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Advancing human gut microbiota research by considering gut transit time
Accumulating evidence indicates that gut transit time is a key factor in shaping the gut microbiota composition and activity, which are linked to human health. Both population-wide and small-scale studies have identified transit time as a top covariate contributing to the large interindividual variation in the faecal microbiota composition. Despite this, transit time is still rarely being considered in the field of the human gut microbiome. Here, we review the latest research describing how and why whole gut and segmental transit times vary substantially between and within individuals, and how variations in gut transit time impact the gut microbiota composition, diversity and metabolism. Furthermore, we discuss the mechanisms by which the gut microbiota may causally affect gut motility. We argue that by taking into account the interindividual and intraindividual differences in gut transit time, we can advance our understanding of diet–microbiota interactions and disease-related microbiome signatures, since these may often be confounded by transient or persistent alterations in transit time. Altogether, a better understanding of the complex, bidirectional interactions between the gut microbiota and transit time is required to better understand gut microbiome variations in health and disease.
Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria
Objective
Idiopathic Parkinson’s disease (PD) is characterised by alpha-synuclein (aSyn) aggregation and death of dopaminergic neurons in the midbrain. Recent evidence posits that PD may initiate in the gut by microbes or their toxins that promote chronic gut inflammation that will ultimately impact the brain. In this work, we sought to demonstrate that the effects of the microbial toxin β-N-methylamino-L-alanine (BMAA) in the gut may trigger some PD cases, which is especially worrying as this toxin is present in certain foods but not routinely monitored by public health authorities.
Design
To test the hypothesis, we treated wild-type mice, primary neuronal cultures, cell lines and isolated mitochondria with BMAA, and analysed its impact on gut microbiota composition, barrier permeability, inflammation and aSyn aggregation as well as in brain inflammation, dopaminergic neuronal loss and motor behaviour. To further examine the key role of mitochondria, we also determined the specific effects of BMAA on mitochondrial function and on inflammasome activation.
Results
BMAA induced extensive depletion of segmented filamentous bacteria (SFB) that regulate gut immunity, thus triggering gut dysbiosis, immune cell migration, increased intestinal inflammation, loss of barrier integrity and caudo-rostral progression of aSyn. Additionally, BMAA induced in vitro and in vivo mitochondrial dysfunction with cardiolipin exposure and consequent activation of neuronal innate immunity. These events primed neuroinflammation, dopaminergic neuronal loss and motor deficits.
Conclusion
Taken together, our results demonstrate that chronic exposure to dietary BMAA can trigger a chain of events that recapitulate the evolution of the PD pathology from the gut to the brain, which is consistent with ‘gut-first’ PD.
Toxic trail from the gut to the brain
The GI tract faces a great challenge as it needs to organise nutrient uptake while at the same time prevent toxic substances and harmful organisms from entering the host. To execute this complex task, the intestinal wall is endowed with a myriad of cell types (muscle, neurons, glia, interstitial cells, endocrine, immune and epithelial cells, and vasculature) that have to work in concert. These cells are meticulously organised in concentric layers, within which the enteric nervous system (ENS) controls gut motility, blood flow and secretion.1 Scattered throughout these layers, especially in the lamina propria, are different immune cells that constitute the prime line of defence. The ENS consists of glia and different populations of neurons that communicate like any other nervous system via synaptic contacts. The enteric presynaptic terminals contain mitochondria and a host of presynaptic proteins necessary for synaptic neurotransmitter release. As part of their synaptic…
Promote or prevent? Gut microbial function and immune status may determine the effect of fiber in IBD
Guardian, Intermediary, or Perpetrator? New insights into environmental exposure, the gut microbiome, and NAFLD
The Value of a Gut Punch
From the stinging words of disappointment from his attending physician, an internal medicine physician in this narrative medicine essay tells how that moment of bare truth altered him and suggests that medical students may fare better from blunt but kind corrective conversations.
Unfavourable intrauterine environment contributes to abnormal gut microbiome and metabolome in twins
Objective
Fetal growth restriction (FGR) is a devastating pregnancy complication that increases the risk of perinatal mortality and morbidity. This study aims to determine the combined and relative effects of genetic and intrauterine environments on neonatal microbial communities and to explore selective FGR-induced gut microbiota disruption, metabolic profile disturbances and possible outcomes.
Design
We profiled and compared the gut microbial colonisation of 150 pairs of twin neonates who were classified into four groups based on their chorionicity and discordance of fetal birth weight. Gut microbiota dysbiosis and faecal metabolic alterations were determined by 16S ribosomal RNA and metagenomic sequencing and metabolomics, and the long-term effects were explored by surveys of physical and neurocognitive development conducted after 2~3 years of follow-up.
Results
Adverse intrauterine environmental factors related to selective FGR dominate genetics in their effects of elevating bacterial diversity and altering the composition of early-life gut microbiota, and this effect is positively related to the severity of selective FGR in twins. The influence of genetic factors on gut microbes diminishes in the context of selective FGR. Gut microbiota dysbiosis in twin neonates with selective FGR and faecal metabolic alterations features decreased abundances of Enterococcus and Acinetobacter and downregulated methionine and cysteine levels. Correlation analysis indicates that the faecal cysteine level in early life is positively correlated with the physical and neurocognitive development of infants.
Conclusion
Dysbiotic microbiota profiles and pronounced metabolic alterations are associated with selective FGR affected by adverse intrauterine environments, emphasising the possible effects of dysbiosis on long-term neurobehavioural development.
Cigarette smoke promotes colorectal cancer through modulation of gut microbiota and related metabolites
Objective
Cigarette smoking is a major risk factor for colorectal cancer (CRC). We aimed to investigate whether cigarette smoke promotes CRC by altering the gut microbiota and related metabolites.
Design
Azoxymethane-treated C57BL/6 mice were exposed to cigarette smoke or clean air 2 hours per day for 28 weeks. Shotgun metagenomic sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Germ-free mice were transplanted with stools from smoke-exposed and smoke-free control mice.
Results
Mice exposed to cigarette smoke had significantly increased tumour incidence and cellular proliferation compared with smoke-free control mice. Gut microbial dysbiosis was observed in smoke-exposed mice with significant differential abundance of bacterial species including the enrichment of Eggerthella lenta and depletion of Parabacteroides distasonis and Lactobacillus spp. Metabolomic analysis showed increased bile acid metabolites, especially taurodeoxycholic acid (TDCA) in the colon of smoke-exposed mice. We found that E. lenta had the most positive correlation with TDCA in smoke-exposed mice. Moreover, smoke-exposed mice manifested enhanced oncogenic MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2) signalling (a downstream target of TDCA) and impaired gut barrier function. Furthermore, germ-free mice transplanted with stools from smoke-exposed mice (GF-AOMS) had increased colonocyte proliferation. Similarly, GF-AOMS showed increased abundances of gut E. lenta and TDCA, activated MAPK/ERK pathway and impaired gut barrier in colonic epithelium.
Conclusion
The gut microbiota dysbiosis induced by cigarette smoke plays a protumourigenic role in CRC. The smoke-induced gut microbiota dysbiosis altered gut metabolites and impaired gut barrier function, which could activate oncogenic MAPK/ERK signalling in colonic epithelium.
Tiny contributors to severe obesity inside the gut
Obesity is a key player in the current global health crisis, acting as a leading risk factor in the main causes of morbidity and mortality, ranging from cardiovascular disease (CVD) and type 2 diabetes (T2D) to respiratory illnesses.1 While unhealthy diets and sedentary lifestyles together with polygenetic risks represent major causes of obesity, recent studies suggest that the gut microbiota also plays a part.2 A large body of evidence has revealed alterations in the gut microbiota composition and function of obese subjects compared with healthy controls.3–5 Moreover, certain prospective observational and interventional studies have identified microbiome signatures that precede the onset of obesity6 7 or influence the response to diet.8 Notwithstanding, precise identification of microbiome biomarkers is difficult due to the large interindividual variability of the microbiota as well as of the host…
Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism
Objectives
Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome’s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation.
Design
We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice.
Results
Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration.
Conclusion
Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity.
Trial registration number
NCT02059538.
Influence of maternal body mass index on human milk composition and associations to infant metabolism and gut colonisation: MAINHEALTH – a study protocol for an observational birth cohort
Introduction
Human milk provides all macronutrients for growth, bioactive compounds, micro-organisms and immunological components, which potentially interacts with and primes infant growth and, development, immune responses and the gut microbiota of the new-born. Infants with an overweight mother are more likely to become overweight later in life and overweight has been related to the gut microbiome. Therefore, it is important to investigate the mother-milk-infant triad as a biological system and if the maternal weight status influences the human milk composition, infant metabolism and gut microbiome.
Methods and analysis
This study aims to include 200 mother–infant dyads stratified into one of three body mass index (BMI) categories based on mother’s prepregnancy BMI. Multiomics analyses include metabolomics, proteomics, glycomics and microbiomics methods, aiming to characterise human milk from the mothers and further relate the composition to infant gut microbiota and its metabolic impact in the infant. Infant gut microbiota is analysed using 16S sequencing of faeces samples. Nuclear magnetic resonance and mass spectrometry are used for the remaining omics analysis. We investigate whether maternal pre-pregnancy BMI results in a distinct human milk composition that potentially affects the initial priming of the infant’s gut environment and metabolism early in life.
Ethics and dissemination
The Central Denmark Region Committees on Health Research Ethics has approved the protocol (J-nr. 1-10-72-296-18). All participants have before inclusion signed informed consent and deputy informed consent in accordance with the Declaration of Helsinki II. Results will be disseminated to health professionals including paediatricians, research community, nutritional policymakers, industry and finally the public. The scientific community will be informed via peer-reviewed publications and presentations at scientific conferences, the industry will be invited for meetings, and the public will be informed via reports in science magazines and the general press. Data cleared for personal data, will be deposited at public data repositories.
Trial registration number
Danish regional committee of the Central Jutland Region, journal number: 1-10-72-296-18, version 6.
Danish Data Protection Agency, journal number: 2016-051-000001, 1304.
ClinicalTrials.gov, identifier: NCT05111990.
Abstract 13266: Sex Specific Differences in the Gut Microbiome in Patients With Pulmonary Arterial Hypertension
Circulation, Volume 146, Issue Suppl_1, Page A13266-A13266, November 8, 2022. Introduction:Pulmonary arterial hypertension (PAH) patients exhibit sexual dimorphism in pulmonary vascular remodeling and right ventricular (RV) dysfunction. While female PAH patients have severe pulmonary vascular remodeling, male PAH patients have worse RV function. Inflammation, a key component of PAH pathobiology, has been implicated as a potential mechanism for sexual dimorphism. Gut dysbiosis causes systemic inflammation. However, it is unknown whether gut dysbiosis contributes to sexual dimorphism in PAH.Hypothesis:There are sex-specific differences in the gut microbiome and microbial metabolites of PAH patients.Methods:16S ribosomal ribonucleic acid gene sequencing was performed on stool samples from PAH patients (n=73). Markers of inflammation and circulating microbial metabolites were measured using plasma samples.Results:There was no significant difference in the Shannon diversity indices or species richness (Chao1 indices) between the gut microbiomes of male and female PAH patients. Moreover, principal component analysis of pairwise Bray-Curtis dissimilarity indices revealed no distinct microbiome compositions dependent on sex. There was no difference in serum claudin-3, a marker of gut permeability, and serum interleukin 6 levels between male and female PAH patients. When examining microbial metabolites, including trimethylamine N-oxide, short chain fatty acids, and secondary bile acids, no sex-specific differences were observed. Linear discriminant analysis of effect size revealed that there were no taxonomic differences based on sex.Conclusions:Male and female PAH patients do not possess distinct differences in their gut microbiomes or metabolites. There are also no sex-specific taxonomic differences. These findings do not support our hypothesis that gut dysbiosis may serve as a possible explanation for the sexual dimorphism observed in PAH.
Abstract 11083: Post-Infarction Cardiac Protection by Gut Butyrate-Producers
Circulation, Volume 146, Issue Suppl_1, Page A11083-A11083, November 8, 2022. BackgroundThe gut microbiota and their metabolites have been shown to contribute to the development of coronary artery diseases. However, little is known about their roles in post-injury cardiac repair. Here, we investigated the gut microbiota and plasma metabolomes distinct in patients with ST-elevation myocardial infarction (STEMI), and explored their roles on adaptive responses, using germ-free (GF) mice and nonhuman primate models.MethodsWe recruited 70 controls and 77 coronary angiogram-confirmed STEMI patients, and collected their stool and plasma. The stool and plasma of STEMI patients were collected immediately following percutaneous coronary intervention (PCI, STEMIT1) and again at 28 days after PCI (STEMIT2). We used 16S V3-V4 rRNA NGS and shotgun metagenomics to map the gut microbiota and both NMR and LC-MS metabolomics to profile the plasma metabolites. To determine therole of the gut microbiota and their metabolites on post-injury cardiac repair, we inoculated identified bacteria in GF mice and treated specific pathogen free mice with candidate metabolites. Moreover, we validated the microbiome and metabolomics findings in a nonhuman primate coronary ischemia-reperfusion (IR) injury model.ResultsThe 16S V3-V4 rRNA NGS and shotgun metagenomic analysis revealed an enrichment of butyrate-producing bacteria in STEMIT1, as compared to STEMIT2 or to control cases. Fecal microbiome transplantation of STEMI samples in GF mice deteriorated host post-injury cardiac function, showing reduced left ventricle ejection fraction and cardiac mechanics. Moreover, plasma ketogenesis increased in the STEMI patients using NMR and LC-MS metabolomics. The protective effect of butyrate was more profound with intact commensal gut flora. Furthermore, inoculation of butyrate-producers in GF mice elevated plasma ketone body and better preserved post-injury cardiac function. Agreed with the clinical finding, we observed injury-induced elevation of gut butyrate-producers and plasma ketone bodies in the nonhuman primate IR model.ConclusionThis study demonstrates the pivotal role of gut butyrate-producers and the derived ketogenesis in post-injury cardiac repair, which may lead to new prevention strategies and treatment for heart failure.
Abstract 12300: Circulating Gut-Microbiota-Related Metabolite Phenylacetylglutamine Levels, Diet Quality, and Risk of Incident Coronary Heart Disease Among Women
Circulation, Volume 146, Issue Suppl_1, Page A12300-A12300, November 8, 2022. Introduction:Phenylacetylglutamine (PAGln) has been recently discovered as a gut-microbiota-related metabolite, and circulating PAGln may be related to risks of cardiometabolic abnormalities. Gut microbiota-related dietary intakes and high-protein foods may affect circulating PAGln levels.Hypothesis:We assessed whether circulating PAGln levels may be related to intakes of gut-microbiota-related food intakes, and higher levels of PAGln may be associated with greater degrees of cardiometabolic abnormalities. We also tested a hypothesis that higher levels of circulating PAGln may be related to higher risk of the incident coronary heart disease (CHD).Methods:Circulating levels of PAGln, diet assessed using 7-day dietary records, and cardiometabolic abnormalities were assessed in the Women’s Lifestyle Validation Study (WLVS) (n=723). The associations between plasma PAGln levels and risk of incident CHD were analyzed in a prospective nested case-control of 1520 women (760 incident cases of fatal CHD and nonfatal myocardial infarction and 760 controls) from the Nurses’ Health Study (NHS). We identified incident cases of CHD over 10-14 years of follow-up time.Results:Higher levels of PAGln were associated with higher levels of circulating insulin, triglycerides, as well as lower levels of HDL cholesterol. We found that greater intakes of red meat and processed meat (p=0.01), but not of poultry or fish (p >0.05), and lower intakes of vegetables (p=0.03) were significant factors associated with higher levels of circulating PAGln. In the prospective nested case-control study setting, higher levels of PAGln were associated with higher risk of the incident CHD. Every 1 unit increment of log-transformed PAGln was associated with a relative risk of 1.21 (95% CI: 1.01, 1.45) for the incident CHD.Conclusions:Gut-microbiota-affecting diet quality were related to circulating levels of PAGln. Circulating PAGln levels may be associated with cardiometabolic abnormalities and risk of incident CHD among women.
Abstract 11851: Acetate Rescues the Gut Microbial Metabolites PAA/PAG-induced Vascular Senescence by Epigenetic and SASP Regulation
Circulation, Volume 146, Issue Suppl_1, Page A11851-A11851, November 8, 2022. Introduction:Age-related gut microbiota alteration may underpin vascular disease. Yet, little is known about the role of cardiovascular disease-linked gut microbial metabolite phenylacetyl glutamine (PAG) in vascular aging.Hypothesis:1)PAG promotes endothelial senescence via epigenetic and SASP modulation;2)Acetate rescues PAG-induced endothelial senescence and impaired angiogenesis.Methods:We quantitated plasma concentrations of PAG and its precursor phenylacetic acid (PAA) in old and young healthy humans ( >65vs.18-35 years, n=41-45) and mice (24vs.3 months, n=6) by LC-MS/MS. Fecal acetate was measured by HPLC-RI. We then treated proliferating human aortic endothelial cells (PEC) with PAA+Glutamine (for PAG production) to examine its effects on cellular senescence, epigenetic and SASP state, mitochondrial respiration, and angiogenesis.Results:We showed markedly higher plasma PAA and PAG concentrations in old humans and micevs.young ones. Yet, fecal acetate level was significantly lower in oldvs.young mice. PAG significantly induced senescence (increased SA-β-gal positive cells and transcripts p16, p19, p21) and mitochondrial ROS production in PEC associated with upregulated SASP (IL1α, IL1β, TNF-α and adhesion molecule VCAM-1), and reduced mitochondrial respiration. PAG markedly reduced angiogenesis (endothelial sprouting and tube formation) accompanied by decreases in CaMKKβT286and histone deacetylase 4 (HDAC4S632) phosphorylation, histone 3 (H3) acetylation, and the subsequent Mef2A-mediated eNOSS1177phosphorylation. By contrast, acetate (3 μM) rescued senescence and impaired angiogenesis and mitochondrial function and reversed SASP and epigenetic alteration induced by PAG in PEC.Conclusions:We conclude that acetate regulates the aging gut microbial metabolite PAG-induced SASP and epigenetic alteration, by which rescues endothelial senescence and represents a potential vascular regenerative strategy.