Roles of Gut Microbiota in the Regulation of Hippocampal Plasticity, Inflammation, and Hippocampus-Dependent Behaviors

The study of the gut microbiota-brain axis has become an intriguing field, attracting attention from both gastroenterologists and neurobiologists. The hippocampus is the center of learning and memory, and plays a pivotal role in neurodegenerative diseases, such as Alzheimer’s disease (AD). Previous studies using diet administration, antibiotics, probiotics, prebiotics, germ-free mice, and fecal analysis of normal and specific pathogen-free animals have shown that the structure and function of the hippocampus are affected by the gut microbiota. Furthermore, hippocampal pathologies in AD are positively correlated with changes in specific microbiota. Genomic and neurochemical analyses revealed significant alterations in genes and amino acids in the hippocampus of AD subjects following a remarkable shift in the gut microbiota. In a recent study, when young animals were transplanted with fecal microbiota derived from AD patients, the recipients showed significant impairment of cognitive behaviors, AD pathologies, and changes in neuronal plasticity and cytokines. Other studies have demonstrated the side effects of antibiotic administration along with the beneficial effects of probiotics, prebiotics, and specific diets on the composition of the gut microbiota and hippocampal functions, but these have been mostly preliminary with unclear mechanisms. Since some specific gut bacteria are positively or negatively correlated to the structure and function of the hippocampus, it is expected that specific gut bacteria administration and other microbiota-based interventions could be potentially applied to prevent or treat hippocampus-based memory impairment and neuropsychiatric disorders such as AD.

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Multiplatform Physiologic and Metabolic Phenotyping Reveals Microbial Toxicity

mSystems ◽

10.1128/msystems.00123-18 ◽

2018 ◽

Vol 3 (6) ◽

Cited By ~ 2

Author(s):

Jingwei Cai ◽

Robert G. Nichols ◽

Imhoi Koo ◽

Zachary A. Kalikow ◽

Limin Zhang ◽

...

Keyword(s):

Mass Spectrometry ◽

Amino Acids ◽

Flow Cytometry ◽

Free Radical ◽

Gut Microbiota ◽

Structure And Function ◽

Metabolic Phenotyping ◽

And Function

ABSTRACTThe gut microbiota is susceptible to modulation by environmental stimuli and therefore can serve as a biological sensor. Recent evidence suggests that xenobiotics can disrupt the interaction between the microbiota and host. Here, we describe an approach that combinesin vitromicrobial incubation (isolated cecal contents from mice), flow cytometry, and mass spectrometry- and1H nuclear magnetic resonance (NMR)-based metabolomics to evaluate xenobiotic-induced microbial toxicity. Tempol, a stabilized free radical scavenger known to remodel the microbial community structure and functionin vivo, was studied to assess its direct effect on the gut microbiota. The microbiota was isolated from mouse cecum and was exposed to tempol for 4 h under strict anaerobic conditions. The flow cytometry data suggested that short-term tempol exposure to the microbiota is associated with disrupted membrane physiology as well as compromised metabolic activity. Mass spectrometry and NMR metabolomics revealed that tempol exposure significantly disrupted microbial metabolic activity, specifically indicated by changes in short-chain fatty acids, branched-chain amino acids, amino acids, nucleotides, glucose, and oligosaccharides. In addition, a mouse study with tempol (5 days gavage) showed similar microbial physiologic and metabolic changes, indicating that thein vitroapproach reflectedin vivoconditions. Our results, through evaluation of microbial viability, physiology, and metabolism and a comparison ofin vitroandin vivoexposures with tempol, suggest that physiologic and metabolic phenotyping can provide unique insight into gut microbiota toxicity.IMPORTANCEThe gut microbiota is modulated physiologically, compositionally, and metabolically by xenobiotics, potentially causing metabolic consequences to the host. We recently reported that tempol, a stabilized free radical nitroxide, can exert beneficial effects on the host through modulation of the microbiome community structure and function. Here, we investigated a multiplatform phenotyping approach that combines high-throughput global metabolomics with flow cytometry to evaluate the direct effect of tempol on the microbiota. This approach may be useful in deciphering how other xenobiotics directly influence the microbiota.

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Longitudinal Analyses Reveal That Aging-related Alterations in the Intestinal Environment Lead to Gut Dysbiosis With the Potential to Induce Obesity

10.21203/rs.3.rs-119480/v1 ◽

2020 ◽

Author(s):

Yumiko Nakanishi ◽

Ryouko Nozu ◽

Masami Ueno ◽

Kyoji Hioki ◽

Chiharu Ishii ◽

...

Keyword(s):

Gut Microbiota ◽

Middle Age ◽

Fecal Microbiota Transplantation ◽

Fold Increase ◽

Fecal Microbiota ◽

Whole Body ◽

Cellular Functions ◽

Intestinal Environment ◽

Gut Dysbiosis ◽

Specific Pathogen

Abstract Background: Aging is a progressive decline of cellular functions that ultimately affects whole-body homeostasis. Alterations in the gut microbiota associated with aging have been reported, however the molecular basis of the relationships between host aging and the gut microbiota is poorly understood.Result: By using longitudinal microbiome and metabolome characterization, we show that the aging-related alterations in the intestinal environment lead to gut dysbiosis with a potential to induce obesity in mice. In middle-age mice, we observed more than a 2-fold increase in fecal carbohydrates derived from dietary polysaccharides and a significant reduction of gut microbial diversity resembling the microbiota characteristic of obese mice. Consistently, fecal microbiota transplantation from middle-age specific pathogen-free (SPF) mice into young germ-free (GF) mice resulted in increased weight gain and impaired glucose tolerance.Conclusion: Our findings provide new insights into the relationships between host aging and gut dysbiosis and may contribute to the development of a possible solution to aging-related obesity.

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Abstract 2468: Is the LV Reverse Remodeling Imparted by Aortic Valve Replacement for Severe Aortic Stenosis Durable? A Cardiovascular MRI Study sponsored by the American Heart Association

Circulation ◽

10.1161/circ.116.suppl_16.ii_543-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Robert W Biederman ◽

James A Magovern ◽

Saundra Grant ◽

Ronald Williams ◽

June Yamrozik ◽

...

Keyword(s):

Aortic Valve ◽

Aortic Stenosis ◽

Aortic Valve Replacement ◽

Severe Aortic Stenosis ◽

Structure And Function ◽

Reverse Remodeling ◽

Beneficial Effects ◽

And Function ◽

Surgically Induced

Background In patients with severe aortic stenosis (AS), long-term data tracking surgically induced beneficial effects of afterload reduction on reverse LV remodeling are not available. Echocardiographic data is available short term, but in limited fashion beyond one year. Cardiac MRI (CMR) offers the ability to track changes in LV metrics with small numbers due to its inherent high spatial resolution and low variability. Hypothesis We hypothesize that progressive changes following aortic valve replacement (AVR) are detectable by CMR and changes in LV structure and function, triggered by AVR, continue for an extended period following AVR. Methods Ten patients (67±12 yrs, 6 female) with severe, but compensated AS, underwent CMR pre-AVR and post AVR at 6±2mo, 1yr±2mo, 4yrs±5mo. LV mass index (LVMI), LV geometry, volumetrics and EF were measured (GE, EXCITE 1.5T, Milwaukee, WI). A Kruskall-Wallis one-way ANOVA was performed. Results All 10 pts survived AVR and underwent CMR at the 4-year time point (40 total time points). LVMI markedly decreased at 6 months (157±42 to 134±32g/m 2 , p<0.005) and continued to trend down at 4 yrs (127±32g/m 2 ). Similarly, EF increased pre to post AVR (55±22 to 65±11%, (p<0.05)) and continued trending upward, remaining stable at years 1–4 (66±11 vs. 65±9%). LVEDV index, initially high pre AVR, normalized post AVR (83±30 to 68±11ml/m 2 , p<0.05) trending even lower by yr 4 (66±10 ml/m 2 ). LV stroke volume increased rapidly from pre to post AVR (40±11 to 44±7ml) continuing to increase at 4 yrs (49±14ml, p=0.3). Most importantly, LVMI/volume, a 3D measure of LV geometry, remained unchanged initially but over 4 yrs markedly improved (1.07±0.2 to 0.94±0.24, p<0.05) all paralleling improvements in NYHA (3.2±1.0 to 1.5±1.1, p<0.05). Conclusion After the initial beneficial effects imparted by AVR in severe AS patients, there are, as expected, marked improvements in LV reverse remodeling. We have shown, via CMR, that surgically induced benefits to LV structure and function, including favorable alterations in LV geometry, are durable and, unexpectedly, show continued improvement past 4 years concordant with sustained improved clinical status. This supports down regulation of both mRNA and MMP activity acutely and robust suppression long term.

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Beneficial Effects of Dietary Polyphenols on Gut Microbiota and Strategies to Improve Delivery Efficiency

Nutrients ◽

10.3390/nu11092216 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2216 ◽

Cited By ~ 56

Author(s):

Amit Kumar Singh ◽

Célia Cabral ◽

Ramesh Kumar ◽

Risha Ganguly ◽

Harvesh Kumar Rana ◽

...

Keyword(s):

Gut Microbiota ◽

Clinical Data ◽

Antimicrobial Activities ◽

Dietary Polyphenols ◽

Beneficial Effects ◽

Obesity And Diabetes ◽

Bacterial Quorum Sensing ◽

Health And Disease ◽

Bacterial Quorum ◽

And Function

The human intestine contains an intricate ecological community of dwelling bacteria, referred as gut microbiota (GM), which plays a pivotal role in host homeostasis. Multiple factors could interfere with this delicate balance, including genetics, age, antibiotics, as well as environmental factors, particularly diet, thus causing a disruption of microbiota equilibrium (dysbiosis). Growing evidences support the involvement of GM dysbiosis in gastrointestinal (GI) and extra-intestinal cardiometabolic diseases, namely obesity and diabetes. This review firstly overviews the role of GM in health and disease, then critically reviews the evidences regarding the influence of dietary polyphenols in GM based on preclinical and clinical data, ending with strategies under development to improve efficiency of delivery. Although the precise mechanisms deserve further clarification, preclinical and clinical data suggest that dietary polyphenols present prebiotic properties and exert antimicrobial activities against pathogenic GM, having benefits in distinct disorders. Specifically, dietary polyphenols have been shown ability to modulate GM composition and function, interfering with bacterial quorum sensing, membrane permeability, as well as sensitizing bacteria to xenobiotics. In addition, can impact on gut metabolism and immunity and exert anti-inflammatory properties. In order to overcome the low bioavailability, several different approaches have been developed, aiming to improve solubility and transport of dietary polyphenols throughout the GI tract and deliver in the targeted intestinal regions. Although more research is still needed, particularly translational and clinical studies, the biotechnological progresses achieved during the last years open up good perspectives to, in a near future, be able to improve the use of dietary polyphenols modulating GM in a broad range of disorders characterized by a dysbiotic phenotype.

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Structure and function of proteins controlling strain-specific pathogen resistance in plants

Current Opinion in Plant Biology ◽

10.1016/1369-5266(88)80048-7 ◽

1998 ◽

Vol 1 (4) ◽

pp. 288-293 ◽

Cited By ~ 88

Author(s):

Jeff Ellis ◽

David Jones

Keyword(s):

Pathogen Resistance ◽

Structure And Function ◽

Specific Pathogen ◽

And Function

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Differential Effects of Antibiotic Therapy on the Structure and Function of Human Gut Microbiota

PLoS ONE ◽

10.1371/journal.pone.0080201 ◽

2013 ◽

Vol 8 (11) ◽

pp. e80201 ◽

Cited By ~ 106

Author(s):

Ana Elena Pérez-Cobas ◽

Alejandro Artacho ◽

Henrik Knecht ◽

María Loreto Ferrús ◽

Anette Friedrichs ◽

...

Keyword(s):

Gut Microbiota ◽

Antibiotic Therapy ◽

Structure And Function ◽

Human Gut ◽

Differential Effects ◽

Human Gut Microbiota ◽

And Function

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Intestinal microbiota shapes gut physiology and regulates enteric neurons and glia

Microbiome ◽

10.1186/s40168-021-01165-z ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Fernando A. Vicentini ◽

Catherine M. Keenan ◽

Laurie E. Wallace ◽

Crystal Woods ◽

Jean-Baptiste Cavin ◽

...

Keyword(s):

Gut Microbiota ◽

Molecular Mechanisms ◽

Neuronal Survival ◽

Neuronal Loss ◽

Structure And Function ◽

Enteric Neurons ◽

Intestinal Function ◽

Gi Tract ◽

Enteric Glia ◽

And Function

Abstract Background The intestinal microbiota plays an important role in regulating gastrointestinal (GI) physiology in part through interactions with the enteric nervous system (ENS). Alterations in the gut microbiome frequently occur together with disturbances in enteric neural control in pathophysiological conditions. However, the mechanisms by which the microbiota regulates GI function and the structure of the ENS are incompletely understood. Using a mouse model of antibiotic (Abx)-induced bacterial depletion, we sought to determine the molecular mechanisms of microbial regulation of intestinal function and the integrity of the ENS. Spontaneous reconstitution of the Abx-depleted microbiota was used to assess the plasticity of structure and function of the GI tract and ENS. Microbiota-dependent molecular mechanisms of ENS neuronal survival and neurogenesis were also assessed. Results Adult male and female Abx-treated mice exhibited alterations in GI structure and function, including a longer small intestine, slower transit time, increased carbachol-stimulated ion secretion, and increased intestinal permeability. These alterations were accompanied by the loss of enteric neurons in the ileum and proximal colon in both submucosal and myenteric plexuses. A reduction in the number of enteric glia was only observed in the ileal myenteric plexus. Recovery of the microbiota restored intestinal function and stimulated enteric neurogenesis leading to increases in the number of enteric glia and neurons. Lipopolysaccharide (LPS) supplementation enhanced neuronal survival alongside bacterial depletion, but had no effect on neuronal recovery once the Abx-induced neuronal loss was established. In contrast, short-chain fatty acids (SCFA) were able to restore neuronal numbers after Abx-induced neuronal loss, demonstrating that SCFA stimulate enteric neurogenesis in vivo. Conclusions Our results demonstrate a role for the gut microbiota in regulating the structure and function of the GI tract in a sex-independent manner. Moreover, the microbiota is essential for the maintenance of ENS integrity, by regulating enteric neuronal survival and promoting neurogenesis. Molecular determinants of the microbiota, LPS and SCFA, regulate enteric neuronal survival, while SCFA also stimulates neurogenesis. Our data reveal new insights into the role of the gut microbiota that could lead to therapeutic developments for the treatment of enteric neuropathies.

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Obesity-induced gut microbiota dysbiosis can be ameliorated by fecal microbiota transplantation: a multiomics approach

10.1101/654228 ◽

2019 ◽

Author(s):

Maria Guirro ◽

Andrea Costa ◽

Andreu Gual-Grau ◽

Pol Herrero ◽

Helena Torrell ◽

...

Keyword(s):

Gut Microbiota ◽

High Fat Diet ◽

Fecal Microbiota Transplantation ◽

Obese Subject ◽

Fecal Microbiota ◽

Obesity Therapy ◽

Treatment Of Obesity ◽

And Function ◽

Hypercaloric Diet ◽

Gut Microbiota Dysbiosis

AbstractObesity and its comorbidities are currently considered an epidemic, and the involved pathophysiology is well studied. Recently, the gut microbiota has emerged as a new potential therapeutic target for the treatment of obesity. Diet and antibiotics are known to play crucial roles in changes in the microbiota ecosystem and the disruption of its balance; therefore, the manipulation of gut microbiota may represent a strategy for obesity treatment. Fecal microbiota transplantation, during which fecal microbiota from a healthy donor is transplanted to an obese subject, has aroused interest as an effective approach for the treatment of obesity. To determine its success, a multiomics approach was used that combined metagenomics and metaproteomics to study microbiota composition and function.To do this, a study was performed in rats that evaluated the effect of a hypercaloric diet on the gut microbiota, and this was combined with antibiotic treatment to deplete the microbiota before fecal microbiota transplantation to verify its effects on gut microbiota-host homeostasis. Our results showed that a high-fat diet induces changes in microbiota biodiversity and alters its function in the host. Moreover, we found that antibiotics depleted the microbiota enough to reduce its bacterial content. Finally, we assessed the use of fecal microbiota transplantation as an obesity therapy, and we found that it reversed the effects of antibiotics and reestablished the microbiota balance, which restored normal functioning and alleviated microbiota disruption.

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The Role of Gut Microbiota in Lung Cancer: From Carcinogenesis to Immunotherapy

Frontiers in Oncology ◽

10.3389/fonc.2021.720842 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiangjun Liu ◽

Ye Cheng ◽

Dan Zang ◽

Min Zhang ◽

Xiuhua Li ◽

...

Keyword(s):

Lung Cancer ◽

Gut Microbiota ◽

Gut Microbiome ◽

Fecal Microbiota Transplantation ◽

Checkpoint Inhibitors ◽

Fecal Microbiota ◽

Immune Homeostasis ◽

Gut Dysbiosis ◽

Underlying Mechanisms ◽

And Function

The influence of microbiota on host health and disease has attracted adequate attention, and gut microbiota components and microbiota-derived metabolites affect host immune homeostasis locally and systematically. Some studies have found that gut dysbiosis, disturbance of the structure and function of the gut microbiome, disrupts pulmonary immune homeostasis, thus leading to increased disease susceptibility; the gut-lung axis is the primary cross-talk for this communication. Gut dysbiosis is involved in carcinogenesis and the progression of lung cancer through genotoxicity, systemic inflammation, and defective immunosurveillance. In addition, the gut microbiome harbors the potential to be a novel biomarker for predicting sensitivity and adverse reactions to immunotherapy in patients with lung cancer. Probiotics and fecal microbiota transplantation (FMT) can enhance the efficacy and depress the toxicity of immune checkpoint inhibitors by regulating the gut microbiota. Although current studies have found that gut microbiota closely participates in the development and immunotherapy of lung cancer, the mechanisms require further investigation. Therefore, this review aims to discuss the underlying mechanisms of gut microbiota influencing carcinogenesis and immunotherapy in lung cancer and to provide new strategies for governing gut microbiota to enhance the prevention and treatment of lung cancer.

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Fecal Microbiota Alterations Associated With Clinical and Endoscopic Response to Infliximab Therapy in Crohn’s Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa253 ◽

2020 ◽

Vol 26 (11) ◽

pp. 1636-1647

Author(s):

Xiaojun Zhuang ◽

Zhenyi Tian ◽

Rui Feng ◽

Manying Li ◽

Tong Li ◽

...

Keyword(s):

Gut Microbiota ◽

Pathogenic Bacteria ◽

Predictive Biomarkers ◽

Treatment Decision ◽

Fecal Microbiota ◽

Microbiota Composition ◽

16S Sequencing ◽

Treatment Decision Making ◽

Microbial Dysbiosis ◽

And Function

Abstract Background Gut microbiota dysbiosis is associated with the occurrence and development of Crohn disease (CD). Currently, infliximab (IFX) is used more and more to treat CD; however, gut microbiota alterations during IFX therapy are variable and sometimes even contradictory. We longitudinally identified microbial changes during IFX therapy associated with the clinical and endoscopic response to IFX treatment in CD. Methods Fecal-associated microbiota was analyzed using 16S sequencing in 49 patients with active CD who were prospectively recruited at baseline, week 6, and week 30, respectively. Moreover, a model trained on the gut microbiota alterations at week 6 was developed to investigate their potential to predict clinical and endoscopic responses to IFX therapy at weeks 14 and 30. Results Characteristics of fecal microbiota composition in patients with CD after IFX treatment displayed an increased diversity and richness, a significant gain in short-chain fatty acid -producing bacteria, and a loss of pathogenic bacteria. Furthermore, certain functional profiles of Kyoto Encyclopedia of Genes and Genomes pathways were predictably altered during the treatment period. Increased proportions of Lachnospiraceae and Blautia were associated with IFX efficacy; the combined increase of these taxa at week 6 showed 83.4% and 84.2% accuracy in predicting clinical response at weeks 14 and 30, respectively, with a predictive value of 89.1% in predicting endoscopic response at week 30. Conclusions We found that IFX diminished CD-related gut microbial dysbiosis by modifying microbiota composition and function. Specifically, increased Lachnospiraceae and Blautia at week 6 are associated with the clinical and endoscopic response to IFX, providing potentially predictive biomarkers for IFX treatment decision-making.

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