influence the Development of the Brain Metabolome, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 23
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- Citations: 3
Kathrani A, Yen S, Swann JR, et al., 2022, The effect of a hydrolyzed protein diet on the fecal microbiota in cats with chronic enteropathy, SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322
Shehata E, Parker A, Suzuki T, et al., 2022, Microbiomes in physiology: insights into 21st-century global medical challenges, Publisher: WILEY, Pages: 257-264, ISSN: 0958-0670
Heijtz RD, Gressens P, Swann JR, 2022, Targeting microbial metabolites to treat autism, NATURE MEDICINE, Vol: 28, Pages: 448-450, ISSN: 1078-8956
Vatanen T, Sakwinska O, Wilson B, et al., 2022, Transcription shifts in gut bacteria shared between mothers and their infants., Sci Rep, Vol: 12
The infant gut microbiome contains a portion of bacteria that originate from the maternal gut. In the infant gut these bacteria encounter a new metabolic environment that differs from the adult gut, consequently requiring adjustments in their activities. We used pilot community RNA sequencing data (metatranscriptomes) from ten mother-infant dyads participating in the NiPPeR Study to characterize bacterial gene expression shifts following mother-to-infant transmission. Maternally-derived bacterial strains exhibited large scale gene expression shifts following the transmission to the infant gut, with 12,564 activated and 14,844 deactivated gene families. The implicated genes were most numerous and the magnitude shifts greatest in Bacteroides spp. This pilot study demonstrates environment-dependent, strain-specific shifts in gut bacteria function and underscores the importance of metatranscriptomic analysis in microbiome studies.
Church JA, Rukobo S, Govha M, et al., 2021, Associations between biomarkers of environmental enteric dysfunction and oral rotavirus vaccine immunogenicity in rural Zimbabwean infants, ECLINICALMEDICINE, Vol: 41
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- Citations: 1
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.
Spitzer SO, Tkacz A, Savignac HM, et al., 2021, Postnatal prebiotic supplementation in rats affects adult anxious behaviour, hippocampus, electrophysiology, metabolomics, and gut microbiota, ISCIENCE, Vol: 24
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- Citations: 2
Hu G, Ling C, Chi L, et al., 2021, STIMULATING THE TRYPTOPHAN-NAD plus PATHWAY IMPROVES DISTURBED HEPATIC METABOLIC FUNCTION IN A SEVERE MALNUTRITION MODEL IN A SIRT1 DEPENDENT MANNER, Publisher: WILEY, Pages: 1179A-1179A, ISSN: 0270-9139
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, Reply to: Postbiotics - when simplification fails to clarify, NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, Vol: 18, Pages: 827-828, ISSN: 1759-5045
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- Citations: 8
DeBoer MD, Platts-Mills JA, Elwood SE, et al., 2021, Effect of scheduled antimicrobial and nicotinamide treatment on linear growth in children in rural Tanzania: A factorial randomized, double-blind, placebo-controlled trial, PLOS MEDICINE, Vol: 18, ISSN: 1549-1277
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- Citations: 5
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