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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.

Supplementary Figures and Materials and Metholds from SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer

Supplementary Table 2 from SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer

Supplementary Table 1 from SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer

Supplementary Table 3 from SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer

Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinical efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concentrations of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochemical, pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% versus 48% for SAHA (both at maximum tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APCmin mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clinical data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacologic advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients. Mol Cancer Ther; 9(3); 642–52

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. National Medical Research Council (NMRC) Published version This work was supported by the National Natural Science Foundation of China (no.82071414), Leading Talent in Talents Project Guangdong High-level Personnel of Special Support Program, Scientific Research Foundation of Guangzhou (no. 202206010005) to Q.W., ASEAN microbiome nutrition centre to SP, CIFAR to SP, and National Medical Research Council Singapore to E.-K.T.

To investigate the underlying molecular mechanisms on how the gut microbe metabolite, indoles, regulate host organ growth and function, germ-free male mice were mono-colonized with indole-producing wildtypeEscherichia colior tryptophanase-encodingtnaAknockout mutant indole-non-producingE. coli. The indole mutantE. colirecipient mice exhibited significant multiorgan decline and growth retardation combined with catabolism and energy deficiency despite increased food intake compared to control mice. In addition, indole mutant mice displayed malfunctional intestine, enlarged caecum, reduced numbers of colonic enterochromaffin cells and reduced circulating serotonin levels, resulting in reduced gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice also displayed decreased expression ofKcnj12gene, suggesting reduced excitability of enteric neurons thus adding to intestinal dysfunctional phenotype. In conclusion, indoles are necessary to maintain adult metabolic homeostasis across multiple organs in vivo. Impairment of indole levels results in multiorgan functional decline suggesting a mechanism whereby gut microbe metabolites may regulate biological ageing and thus increase the risk for disease.Graphical summary

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.

OBJECTIVE: Irritable bowel syndrome (IBS) is a chronic disorder associated with an abnormal gastrointestinal microbiome. Microbiome-host interactions are known to influence organ function including in the central nervous system; thus, we sought to identify whether IBS may be a risk factor for the development of glaucoma.DESIGN: Two prospective cohort studies.SUBJECTS: The 1958 United Kingdom Birth Cohort (UKBC; 9091 individuals) and the Danish National Registry of Patients (DNRP; 62,541 individuals with IBS and 625,410 matched general population cohort members).METHODS: In the UKBC, participants were surveyed throughout life (including at ages 42 and 50). The DNRP contains records of hospital-based contacts and prescription data from the national prescription database.MAIN OUTCOME MEASURE: The main outcome measure was incidence of glaucoma. In the UKBC, incident glaucoma at age 50 (n = 48) was determined through comparison of survey responses at ages 42 and 50 years. In the DNRP, glaucoma was assessed by hospital diagnosis (n = 1510), glaucoma surgery (n = 582) and initiation of glaucoma medications (n = 1674).RESULTS: In the UKBC, the odds ratio (OR) of developing glaucoma between ages 42 and 50 in persons with a chronic IBS diagnosis was increased [OR: 5.84, 95% confidence interval (CI): 2.26-15.13]. People with an IBS diagnosis in the DNRP had a hazard ratio (HR) of 1.35 for developing physician-diagnosed glaucoma (95% CI: 1.16-1.56), an HR of 1.35 for undergoing glaucoma surgery (95% CI: 1.06-1.70) and an HR of 1.19 for initiating glaucoma medication (95% CI: 1.03-1.38).CONCLUSIONS: In two large European cohort studies, IBS is a risk factor for glaucoma.

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; N

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 (χ2 p = 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.

Introduction: Recent research has demonstrated shifts in intestinal microbial composition in response to cardiovascular disease (CVD) development. Left ventricular (LV) diastolic dysfunction is an early manifestation of myocardial ageing. We aimed to examine whether gut microbial composition is associated with LV diastolic function among healthy older adults. Methods: Among community older adults, 15 subjects with preserved LV ejection fraction on echocardiography underwent gut microbial composition examination in this proof-of-concept cross-sectional study. Myocardial relaxation (diastolic function) was impaired in those subjects with lower ratios of peak early (E) to late diastolic (A, atrial contraction) velocities. Metagenomic reads from stool samples were analyzed after excluding human reference genome data, and classified into various microbial taxonomic groups using lowest-common-ancestor algorithm. Statistical analysis was performed using linear discriminant analysis (LDA). Results: The subjects (53% males, mean age 75±4 years) were stratified into Groups 1 (n=8) and 2 (n=7) with more severe and lesser diastolic dysfunction, respectively, based on E/A ratios (0.77 vs. 1.28, p Conclusions: Distinct gut microbiota were associated with more severe vs. lesser LV diastolic dysfunction. Future validation in larger cohorts is warranted for targeting the microbiome in myocardial ageing.

Significance While the effects of gut microbes on brain development and function have been described, the mechanisms remain largely unknown. Here, we report that tryptophan-metabolizing gut microbes secrete indoles that regulate neurogenesis in the adult hippocampus. This stimulatory effect on adult neurogenesis is mediated by the metabolic- and immune-linked aryl hydrocarbon receptor (AhR). Another AhR ligand, the tryptophan metabolite kynurenine, failed to induce neurogenesis, suggesting ligand specificity of AhR-mediated regulation of adult neurogenesis. The indole-AhR signaling pathway elevates transcription factors and signaling proteins that promote adult neurogenesis, as well as key markers of synaptic maturation. Our data demonstrate a symbiotic gut–brain coregulatory axis that connects the metabolic status of gut microbes to the control of neurogenesis in the adult hippocampus., 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.

Objective Assess whether treatment with probiotics improve gastrointestinal symptoms in patients with systemic sclerosis (SSc). Methods In this double-blind randomized placebo-controlled parallel-group phase II trial, SSc subjects with total score ≥ 0.1 on a validated SSc-specific gastrointestinal tract (GIT) questionnaire were randomized (1:1) to receive 60 days of high dose multi-strain probiotics (Vivomixx® 1800 billion units/day) or identical placebo, followed by an additional 60 days of probiotics in both groups. Between group differences in GIT score change were assessed after 60 days (primary outcome, time-point T1) and 120 days (secondary outcome, time-point, T2) by an intention-to-treat approach. Stool samples at three time-points were subjected to 16S next generation sequencing. Results Forty subjects were randomized to placebo-probiotics (n = 21) or probiotics-probiotics (n = 19). At T1, no significant improvement was observed between the two groups, reported as mean ± SE for total GIT score (placebo 0.14 ± 0.06 versus probiotics 0.13 ± 0.07; p = 0.85) or its subdomains. At T2, whilst there was no significant improvement in total GIT score (placebo-probiotics –0.05±0.06; probiotics-probiotics –0.18 ± 0.07; p = 0.14), there was significant improvement of GIT-reflux in the probiotic group (–0.22 ± 0.05 versus placebo-probiotics 0.05 ± 0.07; p = 0.004). Subjects on probiotics exhibited increasing stool microbiota alpha diversity compared to the placebo-probiotics group. Adverse events (AEs) were mild, with similar proportion of subjects with AEs and serious AEs in both groups. Conclusion Whilst there was no clear improvement in overall GI symptoms after 60 days, we observed significantly improved GI reflux after 120 days of probiotics. The trial confirmed safety of multi-strain probiotics in SSc patients. Trial registration. Clinicaltrials.gov; NCT01804959

Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and oligodendroglial population dynamics in the mixed-sex BACHD mouse model of HD. Ultrastructural analysis of myelin in the corpus callosum revealed alterations of myelin thickness in BACHD GF compared to specific-pathogen free (SPF) mice, whereas no differences were observed between wild-type (WT) groups. In contrast, myelin compaction was altered in all groups when compared to WT SPF animals. Levels of myelin-related proteins were generally reduced, and the number of mature oligodendrocytes was decreased in the prefrontal cortex under GF compared to SPF conditions, regardless of genotype. Minor differences in commensal bacteria at the family and genera levels were found in the gut microbiota of BACHD and WT animals housed in standard living conditions. Our findings indicate complex effects of a germ-free status on myelin-related characteristics, and highlight the adaptive properties of myelination as a result of environmental manipulation. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University Published version M.A.P. was supported by funds from theAgency for Science Technology and Research and the NationalUniversity of Singapore. S.P. was supported by funds from LKC Schoolof Medicine and SCELSE.

The human microbiota provides tonic signals that calibrate the host immune response1,2, but their identity is unknown. Bacterial peptidoglycan (PGN) subunits are likely candidates since they are well-known immunity-enhancing adjuvants, released by most bacteria during growth, and have been found in the blood of healthy people3-7. We developed a monoclonal antibody (mAb), 2E7, that targets muramyl-L-alanyl-D-isoglutamine (MDP), a conserved and minimal immunostimulatory structure of PGN. Using 2E7-based assays, we detected PGN ubiquitously in human blood at a broad range of concentrations that is relatively stable in each individual. We also detected PGN in the serum of several warm-blooded animals. However, PGN is barely detectable in the serum of germ-free mice, indicating that its origin is the host microbiota. Neutralization of circulating PGN via intraperitoneal administration of 2E7 suppressed the development of autoimmune arthritis and experimental autoimmune encephalomyelitis in mice. Arthritic NOD2-/- mice lacking the MDP sensor did not respond to 2E7, indicating that 2E7 dampens inflammation by blocking nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-mediated pathways. We propose that circulating PGN acts as a natural immune potentiator that tunes the host immune response; altering its level is a promising therapeutic strategy for immune-mediated diseases. National Medical Research Council (NMRC) This work was supported by National Medical Research Council grant no. BMRC/ BnB/0001b/2012 awarded to Y.W., L.C., and N.P.

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.

The COVID-19 pandemic has the potential to affect the human microbiome in infected and uninfected individuals, having a substantial impact on human health over the long term. This pandemic intersects with a decades-long decline in microbial diversity and ancestral microbes due to hygiene, antibiotics, and urban living (the hygiene hypothesis). High-risk groups succumbing to COVID-19 include those with preexisting conditions, such as diabetes and obesity, which are also associated with microbiome abnormalities. Current pandemic control measures and practices will have broad, uneven, and potentially long-term effects for the human microbiome across the planet, given the implementation of physical separation, extensive hygiene, travel barriers, and other measures that influence overall microbial loss and inability for reinoculation. Although much remains uncertain or unknown about the virus and its consequences, implementing pandemic control practices could significantly affect the microbiome. In this Perspective, we explore many facets of COVID-19−induced societal changes and their possible effects on the microbiome, and discuss current and future challenges regarding the interplay between this pandemic and the microbiome. Recent recognition of the microbiome’s influence on human health makes it critical to consider both how the microbiome, shaped by biosocial processes, affects susceptibility to the coronavirus and, conversely, how COVID-19 disease and prevention measures may affect the microbiome. This knowledge may prove key in prevention and treatment, and long-term biological and social outcomes of this pandemic.

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.

International audience; The COVID-19 pandemic has the potential to affect the human microbiome in infected and uninfected individuals, having a substantial impact on human health over the long term. This pandemic intersects with a decades-long decline in microbial diversity and ancestral microbes due to hygiene, antibiotics, and urban living (the hygiene hypothesis). High-risk groups succumbing to COVID-19 include those with preexisting conditions, such as diabetes and obesity, which are also associated with microbiome abnormalities. Current pandemic control measures and practices will have broad, uneven, and potentially long-term effects for the human microbiome across the planet, given the implementation of physical separation, extensive hygiene, travel barriers, and other measures that influence overall microbial loss and inability for reinoculation. Although much remains uncertain or unknown about the virus and its consequences, implementing pandemic control practices could significantly affect the microbiome. In this Perspective, we explore many facets of COVID-19−induced societal changes and their possible effects on the microbiome, and discuss current and future challenges regarding the interplay between this pandemic and the microbiome. Recent recognition of the microbiome’s influence on human health makes it critical to consider both how the microbiome, shaped by biosocial processes, affects susceptibility to the coronavirus and, conversely, how COVID-19 disease and prevention measures may affect the microbiome. This knowledge may prove key in prevention and treatment, and long-term biological and social outcomes of this pandemic.

Background:Patients with systemic lupus erythematosus (SLE) experience a considerably impaired health-related quality of life (HRQoL) compared with the general population. Previous literature has implied an association between high body mass index (BMI) and HRQoL diminutions. However, data are scarce and further exploration in large study populations and, importantly, with regard to the clinical significance of this association is needed.Objectives:The aim of this study was to determine whether overweight and/or obesity were associated with impaired physical and/or mental HRQoL aspects in the SLE population of two large clinical trials.Methods:We utilised pooled baseline data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) clinical trials of belimumab (N=1684). Access to data was granted by GlaxoSmithKline. The patients were stratified into four groups based on their body mass index (BMI), according to WHO guidelines. We conducted comparisons between non-overweight versus overweight, and non-obese versus obese SLE patients. HRQoL was self-reported using the Medical Outcomes Study (MOS) short form 36 (SF-36) health survey, the functional assessment of chronic illness therapy (FACIT)-Fatigue scale and the three-level EuroQol- 5 Dimension (EQ-5D) questionnaire. We explored whether the differences in scores were clinically meaningful using previously determined thresholds for minimal clinically important differences (MCIDs). The non-parametric Mann-Whitney U test was used for comparisons between different BMI groups. Linear regression analysis was next applied to test independence in multivariable models, adjusting for age, sex, ethnicity, disease duration, disease activity, organ damage and standard of care treatment.Results:Forty-four per cent (44%) of the patients had a BMI score over the normal range, and 18% were obese. The overweight group performed worse than the non-overweight with regard to FACIT-Fatigue scores (mean ± standard deviation: 27.7 ± 12.1 vs 32.0 ± 11.3; PIn multivariable linear regression analysis, the overweight and obese group showed worse PCS scores (standardised coefficient: β=-0.09; PConclusion:BMI above normal was highly associated with HRQoL impairment, especially in physical aspects. Further survey to examine causality is warranted to support structured weight control strategies as an intervention towards a more favourable HRQoL.Disclosure of Interests:None declared

The gut microbiota evolves as the host ages, yet the effects of these microbial changes on host physiology and energy homeostasis are poorly understood. To investigate these potential effects, we transplanted the gut microbiota of old or young mice into young germ-free recipient mice. Both groups showed similar weight gain and skeletal muscle mass, but germ-free mice receiving a gut microbiota transplant from old donor mice unexpectedly showed increased neurogenesis in the hippocampus of the brain and increased intestinal growth. Metagenomic analysis revealed age-sensitive enrichment in butyrate-producing microbes in young germ-free mice transplanted with the gut microbiota of old donor mice. The higher concentration of gut microbiota-derived butyrate in these young transplanted mice was associated with an increase in the pleiotropic and prolongevity hormone fibroblast growth factor 21 (FGF21). An increase in FGF21 correlated with increased AMPK and SIRT-1 activation and reduced mTOR signaling. Young germ-free mice treated with exogenous sodium butyrate recapitulated the prolongevity phenotype observed in young germ-free mice receiving a gut microbiota transplant from old donor mice. These results suggest that gut microbiota transplants from aged hosts conferred beneficial effects in responsive young recipients.

Microorganisms that colonize the gastrointestinal tract, collectively known as the gut microbiota, are known to produce small molecules and metabolites that significantly contribute to host intestinal development, functions, and homeostasis. Emerging insights from microbiome research reveal that gut microbiota-derived signals and molecules influence another key player maintaining intestinal homeostasis-the intestinal stem cell niche, which regulates epithelial self-renewal. In this review, the literature on gut microbiota-host crosstalk is surveyed, highlighting the effects of gut microbial metabolites on intestinal stem cells. The production of various classes of metabolites, their actions on intestinal stem cells are discussed and, finally, how the production and function of metabolites are modulated by aging and dietary intake is commented upon.

All species, including humans, are cohabited by a myriad of microbial species, which massively influences body function in a diet‐, exercise‐ and age‐dependent manner. The microbiome composition differs between individuals, partly due to the polymorphic immune system, as well as the environment, making the microbe–host interplay unique in each one of us. Ageing is a gradual loss of function in part due to reduced repair mechanisms and accumulation of tissue damage through mechanisms largely unknown. Accumulating evidence suggests that our indigenous microbes, a known major regulator of human physiology, are also connected to regulate the ageing process through signalling pathways and metabolites though the biological mechanisms are unknown. At an ageing meeting in Singapore in 2018, investigators discussed the current understanding of microbe regulation and its impact on healthy ageing. This review summarizes the highlights from the meeting and conveys some of the new ideas that emerged around gut microbes and the biology of ageing. While highly speculative, an idea emerged in which gut microbes constantly respond and evolve to environmental cues, as part of an ageing process, thus serving as a second messenger to support and attenuate organ decline in a diet‐, gender‐ and age‐dependent manner.

Animals exist as biodiverse composite organisms that include microbial residents, eukaryotic cells, and organs that collectively form a human being. Through an interdependent relationship and an inherent ability to transmit and reciprocate stimuli in a bidirectional way, a human body or the holobiont secures growth, health, and reproduction. As such, the survival of a holobiont is dependent on the maintenance of biological order including metabolic homeostasis by tight regulation of the communication between its eukaryotic and prokaryotic residents. In this review an overview and perspective are provided on the bidirectional communication between microbes and their host in mutually nurturing biochemical, biological, and social interconnected relationships between the components of the holobiont. An emphasis is placed on exemplifying microbiome-mediated effects on host functions-aiming to integrate microbiome functionality to host physiology, be it health or disease. Nutrition, immunology, and sexual dimorphism have been traversed extensively to reflect on health and mind states, social interactions, and urbanization defects/effects. Finally, examples of molecular mechanisms potentially orchestrating these complex transkingdom interactions are provided.

Background:Smoking is associated with worse treatment response1 and higher mortality2 in rheumatoid arthritis (RA).Objectives:To assess the effect of a smoking cessation intervention in a rheumatology setting.Methods:We designed a smoking cessation interventional feasibility study. RA patients who were active smokers were asked to participate. A nurse-delivered program consisting of behavioural changes techniques and voluntary pharmacotherapy was executed. The intervention was at baseline and at several time points during a 24 month period, based on the individual patient’s needs. Smoking status was collected at baseline, 6, 12, 18 and 24 months. Smoking cessation was verified by 7-days abstinence and carbon monoxide in expiratory air. The main outcome was the proportion of patients who quit smoking (QS) at 24 months.Results:A total of 99 patients were included in the study between 2011-2020. Median (IQR) age of patients was 58 (50 - 64), 69 % were female and 82% were RF and/or ACPA positive. 59% of patients had a newly diagnosed RA, (included from the early RA-track), with a median (IQR) symptom duration of 5 (2-9,5) months. Patients with established RA 41% (included from regular rheumatology department) had a median disease duration of 4 (2-8) years. After 24 months 21% quit smoking (QS) (Table 1). At months 6, 12, 18 and 24 the proportion of QS patients was 12, 13, 15 and 21, respectively. The proportion of QS patients at month 12 and continued being in the QS group throughout the study period was 10%. In the subgroup of patients who continued smoking (CS) the median number of cigarettes per day was significantly reduced at all follow-up time points (Table 1). No significant differences were observed at baseline between CS at 24 months and QS, apart from the proportion of patients who reported anxiety (extracted from EQ-5D and defined as absent or present), which was significantly fewer in the QS group (Table). In the QS group at month 24, the proportion of females was numerically lower compared to CS (52% vs. 73%, p=0.07).Table 1.Baseline demographical, clinical characteristics and number of cigarettes at specific time-points for patients who were non-smokers (QS) and smokers (CS) at month 24.QSN=21 (21%)CSN=78 (79%)Difference between QS and CS(p-value)Age*(median, IQR)60 (53-62)57 (50-64)0.94Symptom duration in early RA patients (months) (median, IQR)6 (2-12)4.5 (2-8.5)0.49Disease duration of patients with established RA (years) (median, IQR)8 (3.5-16.5)3 (2-6)0.12% females52730.07% RF and/or ACPA positive85810.70DAS28* (median, IQR)4.24 (3.13-5.72)4.11 (2.88-5.36)0.69HAQ* (median, IQR)0.75 (0.25 -1.38)0.88 (0.38-1.25)0.74VAS pain* (median, IQR)46.0 (11-60)34.5 (12-70)0.90% of patients with reported anxiety* (part of EQ5D)28580.02Smoking duration (years)(median, IQR)40 (30-50)40 (34-49)0.92Median number of cigarettes per day-at baseline10 (7-15)12 (10-20)0.22-at 6 months0 (0-3)6 (3-10)0.006-at 12 months0 (0-5)6 (3-10)0.0003-at 18 months0 (0-0)6 (2-10)0.00-at 24 months0 (0-0)6 (3-10)0.00*=measured at baselineConclusion:Smoking cessation intervention in a rheumatology clinic setting may facilitate reduced smoking or complete cessation in patients with RA. Patient who did not report anxiety were more likely to quit smoking.References:[1]Saevarsdottir, S., et al (2011). Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts. Arthritis Rheum, 63(1), 26-36.[2]Joseph, R´., et al (2016) Smoking-Related Mortality in Patients With Early Rheumatoid Arthritis: A Retrospective Cohort Study Using the Clinical Practice Research Datalink Arthritis Care Res (Hoboken) 68 (11) 1598-1606Acknowledgements:This study was partly funded by grants from Swedish Reumatism Association.Disclosure of Interests:Marie-Louise Karlsson Speakers bureau: MLK has recivied fee form Novartis Sverige AB, Grant/research support from: MLK had recivied finical grants from Novartis Sverige. Abbvie has fincial support brochure wich was used in the study, Katarina Hertzberg-Nyquist: None declared, Saedis Saevarsdottir Employee of: S is a part-time employee of deCODE genetics Inc., unrelated to this work., Ingrid E. Lundberg Consultant of: I Lundberg har recieved consulting fees from Corbus Pharmaceutical, EMD Serono Research & Development Institute, Octapharma AG, Orphazyme, Janssen, Kezar Life Sciences Inc., Ingrid Demmelmaie: None declared, Susanne Pettersson: None declared, Katerina Chatzidionysiou Consultant of: KC has received consultancy fees from Eli Lilly, AbbVie and Pfizer.

Background:Being diagnosed with ANCA associated vasculitis (AAV) can be a frightening experience and means facing changes that involves adapting to new situations1. Patients that are provided adequate information are better equipped to make well informed decisions regarding their care and stay compliant to the treatment plan. In order to provide adequate patient-centered information at the appropriate time and to identify those who may need extra support, the information needs must be explored2. There have been several studies on the information needs of rheumatological patients, although very few studies for patients with AAV.Objectives:The aim of this study was to explore what information patients with AAV need from their rheumatological team and how it differs between groups (gender, disease duration).Methods:Men and women over 18 years were included through a consecutive sample from a Rheumatology or Nephrology Clinic at Karolinska University Hospital in Sweden during 2008-2019. Patients with all forms of AAV (GPA, MPA and EGPA), that had the Rheumatology clinic as primary contact, were included.The participants were given Educational Needs Assessment Tool (ENAT) that measures the patient’s information needs3. The initial question, ‘Do you need information right now about something that can help you with your rheumatic disease?’ is answered yes/no. ENAT then includes 7 domains (Managing pain, Movement, Feelings, Disease process, Treatments, Self-help measures and Support systems) each containing 4-7 items (4-point Likert scale, ’not at all important = 0’ to ‘extremely important = 3’). The total sum is divided by the maximum score and gives the percentage response of maximum score (0-100%), 0% meaning no information need and 100% highest information need. The responses are presented as “mean % of the domain score”. Independent-sample t-test was used to compare the mean between groups. One way ANOVA was used to compare the mean domain score between the different diagnoses and age groups.Results:178 individuals completed the questionnaire, equally divided by gender. Age ranged from 18-85, median 61. 33,7% had been diagnosed within 2 years.The mean total score was 56,8 % of the highest possible score (0-100%). The highest information need was found in the domains ‘Disease process’ (78,1%), ‘Self-help measures’ (68,5%) and ‘Treatments’ (63,6%) whereas lesser need for information was found in the domains ‘Managing pain’ (47,5%), ‘Support systems’ (46,5%) and ‘Movement’ (41,1%). The domain ‘Feelings’ was scored as moderate (55,5%).Those who acknowledge a present information need also scored significantly higher overall in all the domains. Disease duration and gender showed significantly affect the information need. Highest scores were found among women with a disease duration < 2 years with significant difference in 3/7 domains. Age, disease activity, diagnosis and social status did not affect the ENAT scores.Conclusion:Even though only 38% of participants stated a current need for information, the results indicate that there are certain areas that patients with AAV consider important to receive more information about. Special consideration needs to be taken to women with short disease duration since they were shown to have a significantly higher need for information.References:[1]Mooney, J., et al. (2013). ‘In one ear and out the other - it’s a lot to take in’: a qualitative study exploring the informational needs of patients with ANCA-associated vasculitis. Musculoskeletal Care, 11(1)[2]Ntatsaki, E., et al. (2014). BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology (Oxford), 53(12)[3]Hardware, B., et al. (2004). Towards the development of a tool to assess educational needs in patients with arthritis. Clinical Effectiveness in Nursing, 8(2)Disclosure of Interests:None declared

The microbiome located within a given host and its organs forms a holobiont, an intimate functional entity with evolutionarily designed interactions to support nutritional intake and reproduction. Thus, all organs in a holobiont respond to changes within the microbiome. The development and function of the central nervous system and its homeostatic mechanisms are no exception and are also subject to regulation by the gut microbiome. In order for the holobiont to function effectively, the microbiome and host must communicate. The aryl hydrocarbon receptor is an evolutionarily conserved receptor recognizing environmental compounds, including a number of ligands produced directly and indirectly by the microbiome. This review focuses on the microbiome-gut-brain axis in regard to the aryl hydrocarbon receptor signaling pathway and its impact on underlying mechanisms in neurodegeneration.

Cancer often arises by the constitutive activation of mitogenic pathways by mutations in stem cells. Eph receptors are unusual in that although they regulate the proliferation of stem/progenitor cells in many adult organs, they typically fail to transform cells. Multiple ephrins and Eph receptors are often co-expressed and are thought to be redundant, but we here describe an unexpected dichotomy with two homologous ligands, ephrin-B1 and ephrin-B2, regulating specifically migration or proliferation in the intestinal stem cell niche. We demonstrate that the combined activity of two different coexpressed Eph receptors of the A and B class assembled into common signaling clusters in response to ephrin-B2 is required for mitogenic signaling. The requirement of two different Eph receptors to convey mitogenic signals identifies a new type of cooperation within this receptor family and helps explain why constitutive activation of a single receptor fails to transform cells.

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.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic liver disease that is thought to be reversible by changing the diet. To examine the impact of dietary changes on progression and cure of NAFLD, we fed mice a high-fat diet (HFD) or high-fructose diet (HFrD) for 9 weeks, followed by an additional 9 weeks, where mice were given normal chow diet. As predicted, the diet-induced NAFLD elicited changes in glucose tolerance, serum cholesterol, and triglyceride levels in both diet groups. Moreover, the diet-induced NAFLD phenotype was reversed, as measured by the recovery of glucose intolerance and high cholesterol levels when mice were given normal chow diet. However, surprisingly, the elevated serum triglyceride levels persisted. Metagenomic analysis revealed dietary-induced changes of microbiome composition, some of which remained altered even after reversing the diet to normal chow, as illustrated by species of the Odoribacter genus. Genome-wide DNA methylation analysis revealed a “priming effect” through changes in DNA methylation in key liver genes. For example, the lipid-regulating gene Apoa4 remained hypomethylated in both groups even after introduction to normal chow diet. Our results support that dietary change, in part, reverses the NAFLD phenotype. However, some diet-induced effects remain, such as changes in microbiome composition, elevated serum triglyceride levels, and hypomethylation of key liver genes. While the results are correlative in nature, it is tempting to speculate that the dietary-induced changes in microbiome composition may in part contribute to the persistent epigenetic modifications in the liver.