Risultati per: GUT

Objective
The human gut fungal community, known as the mycobiome, plays a fundamental role in the gut ecosystem and health. Here we aimed to investigate the determinants and long-term stability of gut mycobiome among middle-aged and elderly adults. We further explored the interplay between gut fungi and bacteria on metabolic health.

Design
The present study included 1244 participants from the Guangzhou Nutrition and Health Study. We characterised the long-term stability and determinants of the human gut mycobiome, especially long-term habitual dietary consumption. The comprehensive multiomics analyses were performed to investigate the ecological links between gut bacteria, fungi and faecal metabolome. Finally, we examined whether the interaction between gut bacteria and fungi could modulate the metabolic risk.

Results
The gut fungal composition was temporally stable and mainly determined by age, long-term habitual diet and host physiological states. Specifically, compared with middle-aged individuals, Blastobotrys and Agaricomycetes spp were depleted, while Malassezia was enriched in the elderly. Dairy consumption was positively associated with Saccharomyces but inversely associated with Candida. Notably, Saccharomycetales spp interacted with gut bacterial diversity to influence insulin resistance. Bidirectional mediation analyses indicated that bacterial function or faecal histidine might causally mediate an impact of Pichia on blood cholesterol.

Conclusion
We depict the sociodemographic and dietary determinants of human gut mycobiome in middle-aged and elderly individuals, and further reveal that the gut mycobiome may be closely associated with the host metabolic health through regulating gut bacterial functions and metabolites.

Objective
The role of the brain–gut axis is of increasing interest in IBD, as the link between common mental disorders and GI inflammation may be bidirectional. We performed a systematic review examining these issues.

Design
We searched EMBASE Classic and EMBASE, Medline, and APA PsychInfo (to 11 July 2021) for longitudinal follow-up studies examining effect of symptoms of anxiety or depression on subsequent adverse outcomes in IBD, or effect of active IBD on subsequent development of symptoms of anxiety or depression. We pooled relative risks (RRs) and HRs with 95% CIs for adverse outcomes (flare, escalation of therapy, hospitalisation, emergency department attendance, surgery or a composite of any of these) according to presence of symptoms of anxiety or depression at baseline, or RRs and HRs with 95% CIs for new onset of symptoms of anxiety or depression according to presence of active IBD at baseline.

Results
We included 12 separate studies, recruiting 9192 patients. All 12 studies examined brain-to-gut effects. Anxiety at baseline was associated with significantly higher risks of escalation of therapy (RR=1.68; 95% CI 1.18 to 2.40), hospitalisation (RR=1.72; 95% CI 1.01 to 2.95), emergency department attendance (RR=1.30; 95% CI 1.21 to 1.39), or a composite of any adverse outcome. Depression at baseline was associated with higher risks of flare (RR=1.60; 95% CI 1.21 to 2.12), escalation of therapy (RR=1.41; 95% CI 1.08 to 1.84), hospitalisation (RR=1.35; 95% CI 1.17 to 1.57), emergency department attendance (RR=1.38; 95% CI 1.22 to 1.56), surgery (RR=1.63; 95% CI 1.19 to 2.22) or a composite of any of these. Three studies examined gut-to-brain effects. Active disease at baseline was associated with future development of anxiety or depression (RR=2.24; 95% CI 1.25 to 4.01 and RR=1.49; 95% CI 1.11 to 1.98, respectively).

Conclusion
Bidirectional effects of the brain–gut axis are present in IBD and may influence both the natural history of the disease and psychological health.

Circadian timekeeping in intestinal organoids is reset by gut microbe-generated short- chain fatty acids through an epigenetic mechanism of histone deacetylases inhibition.

Gut commensal bacteria modulate synthesis of resolvin D1 in colonic tuft cells. Decreased synthesis of colonic resolvin D1 may contribute to the development of pain in patients with irritable bowel syndrome with diarrhea.

Stroke, Ahead of Print. Poststroke infections are common complications of stroke and are highly associated with poor outcomes for patients. Stroke induces profound immunodepression coupled with alterations to autonomic signaling, which together render the body more susceptible to infection from without (nosocomial/community-acquired infection) and from within (commensal bacterial infection). Critical to the hypothesis of commensal infection is the phenomenon of poststroke gut permeability and gut dysbiosis. Few studies have provided adequate explanations for the mechanisms underlying the molecular alterations that produce a more permeable gut and perturbed gut microbiota after stroke. A dysregulation in the production of matrix MMP-7 (metalloproteinase-7) may play a critical role in the progression of gut permeability after stroke. By cleaving junctional and extracellular matrix proteins, MMP-7 is capable of compromising gut barrier integrity. Because of MMP-7’s unique abundance in the small intestine and its capacity to be induced in states of bacterial invasion and inflammation, along with its unique degradative capability, MMP-7 may be crucially important to the progression of gut permeability after ischemic stroke.

Alterations in gut microbiome are associated with gut barrier dysfunction in healthy humans.

Objective
Recent studies have provided insights into the gut microbiota in autism spectrum disorder (ASD); however, these studies were restricted owing to limited sampling at the unitary stage of childhood. Herein, we aimed to reveal developmental characteristics of gut microbiota in a large cohort of subjects with ASD combined with interindividual factors impacting gut microbiota.

Design
A large cohort of 773 subjects with ASD (aged 16 months to 19 years), 429 neurotypical (NT) development subjects (aged 11 months to 15 years) were emolyed to determine the dynamics change of gut microbiota across different ages using 16S rRNA sequencing.

Result
In subjects with ASD, we observed a distinct but progressive deviation in the development of gut microbiota characterised by persistently decreased alpha diversity, early unsustainable immature microbiota, altered aboudance of 20 operational taxonomic units (OTUs), decreased taxon detection rate and 325 deregulated microbial metabolic functions with age-dependent patterns. We further revealed microbial relationships that have changed extensively in ASD before 3 years of age, which were associated with the severity of behaviour, sleep and GI symptoms in the ASD group. This analysis demonstrated that a signature of the combination of 2 OTUs, Veillonella and Enterobacteriaceae, and 17 microbial metabolic functions efficiently discriminated ASD from NT subjects in both the discovery (area under the curve (AUC)=0.86), and validation 1 (AUC=0.78), 2 (AUC=0.82) and 3 (AUC=0.67) sets.

Conclusion
Our large cohort combined with clinical symptom analysis highlights the key regulator of gut microbiota in the pathogenesis of ASD and emphasises the importance of monitoring and targeting the gut microbiome in future clinical applications of ASD.

In celiac disease, bacterial composition and function differ according to gut location.

Introduction
Ulcerative colitis (UC) and irritable bowel syndrome (IBS) are distressing chronic diseases associated with abdominal pain and altered bowel habits of unknown aetiology. Results from previous studies indicate that, across both diseases, increased levels of illness-related anxiety and dysfunctional symptom expectations contribute to symptom persistence. Thus, comparing both disorders with regard to common and disease-specific factors in the persistence and modification of gastrointestinal symptoms seems justified. Our primary hypothesis is that persistent gastrointestinal symptoms in UC and IBS can be improved by modifying dysfunctional symptom expectations and illness-related anxiety using expectation management strategies.

Methods and analysis
To assess the extent to which persistent somatic symptoms are modifiable in adult patients with UC and IBS, we will conduct an observer-blinded, three-arm randomised controlled trial. A total of 117 patients with UC and 117 patients with IBS will be randomised into three groups of equal size: targeted expectation management aiming to reduce illness-related anxiety and dysfunctional symptom expectations in addition to standard care (SC, intervention 1), non-specific supportive treatment in addition to SC (intervention 2) or SC only (control). Both active intervention groups will comprise three individual online consultation sessions and a booster session after 3 months. The primary outcome is baseline to postinterventional change in gastrointestinal symptom severity.

Ethics and dissemination
The study was approved by the Ethics Committee of the Hamburg Medical Association (2020-10198-BO-ff). The study will shed light onto the efficacy and mechanisms of action of a targeted expectation management intervention for persistent gastrointestinal symptoms in patients with UC and IBS. Furthermore, the detailed analysis of the complex biopsychosocial mechanisms will allow the further advancement of aetiological models and according evidence-based intervention strategies.

Trial registration number
ISRCTN30800023.

Introduction
Immunotherapy is the fourth leading therapy for lung cancer following surgery, chemotherapy and radiotherapy. Recently, several studies have reported about the potential association between the gut microbiome and therapeutic response to immunotherapy. Nevertheless, the specific composition of the gut microbiome or combination of gut microbes that truly predict the efficacy of immunotherapy is not definitive.

Methods and analysis
The present multicentre, prospective, observational study aims to discover the specific composition of the gut microbiome or combination of gut microbes predicting the therapeutic response to immunotherapy in lung cancer using artificial intelligence. The main inclusion criteria are as follows: (1) pathologically or cytologically confirmed metastatic or postoperative recurrent lung cancer including non-small cell lung cancer and small cell lung cancer; (2) age≥20 years at the time of informed consent; (3) planned treatment with immunotherapy including combination therapy and monotherapy, as the first-line immunotherapy; and (4) ability to provide faecal samples. In total, 400 patients will be enrolled prospectively. Enrolment will begin in 2021, and the final analyses will be completed by 2024.

Ethics and dissemination
The study protocol was approved by the institutional review board of each participating centre in 2021 (Kyushu Cancer Center, IRB approved No. 2021-13, 8 June 2021 and Kyushu Medical Center, IRB approved No. 21-076, 31 August 2021). Study results will be disseminated through peer-reviewed journals and national and international conferences.

Trial registration number
UMIN000046428.

Stroke, Ahead of Print. Besides damaging the brain, stroke causes systemic changes, including to the gastrointestinal system. A growing body of evidence supports the role of the gut and its microbiota in stroke, stroke prognosis, and recovery. The gut microbiota can increase the risk of a cerebrovascular event, playing a role in the onset of stroke. Conversely, stroke can induce dysbiosis of the gut microbiota and epithelial barrier integrity. This has been proposed as a contributor to systemic infections. In this review, we describe the role of the gut microbiota, microbiome and microbiota-derived metabolites in experimental and clinical stroke, and their potential use as therapeutic targets. Fourteen clinical studies have identified 62 upregulated (eg,Streptococcus,Lactobacillus, Escherichia) and 29 downregulated microbial taxa (eg,Eubacterium, Roseburia) between stroke and healthy participants. The majority found that stroke patients have reduced gut microbiome diversity. However, other nonbacterial microorganisms are yet to be studied. In experimental stroke, severity is dependent on gut microbiome composition, whereas the latter can greatly change with antibiotics, age, and diet. Consumption of foods rich in choline and L-carnitine are positively associated with stroke onset via production of trimethylamine N-oxide in experimental and clinical stroke. Conversely, in mice, consumption of dietary fiber improves stroke outcome, likely via gut microbiota–derived metabolites called short-chain fatty acids, such as acetate, propionate, and butyrate. The majority of the evidence, however, comes from experimental studies. Clinical interventions targeted at gut microbiota–derived metabolites as new therapeutic opportunities for stroke prevention and treatment are warranted.

Stroke, Volume 53, Issue Suppl_1, Page AWP240-AWP240, February 1, 2022. Microbiome-derived ligands of the aryl hydrocarbon receptor (AHR) including tryptophan-derived indole acetic acid (IAA) have anti-inflammatory effects in some tissues. However, their effect on neuroinflammation after stroke is unknown. Brain-derived ligands of AHR (e.g. kynurenine) increase post-ischemia and are detrimental. Consistently, pharmacological inhibition of AHR after stroke reduces deleterious effects of kynurenine-mediated activation of AHR and improves outcome. However, whether IAA-mediated activation of AHR is detrimental or beneficial after stroke is unknown. We hypothesized that post-stroke treatment with IAA will reduce neuroinflammation and improve outcomes via beneficial activation of microglial (MG) AHR. We used a reversible middle cerebral artery occlusion (MCAO) model in aged (18mo) WT male mice to investigate temporal changes in biome-derived (IAA) versus host-derived (kynurenine) AHR ligands. Using metabolomics analysis, we determined that plasma levels of IAA can be restored in naïve aged mice by oral probiotics administration of AHR ligand producers. We found that brain kynurenine increases but plasma IAA decreases as early as 3 hours after MCAO in aged mice (n=4/gp,p=0.0029) while brain IAA levels remain unchanged. Our 16S rRNA-sequencing shows that aging leads to reduction in AHR ligand-producers (e.g.Bifidobacterium[B]andLactobacillus[L]). Oral gavage with AHR ligand-producing BBL-probiotic cocktail restored the age-related decline in plasma IAA both acutely (24 hours post-treatment) and chronically (weekly for 6 weeks, n=8/gp,p=0.0086andp=0.0073, respectively). Further, the increase in plasma levels of IAA after probiotic bacteriotherapy with AHR ligand producers was associated with modulation of AHR activity in the brain (decreased AHR expression in MG, n=8/gp,p=0.0119) and reduced MG activation (p=0.0069). Our results show that IAA modulates MG-mediated neuroinflammation after stroke. We plan to utilize post-stroke treatment with IAA in aged WT mice and in inducible knock-out mice with microglialAhrdeletion to further validate our hypothesis. Future studies are needed to focus on the regulatory function of other biome-derived AHR ligands in post-stroke neuroinflammation.

Stroke, Volume 53, Issue Suppl_1, Page A83-A83, February 1, 2022. Microfold or membranous cells (M cells) are specialized antigen sampling cells residing in the epithelium of Peyer’s patches (PPs), the gut-associated lymphoid tissue in the small intestine. M cells are in continuous crosstalk with luminal microbes and host immune cells. The detrimental shift of the microbiota seen with aging and after stroke contribute to bacterial antigen translocation. This axis has emerged as an epicenter for post-stroke immune dysfunction and systemic infection. The role of M cells in the PPs as an initiation site for host mucosal immunity after stroke is undefined.Hypothesis:Stroke-induced gut dysbiosis and M cell ablation leads to impaired antigen sampling mechanisms and clearance of translocating bacteria in PPs after stroke. We used a 60-minute reversible middle cerebral artery occlusion model in young (8-10 wks) C57BL/6 male mice to investigate how brain ischemia affects M cells in the PPs. We performed microbiota transplants from the cecal contents of stroke mice to naïve age-matched recipients via oral gavage for three consecutive days before tissue harvest on day four. We determined that stroke-induced changes in gut microbiota alone can cause M cell dysfunction. We found that both the number of PPs and M cells decrease 24 hours after stroke (n=8/gp,p=0.0104andp=0.0054,respectively). Our imaging studies revealed disruption of tissue architecture and reduction in size of PPs after stroke. Microbiota transplant from stroke mice cecum to naïve recipients showed a similar effect on the number of PPs and M cells (n=10/gp,p=0.0568andp=0.0299). The decrease in the number of M cells after microbiota transplantation was associated with immune dysregulation in the PPs, such as a reduction in the number of regulatory T cells (n=5/gp,p=0.0084). This is the first study that specifically examined M cells in a mouse model of stroke. Our results show that 1) stroke reduces the number of PPs and M cells and 2) stroke-induced gut dysbiosis can independently reduce the number of PPs and likely M cells and may regulate gut-originated immune responses after stroke. Future studies are needed to understand the effects of stroke-induced dysbiosis on M cell-mediated antigen processing in the gut and their immunoregulatory functions.

Stroke, Volume 53, Issue Suppl_1, Page A165-A165, February 1, 2022. Background:The gut-brain axis has recently become key in understanding stroke pathogenesis. The bidirectional communication between the gut and the brain are highly involved in the immune response to stroke. The effect of the aged biome, naturally occurring dysbiosis through the process of inflammaging, may have significant impact on offspring in terms of stroke risk factors.Method:Young (3-month) female wildtype C57B/6 mice were subjected to antibiotic treatment to clear their native gut biome and were then treated with fecal microbiome transplants from 3-month (M) control, 14M menopausal, and 18M reproductively senescent female mice, and were bred in our facility. Subsequent pups obtained were aged to 9 months followed by a battery of behavioral tests (novel object recognition (NORT), Y-maze, tail suspension, and open field test) and body weight measurements. Feces was collected periodically for 16s rRNA sequencing analysis.Results:Aged biome affected the female fecundity significantly (p=0.028, n=7/12) and the pup biome showed a significant sex specific difference in composition through 16s sequencing (p=0.009, n=7). Female pup from 14- or 18M biome mothers had consistently higher body weight from 21 days to 9 months of age compared to controls (p=0.183, n=6/9/13). Male pups from 18M biome dams showed significantly low body weight 2 months post birth (p=0.048, n= 7/10). Mothers that received 14M biome had overweight male offspring at 9 months of age (p=0.017. Cognitive assessment through NORT showed that female pups from mothers colonized with 14M biome had a significantly lower discrimination index compared to controls (p=0.045, n=6/9). Only male pups from 14M biome mothers showed a deficit in spatial cognition (p=0.018). Both males and females exhibited an early depressive phenotype compared to controls at 2 months of age (p=0.028), with female pups also exhibiting this phenotype at 9 months (p=0.018).Conclusion:Age of the maternal biome has a significant effect on its offspring’s health, specifically body weight, cognition, and depressive phenotype in a sex and time dependent manner. These effects correlate positively with stroke risk factors highlighting the importance of the microbiome as an epigenetic regulator of offspring health.

Stroke, Volume 53, Issue Suppl_1, Page A17-A17, February 1, 2022. Introduction:Neonatal Hypoxic Ischemic Encephalopathy (nHIE) is a major cause of mortality and morbidity in infants, occurring in 1.5/1000 live births. Inflammation persists years after injury and detrimentally affects neurocognitive outcomes in children. Recent evidence shows that neuroinflammation and gut injury alters microbial populations in the gut (gut dysbiosis) and reduces the level of bacteria capable of producing beneficial, anti-inflammatory tryptophan (Trp) metabolites. Metabolites are detected by microglia (MG) with the aryl hydrocarbon receptor (AHR). Ligand specific AHR activation can influence MG behavior after CNS injury, potentially modifying recovery.We hypothesizethat nHIE leads to chronic gut dysbiosis and reduced microbial-derived Trp metabolites, which exacerbates MG-induced CNS damage. We also hypothesize that Trp-derivatives bind MG AHR to reduce inflammation and improve neurological outcomes in males and females.Methods:We used a modified Rice Vannucci Model on PND9 C57BL/6J mice to investigate the role of MG AHR as a mediator of gut microbiome-brain communication after nHIE and demonstrated direct microbial metabolite modulation of MG usingin vitrocell culture assays.Results:We found an increase in AHR and CD45 expression in MG 24hrs after nHIE (p=0.0169 and p=0.0047 respectively, n=5). RT-qPCR of SIM-A9 MG cells showed that pretreatment with indole-acetic-acid (IAA) followed by LPS injury produced significantly moreIl10than cells pretreated with AHR agonist FICZ, suggesting Trp-derivatives activate an anti-inflammatory response (p=0.013, n=8). IAA mildly reducedIl1β,Il6, andTnfαafter LPS administration. 16S rRNA sequencing, behavior and metabolomics analysis of acute (24hrs) and chronic (7wks) cohorts showed detriments in behavioral tasks and dysbiotic changes after nHIE.Conclusion:nHIE results in increased AHR expression in MG, gut dysbiosis, and alterations in microbial-Trp metabolites in males and females.In vitroassays demonstrated that absence of Trp metabolites result in greater inflammatory activity of MG after injury via the AHR pathway, supporting our hypothesis that reduction of microbial-derived Trp metabolites after nHIE worsens MG-induced CNS damage.

Stroke, Volume 53, Issue Suppl_1, Page AWP236-AWP236, February 1, 2022. Background:It is known that early brain injury (EBI), which occurs early after the onset of subarachnoid hemorrhage (SAH), largely determines the prognosis of SAH; however, an effective treatment for EBI has not been developed. The outcome of various diseases including ischemic stroke is influenced by the composition of the gut microbiome (GM) and we have previously shown that the GM is also associated with the rupture of cerebral aneurysms. Here, we studied whether prior alteration of the GM can prevent EBI after SAH.Methods:We altered the GM of 7-week-old male rats by administering antibiotics-containing water for 2 weeks or performing fecal microbiome transplantation after antibiotics treatment. The composition of the GM was profiled using 16S rRNA. SAH was induced by injection of blood in the subarachnoid space of control rats and rats with altered GM. We evaluated EBI indicators such as the neurological score, brain water content, Evans blue extravasation, and neuronal apoptosis. We also studied inflammatory cells using immunohistochemistry, immunocytochemistry, quantitative PCR and flow cytometry.Results:There were significant differences in alpha and beta diversity between the control and antibiotics-treated rats. Compared with the control rats, the antibiotics-treated rats had significantly reduced neurological symptoms, brain edema, blood-brain barrier disruption and apoptosis. Among inflammatory cells, neutrophil infiltration into the brain was significantly reduced in the antibiotics-treated rats. Interestingly, the preventive effect on neutrophil infiltration was already observed immediately after SAH. Next, the immune status of each group before SAH onset was examined. There was no difference in circulating neutrophil counts, but flow cytometry showed a significant decrease in aged neutrophils which exhibit a highly reactive phenotype in the antibiotics-treated rats. Finally, the neuroprotective effect of antibiotics against EBI disappeared when the GM was recolonized.Conclusions:Our findings suggest that the GM affects the severity of EBI after SAH by regulating neutrophils. In the future, adjustment of the GM to prevent EBI may become a new strategy in patients who are being followed for cerebral aneurysms.