Abstract TP337: Blocking insulin-like growth factor 1 receptor in the gut abrogates IGF-1 mediated long-term neuroprotection in middle-aged female rats

Stroke, Volume 56, Issue Suppl_1, Page ATP337-ATP337, February 1, 2025. Background and Purpose:Our previous studies in a rat model of ischemic stroke identified that intraperitoneal (IP), but not intracerebroventricular (ICV) administration of IGF-1 reduced stroke-induced gut leakiness and peripheral inflammation in the acute phase and attenuated stroke-induced impairment in acyclic middle-aged female rats. These data suggest that the gut may be implicated in IGF-1-mediated effects on stroke-induced cognitive impairment. To directly assess whether the effect of IGF-1 on behavioral improvement is mediated by the gut, study utilized a novel tet-inducible rAAV construct to block IGF1R specifically in the gut.Methods:Female Sprague Dawley rats (9-11 mo) were intragastrically gavaged with either recombinant rAAV construct containing IGFR-shRNA (IGFR-sh) downstream of the IESC promoter Lgr5 in a Tet-inducible system or rAAV-empty vector (Scr-sh) 4 weeks prior to experimental ischemia. Animals were subjected to endothelin-1 induced MCAo. Doxycycline was administered 4h later and IGF-1 was given ip at 4 and 24 h post-stroke. Sensorimotor function as well as peripheral inflammation (in serum samples) was assessed at 5d post-stroke and long-term cognitive impairment was evaluated after 60 days.Results:The mCherry reporter in the rAAV construct was observed in the intestinal crypt, indicating appropriate delivery of the construct. Sensorimotor function evaluated by vibrissae evoked forelimb placement task was significantly impaired in the ipsilateral paw after stroke in IGFR-Sh+IGF-1 compared to Scr-sh+IGF-1(p

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Gennaio 2025

Abstract TMP116: Gut-derived extracellular vesicles promote neurovascular damage and cognitive impairment in diabetic mice

Stroke, Volume 56, Issue Suppl_1, Page ATMP116-ATMP116, February 1, 2025. Background and Purpose:Gut microbiota dysfunction is associated with diabetic cognitive impairment (DCI). However, the mechanisms underlying the interaction of gut microbiota dysbiosis and DCI remain poorly understood. We tested the hypothesis that extracellular vesicles generated by diabetic gut microbiota exacerbate DCI by promoting the impairment of cerebral vascular function.Methods:Gut-EVs from the stools of male non-diabetic dm (dm-gut-EVs) and diabetic (db/db mice) with DCI (db-gut-EVs) mice at 20 weeks of age (20W) were isolated and characterized by means of ultracentrifugation and 16S rRNA sequencing, respectively. Given that db/db mice develop cognitive deficits at 20W, prediabetic db/db mice at 8 weeks of age (8W) were treated with gut-EVs at a dose of 1x1010particles/injection intravenously twice a week for 12 weeks. Cognitive performance was assessed using a battery of behavioral tests.Results:16S rRNA analysis revealed significant alterations in the microbiota composition of db-gut-EVs derived from 20W db/db mice with DCI compared to dm-gut-EVs (n=5/group). Db/db mice treated with db-gut-EVs extracted at 20W, but not with dm-gut-EVs, exhibited a significant decline in learning and memory function, as assayed by the Novel object recognition, Social recognition memory, and Morris water maze assay, starting at 16W and worsening at 20W, compared to db/db mice treated with saline (n=10/group). Additionally, db/db mice treated with db-gut-EVs exhibited increased cerebral vascular thrombosis (18±2 vs 11±2 Fibrin+ vessels/mm2in saline, p

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Gennaio 2025

Abstract TP38: Harnessing the Gut-Brain Axis: The Therapeutic Potential of Akkermansia and Its Exosomes in Ischemic Stroke Recovery

Stroke, Volume 56, Issue Suppl_1, Page ATP38-ATP38, February 1, 2025. Introduction:The gut-brain axis is pivotal in recovery after stroke, with the gut microbiome playing a significant role in neurological outcomes.Akkermansia muciniphila(AKK), a beneficial gut bacterium, has shown promise in metabolic conditions. We hypothesize that AKK and its exosomes (AKK-Exo) can enhance stroke recovery by modulating gut-brain interactions.Methods: Human study:fecal samples from 88 ischemic stroke (IS) patients and 23 healthy elderly were analyzed using 16S rDNA sequencing. Animal study: 6-8 months old male mice subjected to photothrombotic middle cerebral artery occlusion were treated intragastrically with either AKK or AKK-Exo. Neurological recovery was evaluated over 2 weeks, accompanied by 16S rDNA sequencing and metabolomics analysis of fecal and plasma samples. The RT-PCR, Western blotting, and immunofluorescence were employed to assess inflammation, microglial activation, and white matter (WM) remodeling in the brain.Results:Human study demonstrated that IS disrupts gut microbiota, with an increase in pathogenic bacteria likeParabacteroidesand a decrease in beneficial microbes likeLachnospira. Patients with higher levels of AKK exhibited better neurological outcomes. In the mouse model, both AKK and AKK-Exo treatments resulted in improvements in neurological function, also led to a restructuring of gut microecology, characterized by a reduction in pro-inflammatory bacteria and an increase in beneficial species. Moreover, the treatments were associated with a decrease in pro-inflammatory cytokine levels in both the brain and intestines. Metabolomics analysis revealed a notable reduction in trimethylamine N-oxide and an increase in beneficial metabolites such as sphingolipids and flavonoids. These metabolic changes were correlated with improved neurological outcomes. Molecular analyses further demonstrated that AKK and AKK-Exo treatments promoted the integrity of the gut barrier, reduced systemic inflammation, and induced an anti-inflammatory M2 microglial phenotype and facilitated WM remodeling in the brain.Conclusion:This study underscores the therapeutic potential of AKK and its exosomes in promoting recovery after IS, highlighting their role in gut-brain axis modulation. Our findings suggest that AKK and AKK-Exo could serve as promising therapeutic agents for improving stroke outcomes through microbiome-based interventions.Keywords:Gut-brain axis, microbiome, ischemic stroke, Akkermansia, neuroinflammation

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Gennaio 2025

Efficacy of yeast beta-glucan 1,3/1,6 supplementation on respiratory infection, fatigue, immune markers and gut health among moderate stress adults in Klang Valley of Malaysia: protocol for a randomised, double-blinded, placebo-controlled, parallel-group study

Introduction
Yeast beta-glucan (YBG) are recognised for enhancing the immune system by activating macrophages, a key defence mechanism. Given the global prevalence and impact of upper respiratory tract infections (URTIs) on productivity and healthcare costs, YBG has shown promise as a potential therapeutic and preventive strategy for recurrent respiratory tract infections. However, little is known regarding the efficacy of YBG at lower dosages in relation to URTI, fatigue, immune response and uncertainties of how they affect the gut microbiota composition.

Methods and analysis
This 12-week randomised, double-blinded, placebo control, parallel-group clinical trial aims to evaluate the efficacy of YBG 1,3/1,6 on respiratory tract infection, fatigue, immune markers and gut health among adults with moderate stress. The study involves 198 adults aged 18–59 years with moderate stress levels as assessed using Perceived Stress Scale 10 (score 14–26) and Patient Health Questionnaire 9 (score ≥9); and had symptoms of common colds for the past 6 months as assessed using Jackson Cold Scale. These participants will be randomised into three groups, receiving YBG 1,3/1,6 at either 120 mg, 204 mg or a placebo. The outcomes measures include respiratory infection symptoms, fatigue, mood state and quality of life assessed using Wisconsin Upper Respiratory Symptoms Scale, Multidimensional Fatigue Inventory, Profile of Mood State and Short Form 36 Health Survey Questionnaire, respectively. In addition, full blood analysis and assessment of immune, inflammatory and oxidative stress biomarkers will be taken. Secondary outcome includes gut microbiota analysis using stool samples via 16S rRNA sequencing.

Ethics and dissemination
The research protocol of the study was reviewed and approved by the Research Ethics Committee of Universiti Kebangsaan Malaysia (UKM/PPI/111/8/JEP-2023–211). The findings will be disseminated to participants, healthcare professionals and researchers via conference presentations and peer-reviewed publications.

Trial registration number
ISRCTN48336189

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Gennaio 2025

Dynamics of the gut microbiome in FAP patients undergoing intensive endoscopic reduction of polyp burden

In their review, Inamura et al.1 emphasise the need for prospective cohort studies to establish the role of the microbiome as an essential exposome in tumourigenesis. However, establishing the relationship between gut microbiota and sporadic colorectal cancer (CRC) is challenging due to the extended time required for precancerous lesions to develop into cancer.2 Thus, we believe the rapid onset of CRC in patients with familial adenomatous polyposis (FAP) presents a unique opportunity for longitudinal research into the role of the gut microbiome in colorectal carcinogenesis. Previous studies have demonstrated the association of the gut microbiome and metabolites with tumourigenesis in sporadic CRC.3–5 Here, with informed consent and institutional review board approval, we collected stool samples from 130 FAP patients who had not undergone surgery but had undergone repetitive intensive endoscopic reduction of polyp burden (IER)6 7

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Gennaio 2025

Multiomics of the intestine-liver-adipose axis in multiple studies unveils a consistent link of the gut microbiota and the antiviral response with systemic glucose metabolism

Background
The microbiota is emerging as a key factor in the predisposition to insulin resistance and obesity.

Objective
To understand the interplay among gut microbiota and insulin sensitivity in multiple tissues.

Design
Integrative multiomics and multitissue approach across six studies, combining euglycaemic clamp measurements (used in four of the six studies) with other measurements of glucose metabolism and insulin resistance (glycated haemoglobin (HbA1c) and fasting glucose).

Results
Several genera and species from the Proteobacteria phylum were consistently negatively associated with insulin sensitivity in four studies (ADIPOINST, n=15; IRONMET, n=121, FLORINASH, n=67 and FLOROMIDIA, n=24). Transcriptomic analysis of the jejunum, ileum and colon revealed T cell-related signatures positively linked to insulin sensitivity. Proteobacteria in the ileum and colon were positively associated with HbA1c but negatively with the number of T cells. Jejunal deoxycholic acid was negatively associated with insulin sensitivity. Transcriptomics of subcutaneous adipose tissue (ADIPOMIT, n=740) and visceral adipose tissue (VAT) (ADIPOINST, n=29) revealed T cell-related signatures linked to HbA1c and insulin sensitivity, respectively. VAT Proteobacteria were negatively associated with insulin sensitivity. Multiomics and multitissue integration in the ADIPOINST and FLORINASH studies linked faecal Proteobacteria with jejunal and liver deoxycholic acid, as well as jejunal, VAT and liver transcriptomic signatures involved in the actin cytoskeleton, insulin and T cell signalling. Fasting glucose was consistently linked to interferon-induced genes and antiviral responses in the intestine and VAT. Studies in Drosophila melanogaster validated these human insulin sensitivity-associated changes.

Conclusion
These data provide comprehensive insights into the microbiome-gut-adipose-liver axis and its impact on systemic insulin action, suggesting potential therapeutic targets.Cite Now

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Gennaio 2025

Relationship between vaginal and gut microbiome and pregnancy outcomes in eastern Ethiopia: a protocol for a longitudinal maternal-infant cohort study (the EthiOMICS study)

Introduction
Although evidence exists on the impact of microbiota on pregnancy outcomes in many high-resource settings, there is a lack of research in many low-resource settings like Ethiopia. This study aims to fill this gap by studying the gut and vaginal microbiota changes throughout pregnancy and assess how these changes relate to pregnancy outcomes among a cohort of pregnant women in eastern Ethiopia.

Methods and analysis
Vaginal and stool samples will be collected using DNA/RNA Shield Collection kits three times starting at 12–22 weeks, 28–36 weeks and at birth (within 7 days). Postnatally, newborns’ skin swabs (at birth) and rectal swabs will be obtained until 2 years of age. Moreover, breast milk samples at birth and 6 months and environmental samples (water, indoor air and soil) will be collected at enrolment, birth, 6, 12 and 24 months post partum. DNA will be extracted using Roche kits. Metagenomic sequencing will be performed to identify metataxonomic profiling and assess variations in microbial profiles, and α and β diversity of the microbiota. Information on socioeconomic, behavioural, household and biological factors will be collected at enrolment. The collected data will be coded, entered into EpiData 3.1 and analysed using Stata 17.

Ethics and dissemination
The Institutional Health Research Ethics Review Committee (Ref No. IHRERC/033/2022) of Haramaya University, Ethiopia has approved this study ethically. Written informed consent regarding the study and sample storage for biobanking will be obtained from all participants. Results will be published in international peer-reviewed journals, and summaries will be provided to the study funders. Clinical study data will be submitted to Data Compass (https://datacompass.lshtm.ac.uk/), and molecular profiles of the microbiome and whole-genome sequences will be submitted to the European Nucleotide Archive (https://www. ebi.ac.uk/ena). Requests for data should be directed to daberaf@gmail.com. The decision to share data will be made by the study steering committee under the College of Health and Medical Sciences, Haramaya University, Ethiopia.

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Gennaio 2025

Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood

Mood disorders and DGBI are highly prevalent, commonly co-morbid and lack fully effective therapies. Although SSRIs are first line pharmacological treatments for these disorders, they may impart adverse effects including anxiety, anhedonia, dysmotility and, in children exposed in utero, an increased risk of cognitive, mood and gastrointestinal disorders. SSRIs act systemically to block SERT and enhance serotonergic signaling in the brain, intestinal epithelium and enteric neurons. Yet, the compartments that mediate the therapeutic and adverse effects of SSRIs are unknown, as is whether gestational SSRI exposure directly contributes to human DGBI development.

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Dicembre 2024

Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a wide spectrum of liver injuries, ranging from hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis to MASLD-associated hepatocellular carcinoma (MASLD-HCC). Recent studies have highlighted the bidirectional impacts between host genetics/epigenetics and the gut microbial community. Host genetics influence the composition of gut microbiome, while the gut microbiota and their derived metabolites can induce host epigenetic modifications to affect the development of MASLD. The exploration of the intricate relationship between the gut microbiome and the genetic/epigenetic makeup of the host is anticipated to yield promising avenues for therapeutic interventions targeting MASLD and its associated conditions. In this review, we summarise the effects of gut microbiome, host genetics and epigenetic alterations in MASLD and MASLD-HCC. We further discuss research findings demonstrating the bidirectional impacts between gut microbiome and host genetics/epigenetics, emphasising the significance of this interconnection in MASLD prevention and treatment.

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Dicembre 2024

Association of breast milk-derived arachidonic acid-induced infant gut dysbiosis with the onset of atopic dermatitis

Objective
The specific breast milk-derived metabolites that mediate host–microbiota interactions and contribute to the onset of atopic dermatitis (AD) remain unknown and require further investigation.

Design
We enrolled 250 mother–infant pairs and collected 978 longitudinal faecal samples from infants from birth to 6 months of age, along with 243 maternal faecal samples for metagenomics. Concurrently, 239 corresponding breast milk samples were analysed for metabolomics. Animal and cellular experiments were conducted to validate the bioinformatics findings.

Results
The clinical findings suggested that a decrease in daily breastfeeding duration was associated with a reduced incidence of AD. This observation inspired us to investigate the effects of breast milk-derived fatty acids. We found that high concentrations of arachidonic acid (AA), but not eicosapentaenoic acid (EPA) or docosahexaenoic acid, induced gut dysbiosis in infants. Further investigation revealed that four specific bacteria degraded mannan into mannose, consequently enhancing the mannan-dependent biosynthesis of O-antigen and lipopolysaccharide. Correlation analysis confirmed that in infants with AD, the abundance of Escherichia coli under high AA concentrations was positively correlated with some microbial pathways (eg, ‘GDP-mannose-derived O-antigen and lipopolysaccharide biosynthesis’). These findings are consistent with those of the animal studies. Additionally, AA, but not EPA, disrupted the ratio of CD4/CD8 cells, increased skin lesion area and enhanced the proportion of peripheral Th2 cells. It also promoted IgE secretion and the biosynthesis of prostaglandins and leukotrienes in BALB/c mice fed AA following ovalbumin immunostimulation. Moreover, AA significantly increased IL-4 secretion in HaCaT cells costimulated with TNF-α and INF-.

Conclusions
This study demonstrates that AA is intimately linked to the onset of AD via gut dysbiosis.

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Dicembre 2024

Breast milk components modulate gut microbiota to increase susceptibility to atopic dermatitis in early life

The colonisation and assembly of the neonatal microbiota is essential for the development and maturation of the immune system, and the early life from birth to 2 years of age is regarded as a crucial window period. Abnormal microbial colonisation and reduced gut microbiota diversity during this period are linked to the subsequent development of immune-mediated diseases. Dysbiosis of intestinal microbiota in early life can promote dysfunction of the CD4+ T-cell population,1 impacting the development of the child’s immune system and increasing the risk of atopic diseases. Atopic diseases are excessive IgE-mediated immune responses that commonly affect the nose, eyes, skin and lungs. Of these, atopic dermatitis (AD), a chronic and recurring inflammatory skin disease, affects at least 10%–20% of children, often starting in infancy and continuing into adulthood.2 The factors influencing AD are complex. Researchers have conducted meta-analyses of the various factors correlating to…

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Dicembre 2024