Displaying all 17 publications

Abstract:
Sort:
  1. Happy ageing by trusting our gut microbes
    Jayaraman A, Pettersson S
    Biochem Biophys Res Commun, 2022 Dec 10;633:88-91.
    PMID: 36344172 DOI: 10.1016/j.bbrc.2022.09.026
    The human gut microbiota comprises of trillions of micro-organisms in the gut some which secrete metabolites that play a pivotal role in supporting optimal body and organ functions. These dynamic and malleable gut microbes share a bidirectional relationship with their hosts that supports health in an age- and sex-dependent manner. Disruption of the gut microbiota or decrease in their diversity and richness due to unhealthy changes in lifestyle, diet or social disconnection, always results in unwanted outcomes on the host health which fuel chronic disease symptoms including neurodegenerative diseases. Thus, impairment of gut microbiota composition, results in organ decline that accelerates an individual's biological ageing. Here we review evidence supporting the bidirectional relationships between the gut microbiota and biological ageing.
  2. Fulltext When dysbiosis meets dystrophy: an unwanted gut-muscle connection
    Jayaraman A, Pettersson S
    EMBO Mol Med, 2023 Mar 08;15(3):e17324.
    PMID: 36843560 DOI: 10.15252/emmm.202217324
    Duchenne muscular dystrophy (DMD) is a devastating neuromuscular degenerative disease with no known cure to date. In recent years, the hypothesis of a "gut-muscle axis" has emerged suggesting that bidirectional communication between the gut microbiota and the muscular system regulates the muscular function and may be perturbed in several muscular disorders. In addition, the excessive consumption of sugar and of lipid-rich processed food products are factors that further aggravate the phenotype for such diseases and accelerate biological aging. However, these unhealthy microbiota profiles can be reversed by individualized dietary changes to not only alter the microbiota composition but also to reset the production of microbial metabolites known to trigger beneficial effects typically associated with prolonged health span. Two recent studies (in this issue of EMBO Mol Med) highlight the interesting potential of microbiota-informed next-generation dietary intervention programs to be considered in genetically linked muscle disorders like DMD.
  3. Fulltext The link between neuroinflammation and the neurovascular unit in synucleinopathies
    Wang Q, Zheng J, Pettersson S, Reynolds R, Tan EK
    Sci Adv, 2023 Feb 15;9(7):eabq1141.
    PMID: 36791205 DOI: 10.1126/sciadv.abq1141
    The neurovascular unit (NVU) is composed of vascular cells, glial cells, and neurons. As a fundamental functional module in the central nervous system, the NVU maintains homeostasis in the microenvironment and the integrity of the blood-brain barrier. Disruption of the NVU and interactions among its components are involved in the pathophysiology of synucleinopathies, which are characterized by the pathological accumulation of α-synuclein. Neuroinflammation contributes to the pathophysiology of synucleinopathies, including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. This review aims to summarize the neuroinflammatory response of glial cells and vascular cells in the NVU. We also review neuroinflammation in the context of the cross-talk between glial cells and vascular cells, between glial cells and pericytes, and between microglia and astroglia. Last, we discuss how α-synuclein affects neuroinflammation and how neuroinflammation influences the aggregation and spread of α-synuclein and analyze different properties of α-synuclein in synucleinopathies.
  4. Fulltext Regional Diets Targeting Gut Microbial Dynamics to Support Prolonged Healthspan
    Low DY, Hejndorf S, Tharmabalan RT, Poppema S, Pettersson S
    Front Microbiol, 2021;12:659465.
    PMID: 33995322 DOI: 10.3389/fmicb.2021.659465
    In the last 150 years, we have seen a significant increase in average life expectancy, associated with a shift from infectious to non-communicable diseases. The rising incidence of these diseases, for which age is often the largest risk factor, highlights the need for contemporary societies to improve healthy ageing for their growing silver generations. As ageing is an inevitable, non-reversing and highly individualised process, we need to better understand how non-genetic factors like diet choices and commensal gut microbes can modulate the biology of ageing. In this review, we discuss how geographical and ethnic variations influence habitual dietary patterns, nutrient structure, and gut microbial profiles with potential impact on the human healthspan. Several gut microbial genera have been associated with healthy elderly populations but are highly variable across populations. It seems unlikely that a universal pro-longevity gut microbiome exists. Rather, the optimal microbiome appears to be conditional on the microbial functionality acting on regional- and ethnicity-specific trends driven by cultural food context. We also highlight dietary and microbial factors that have been observed to elicit individual and clustered biological responses. Finally, we identify next generation avenues to modify otherwise fixed host functions and the individual ageing trajectory by manipulating the malleable gut microbiome with regionally adapted, personalised food intervention regimens targeted at prolonging human healthspan.
  5. The role of gut dysbiosis in Parkinson's disease: mechanistic insights and therapeutic options
    Wang Q, Luo Y, Ray Chaudhuri K, Reynolds R, Tan EK, Pettersson S
    Brain, 2021 Oct 22;144(9):2571-2593.
    PMID: 33856024 DOI: 10.1093/brain/awab156
    Parkinson's disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson's disease shows unique changes, which may be used as early biomarkers of disease. Alterations in the gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson's disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the CNS, and the microbiota-gut-brain axis may provide a pathway for the transmission of α-synuclein. We highlight recent discoveries about alterations to the gut microbiota in Parkinson's disease and focus on current mechanistic insights into the microbiota-gut-brain axis in disease pathophysiology. Moreover, we discuss the interactions between the production and transmission of α-synuclein and gut inflammation and neuroinflammation. In addition, we draw attention to diet modification, the use of probiotics and prebiotics and faecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson's disease.
  6. Fulltext Distinct gut microbiota composition among older adults with myocardial ageing
    Wong JJ, Purbojati RW, Tan RS, Pettersson S, Koh AS
    ESC Heart Fail, 2022 Dec;9(6):4366-4368.
    PMID: 36071622 DOI: 10.1002/ehf2.14139
  7. Gut microbiome profiling in systemic sclerosis: a metagenomic approach
    Tan TC, Chandrasekaran L, Leung YY, Purbojati R, Pettersson S, Low AHL
    Clin Exp Rheumatol, 2023 Aug;41(8):1578-1588.
    PMID: 36826808 DOI: 10.55563/clinexprheumatol/jof7nx
    OBJECTIVES: The early gastrointestinal (GI) manifestation of systemic sclerosis (SSc) suggests a possible GI microbiota engagement in the pathophysiology and/or progression of SSc. Previous studies have revealed dysbiosis among Caucasian SSc patients. This study extends these findings to Asian SSc patients.

    METHODS: Adult SSc patients, stratified according to 1) on immunosuppressive (On-IS) drugs or 2) no immunosuppressive drugs (No-IS), and age-and-sex-matched healthy controls (HC) were recruited. Metagenomic sequencing of stool DNA was compared between SSc patients and HC, and between SSc (On-IS) and (No-IS) patients. Alpha and beta-diversity, taxonomic and functional profiling were evaluated.

    RESULTS: Twenty-three female SSc patients (12 On-IS; 11 No-IS; 5 diffuse and 18 limited SSc subtype) and 19 female HC, with median age of 54 years and 56 years, respectively, were recruited. Median SSc disease duration was 3.3 years. Alpha diversity was significantly higher in SSc versus HC (p=0.014) and in SSc (No-IS) versus HC (p=0.006). There was no significant difference in beta diversity between SSc and HC (p=0.307). At the phyla level, there were significantly increased abundance of Firmicutes and Actinobacteria in SSc versus HC, and reduced abundance of Bacteroidetes (all p<0.001). At the species level, there were significantly increased abundance of several Lactobacillus, Bifidobacterium, and Coprococcus species in SSc, and increased abundance of Odoribacter, Bacteroides and Prevotella species in HC. KEGG pathway analysis demonstrated distinct differences between SSc versus HC, and between SSc (No-IS) and SSc (On-IS).

    CONCLUSIONS: Using metagenomic sequencing, our study further underlines distinct alterations in microbiota profiling among Asian SSc patients.

  8. Fulltext Nuanced contribution of gut microbiome in the early brain development of mice
    Yeo XY, Chae WR, Lee HU, Bae HG, Pettersson S, Grandjean J, et al.
    Gut Microbes, 2023 Dec;15(2):2283911.
    PMID: 38010368 DOI: 10.1080/19490976.2023.2283911
    The complex symbiotic relationship between the mammalian body and gut microbiome plays a critical role in the health outcomes of offspring later in life. The gut microbiome modulates virtually all physiological functions through direct or indirect interactions to maintain physiological homeostasis. Previous studies indicate a link between maternal/early-life gut microbiome, brain development, and behavioral outcomes relating to social cognition. Here we present direct evidence of the role of the gut microbiome in brain development. Through magnetic resonance imaging (MRI), we investigated the impact of the gut microbiome on brain organization and structure using germ-free (GF) mice and conventionalized mice, with the gut microbiome reintroduced after weaning. We found broad changes in brain volume in GF mice that persist despite the reintroduction of gut microbes at weaning. These data suggest a direct link between the maternal gut or early-postnatal microbe and their impact on brain developmental programming.
  9. Fulltext Helicobacter pylori infection can affect energy modulating hormones and body weight in germ free mice
    Khosravi Y, Seow SW, Amoyo AA, Chiow KH, Tan TL, Wong WY, et al.
    Sci Rep, 2015;5:8731.
    PMID: 25736205 DOI: 10.1038/srep08731
    Helicobacter pylori, is an invariably commensal resident of the gut microbiome associated with gastric ulcer in adults. In addition, these patients also suffered from a low grade inflammation that activates the immune system and thus increased shunting of energy to host defense mechanisms. To assess whether a H. pylori infection could affect growth in early life, we determined the expression levels of selected metabolic gut hormones in germ free (GF) and specific pathogen-free (SPF) mice with and without the presence of H. pylori. Despite H. pylori-infected (SPFH) mice display alteration in host metabolism (elevated levels of leptin, insulin and peptide YY) compared to non-infected SPF mice, their growth curves remained the same. SPFH mice also displayed increased level of eotaxin-1. Interestingly, GF mice infected with H. pylori (GFH) also displayed increased levels of ghrelin and PYY. However, in contrast to SPFH mice, GFH showed reduced weight gain and malnutrition. These preliminary findings show that exposure to H. pylori alters host metabolism early in life; but the commensal microbiota in SPF mice can attenuate the growth retarding effect from H. pylori observed in GF mice. Further investigations of possible additional side effects of H. pylori are highly warranted.
  10. Fulltext Helicobacter pylori and gut microbiota modulate energy homeostasis prior to inducing histopathological changes in mice
    Khosravi Y, Bunte RM, Chiow KH, Tan TL, Wong WY, Poh QH, et al.
    Gut Microbes, 2016;7(1):48-53.
    PMID: 26939851 DOI: 10.1080/19490976.2015.1119990
    Helicobacter pylori have been shown to influence physiological regulation of metabolic hormones involved in food intake, energy expenditure and body mass. It has been proposed that inducing H. pylori-induced gastric atrophy damages hormone-producing endocrine cells localized in gastric mucosal layers and therefore alter their concentrations. In a recent study, we provided additional proof in mice under controlled conditions that H. pylori and gut microbiota indeed affects circulating metabolic gut hormones and energy homeostasis. In this addendum, we presented data from follow-up investigations that demonstrated H. pylori and gut microbiota-associated modulation of metabolic gut hormones was independent and precedes H. pylori-induced histopathological changes in the gut of H. pylori-infected mice. Thus, H. pylori-associated argumentation of energy homeostasis is not caused by injury to endocrine cells in gastric mucosa.
  11. Fulltext Quantum changes in Helicobacter pylori gene expression accompany host-adaptation
    Chua EG, Wise MJ, Khosravi Y, Seow SW, Amoyo AA, Pettersson S, et al.
    DNA Res, 2017 Feb 01;24(1):37-49.
    PMID: 27803027 DOI: 10.1093/dnares/dsw046
    Helicobacter pylori is a highly successful gastric pathogen. High genomic plasticity allows its adaptation to changing host environments. Complete genomes of H. pylori clinical isolate UM032 and its mice-adapted serial derivatives 298 and 299, generated using both PacBio RS and Illumina MiSeq sequencing technologies, were compared to identify novel elements responsible for host-adaptation. The acquisition of a jhp0562-like allele, which encodes for a galactosyltransferase, was identified in the mice-adapted strains. Our analysis implies a new β-1,4-galactosyltransferase role for this enzyme, essential for Ley antigen expression. Intragenomic recombination between babA and babB genes was also observed. Further, we expanded on the list of candidate genes whose expression patterns have been mediated by upstream homopolymer-length alterations to facilitate host adaption. Importantly, greater than four-fold reduction of mRNA levels was demonstrated in five genes. Among the down-regulated genes, three encode for outer membrane proteins, including BabA, BabB and HopD. As expected, a substantial reduction in BabA protein abundance was detected in mice-adapted strains 298 and 299 via Western analysis. Our results suggest that the expression of Ley antigen and reduced outer membrane protein expressions may facilitate H. pylori colonisation of mouse gastric epithelium.
  12. Fulltext Implicit satiety goals and food-related expectations predict portion size in older adults: Findings from the BAMMBE cohort
    Pink AE, Lee LL, Low DY, Yang Y, Fong LZ, Kang AYH, et al.
    Appetite, 2023 Jan 01;180:106361.
    PMID: 36332849 DOI: 10.1016/j.appet.2022.106361
    Portion size selection is an indicator of appetite and within younger adults, is predicted by factors such as expected satiety, liking and motivations to achieve an ideal sensation of fullness (i.e., implicit satiety goals). Currently, there is limited research available on the determinants of portion size selection within older adults. Therefore, the current study aimed to examine the relationship between individual differences in implicit satiety goals, food-related expectations, and portion size selection in older adults. Free-living older adult Singaporeans (N = 115; Nmales = 62; age: M = 66.21 years, SD = 4.78, range = 60-83 years) participated as part of the Brain, Ageing, Microbiome, Muscle, Bone, and Exercise Study (BAMMBE). Participants completed questionnaires on their subjective requirements for experiencing different states of satiety and food-related expectations (i.e., liking, how filling) as well as a computerised portion size selection task. Using a multiple regression, we found that goals to feel comfortably full (B = 3.08, SE = 1.04, t = 2.96, p = .004) and to stop hunger (B = -2.25, SE = 0.82, t = -2.75, p = .007) significantly predicted larger portion size selection (R2 = 0.24, F(4,87) = 6.74, p 
  13. Fulltext Comparing the genomes of Helicobacter pylori clinical strain UM032 and Mice-adapted derivatives
    Khosravi Y, Rehvathy V, Wee WY, Wang S, Baybayan P, Singh S, et al.
    Gut Pathog, 2013;5:25.
    PMID: 23957912 DOI: 10.1186/1757-4749-5-25
    Helicobacter pylori is a Gram-negative bacterium that persistently infects the human stomach inducing chronic inflammation. The exact mechanisms of pathogenesis are still not completely understood. Although not a natural host for H. pylori, mouse infection models play an important role in establishing the immunology and pathogenicity of H. pylori. In this study, for the first time, the genome sequences of clinical H. pylori strain UM032 and mice-adapted derivatives, 298 and 299, were sequenced using the PacBio Single Molecule, Real-Time (SMRT) technology.
  14. Fulltext Systemic Perturbations in Amine and Kynurenine Metabolism Associated with Acute SARS-CoV-2 Infection and Inflammatory Cytokine Responses
    Lawler NG, Gray N, Kimhofer T, Boughton B, Gay M, Yang R, et al.
    J Proteome Res, 2021 May 07;20(5):2796-2811.
    PMID: 33724837 DOI: 10.1021/acs.jproteome.1c00052
    We performed quantitative metabolic phenotyping of blood plasma in parallel with cytokine/chemokine analysis from participants who were either SARS-CoV-2 (+) (n = 10) or SARS-CoV-2 (-) (n = 49). SARS-CoV-2 positivity was associated with a unique metabolic phenotype and demonstrated a complex systemic response to infection, including severe perturbations in amino acid and kynurenine metabolic pathways. Nine metabolites were elevated in plasma and strongly associated with infection (quinolinic acid, glutamic acid, nicotinic acid, aspartic acid, neopterin, kynurenine, phenylalanine, 3-hydroxykynurenine, and taurine; p < 0.05), while four metabolites were lower in infection (tryptophan, histidine, indole-3-acetic acid, and citrulline; p < 0.05). This signature supports a systemic metabolic phenoconversion following infection, indicating possible neurotoxicity and neurological disruption (elevations of 3-hydroxykynurenine and quinolinic acid) and liver dysfunction (reduction in Fischer's ratio and elevation of taurine). Finally, we report correlations between the key metabolite changes observed in the disease with concentrations of proinflammatory cytokines and chemokines showing strong immunometabolic disorder in response to SARS-CoV-2 infection.
  15. Fulltext A tryptophan metabolite made by a gut microbiome eukaryote induces pro-inflammatory T cells
    Wojciech L, Png CW, Koh EY, Kioh DYQ, Deng L, Wang Z, et al.
    EMBO J, 2023 Nov 02;42(21):e112963.
    PMID: 37743772 DOI: 10.15252/embj.2022112963
    The large intestine harbors microorganisms playing unique roles in host physiology. The beneficial or detrimental outcome of host-microbiome coexistence depends largely on the balance between regulators and responder intestinal CD4+ T cells. We found that ulcerative colitis-like changes in the large intestine after infection with the protist Blastocystis ST7 in a mouse model are associated with reduction of anti-inflammatory Treg cells and simultaneous expansion of pro-inflammatory Th17 responders. These alterations in CD4+ T cells depended on the tryptophan metabolite indole-3-acetaldehyde (I3AA) produced by this single-cell eukaryote. I3AA reduced the Treg subset in vivo and iTreg development in vitro by modifying their sensing of TGFβ, concomitantly affecting recognition of self-flora antigens by conventional CD4+ T cells. Parasite-derived I3AA also induces over-exuberant TCR signaling, manifested by increased CD69 expression and downregulation of co-inhibitor PD-1. We have thus identified a new mechanism dictating CD4+ fate decisions. The findings thus shine a new light on the ability of the protist microbiome and tryptophan metabolites, derived from them or other sources, to modulate the adaptive immune compartment, particularly in the context of gut inflammatory disorders.
  16. Fulltext Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor
    Wei GZ, Martin KA, Xing PY, Agrawal R, Whiley L, Wood TK, et al.
    Proc Natl Acad Sci U S A, 2021 Jul 06;118(27).
    PMID: 34210797 DOI: 10.1073/pnas.2021091118
    While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR-/-) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR-mediated signaling pathway elevated the expression of β-catenin, Neurog2, and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.
  17. Fulltext Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute-Phase Nonhospitalized COVID-19 Patients: Implications for Assessment of Post-Acute COVID-19 Syndrome
    Holmes E, Wist J, Masuda R, Lodge S, Nitschke P, Kimhofer T, et al.
    J Proteome Res, 2021 Jun 04;20(6):3315-3329.
    PMID: 34009992 DOI: 10.1021/acs.jproteome.1c00224
    We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID-19 patients and the possible biochemical sequelae of "Post-Acute COVID-19 Syndrome", colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients (n = 27) were compared with controls (n = 41) and hospitalized severe acute respiratory syndrome SARS-CoV-2 positive patients (n = 18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently perturbed, e.g., elevated taurine (p = 3.6 × 10-3 versus controls) and reduced glutamine/glutamate ratio (p = 6.95 × 10-8 versus controls), indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near-complete normalization, e.g., the plasma apolipoprotein B100/A1 ratio was similar to that of healthy controls but significantly lower (p = 4.2 × 10-3) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped with the acute-phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters (χ2p = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.
Related Terms
    Try searching for something
Filters
Contact Us

Please provide feedback to Administrator (afdal@afpm.org.my)

External Links