Research

14 pages, 1005 KiB

Open AccessArticle

Metabolomics and Self-Reported Depression, Anxiety, and Phobic Symptoms in the VA Normative Aging Study

by Nicole Prince, Meryl Stav, Margaret Cote, Su H. Chu, Chirag M. Vyas, Olivia I. Okereke, Natalia Palacios, Augusto A Litonjua, Pantel Vokonas, David Sparrow, Avron Spiro III, Jessica A. Lasky-Su and Rachel S. Kelly

Metabolites 2023, 13(7), 851; https://doi.org/10.3390/metabo13070851 - 15 Jul 2023

Cited by 1 | Viewed by 1209

Abstract

Traditional approaches to understanding metabolomics in mental illness have focused on investigating a single disorder or comparisons between diagnoses, but a growing body of evidence suggests substantial mechanistic overlap in mental disorders that could be reflected by the metabolome. In this study, we [...] Read more.

Traditional approaches to understanding metabolomics in mental illness have focused on investigating a single disorder or comparisons between diagnoses, but a growing body of evidence suggests substantial mechanistic overlap in mental disorders that could be reflected by the metabolome. In this study, we investigated associations between global plasma metabolites and abnormal scores on the depression, anxiety, and phobic anxiety subscales of the Brief Symptom Inventory (BSI) among 405 older males who participated in the Normative Aging Study (NAS). Our analysis revealed overlapping and distinct metabolites associated with each mental health dimension subscale and four metabolites belonging to xenobiotic, carbohydrate, and amino acid classes that were consistently associated across all three symptom dimension subscales. Furthermore, three of these four metabolites demonstrated a higher degree of alteration in men who reported poor scores in all three dimensions compared to men with poor scores in only one, suggesting the potential for shared underlying biology but a differing degree of perturbation when depression and anxiety symptoms co-occur. Our findings implicate pathways of interest relevant to the overlap of mental health conditions in aging veterans and could represent clinically translatable targets underlying poor mental health in this high-risk population. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

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18 pages, 2062 KiB

Open AccessArticle

Relation between Selected Sleep Parameters, Depression, Anti-Tumor Necrosis Factor Therapy, and the Brain-Derived Neurotrophic Factor Pathway in Inflammatory Bowel Disease

by Marcin Sochal, Marta Ditmer, Agata Binienda, Agata Gabryelska, Piotr Białasiewicz, Renata Talar-Wojnarowska, Jakub Fichna and Ewa Małecka-Wojciesko

Metabolites 2023, 13(3), 450; https://doi.org/10.3390/metabo13030450 - 19 Mar 2023

Cited by 2 | Viewed by 1476

Abstract

Inflammatory bowel disease (IBD) patients often have sleep and mood disorders. Brain-derived neurotrophic factor (BDNF) and proBDNF were shown to modulate interactions between the central nervous system and the gastrointestinal tract, possibly contributing to psychological issues. Anti-tumor necrosis factor (TNF) therapy in IBD [...] Read more.

Inflammatory bowel disease (IBD) patients often have sleep and mood disorders. Brain-derived neurotrophic factor (BDNF) and proBDNF were shown to modulate interactions between the central nervous system and the gastrointestinal tract, possibly contributing to psychological issues. Anti-tumor necrosis factor (TNF) therapy in IBD can alter BDNF expression and further affect the brain–gut axis. Eighty IBD patients and 44 healthy controls (HCs) were enrolled and divided into subsets based on disease activity and condition (ulcerative colitis (UC)/Crohn’s disease (CD)). Questionnaires evaluating sleep parameters and depression as well as venous blood were collected. The IBD group had a lower expression of BDNF mRNA, but higher proBDNF and BDNF protein concentration than HCs. The UC group had a higher BDNF protein concentration than the CD. BDNF protein was positively correlated to sleep efficiency in the IBD group. Depression severity was associated positively with BDNF mRNA and negatively with BDNF protein in the remission group. Anti-TNF therapy enhanced BDNF mRNA expression. The BDNF pathway might be disturbed in IBD, linking it to sleep disorders and depression. Systemic inflammation could be the main cause of this disruption. BDNF mRNA is a more reliable parameter than protein due to numerous post-translational modifications. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

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20 pages, 3190 KiB

Open AccessEditor’s ChoiceArticle

Activity of Microbial-Derived Phenolic Acids and Their Conjugates against LPS-Induced Damage in Neuroblastoma Cells and Macrophages

by Dolores González de Llano, Mikel Roldán, Laura Parro, Begoña Bartolomé and M. Victoria Moreno-Arribas

Metabolites 2023, 13(1), 108; https://doi.org/10.3390/metabo13010108 - 09 Jan 2023

Cited by 4 | Viewed by 1727

Abstract

The aim of this study was to investigate whether microbial-derived phenolic acids, 3,4-dihydroxyphenylacetic (DHPA), protocatechuic acid (PCA), and dihydrocaffeic acid (DHCFA) and their conjugated forms (DHCFA 3-O-sulfate and DHCFA 3-O-β-D-glucuronide), exhibit protective effects against neuroinflammation and oxidative stress. Experiments were performed on human [...] Read more.

The aim of this study was to investigate whether microbial-derived phenolic acids, 3,4-dihydroxyphenylacetic (DHPA), protocatechuic acid (PCA), and dihydrocaffeic acid (DHCFA) and their conjugated forms (DHCFA 3-O-sulfate and DHCFA 3-O-β-D-glucuronide), exhibit protective effects against neuroinflammation and oxidative stress. Experiments were performed on human neuronal SH-SY5Y cells stimulated with bacterial lipopolysaccharide (LPS) and tert-butyl hydroperoxide (tBHP). Anti-inflammatory activity in terms of pro-inflammatory cytokine production was also evaluated in LPS-stimulated RAW 264.7 macrophages as a reactive microglial model. Treatment of the SH-SY5Y cells with the free phenolic acids, as well as with the conjugated metabolites, at physiologically concentrations (1, 10 and 50 μM), resulted in increased cell viability of LPS- and tBHP-stimulated cells. Phenolic metabolites and, especially, the conjugated derivatives also protected neuronal cells through significant attenuation of inflammation by decreasing ROS levels. Furthermore, the conjugated and microbial-derived phenolic metabolites significantly inhibited the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-8) in LPS-stimulated macrophages. Among the phenolic metabolites tested, different efficacies were observed, with the glucuronide form standing out. Overall, these results suggest, for the first time, that conjugated derivatives of phenolic acids seem to be more effective at protecting neurons from inflammation damage and oxidative stress. Further in vivo studies are warranted. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

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Review

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23 pages, 807 KiB

Open AccessReview

Gut Microbiota and Neuroinflammation in Acute Liver Failure and Chronic Liver Disease

by Lucia Giuli, Marta Maestri, Francesco Santopaolo, Maurizio Pompili and Francesca Romana Ponziani

Metabolites 2023, 13(6), 772; https://doi.org/10.3390/metabo13060772 - 20 Jun 2023

Cited by 1 | Viewed by 1762

Abstract

Acute liver failure and chronic liver disease are associated with a wide spectrum of neurological changes, of which the best known is hepatic encephalopathy (HE). Historically, hyperammonemia, causing astrocyte swelling and cerebral oedema, was considered the main etiological factor in the pathogenesis of [...] Read more.

Acute liver failure and chronic liver disease are associated with a wide spectrum of neurological changes, of which the best known is hepatic encephalopathy (HE). Historically, hyperammonemia, causing astrocyte swelling and cerebral oedema, was considered the main etiological factor in the pathogenesis of cerebral dysfunction in patients with acute and/or chronic liver disease. However, recent studies demonstrated a key role of neuroinflammation in the development of neurological complications in this setting. Neuroinflammation is characterized by activation of microglial cells and brain secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which alter neurotransmission, leading to cognitive and motor dysfunction. Changes in the gut microbiota resulting from liver disease play a crucial role in the pathogenesis of neuroinflammation. Dysbiosis and altered intestinal permeability, resulting in bacterial translocation and endotoxemia, are responsible for systemic inflammation, which can spread to brain tissue and trigger neuroinflammation. In addition, metabolites derived from the gut microbiota can act on the central nervous system and facilitate the development of neurological complications, exacerbating clinical manifestations. Thus, strategies aimed at modulating the gut microbiota may be effective therapeutic weapons. In this review, we summarize the current knowledge on the role of the gut–liver–brain axis in the pathogenesis of neurological dysfunction associated with liver disease, with a particular focus on neuroinflammation. In addition, we highlight emerging therapeutic approaches targeting the gut microbiota and inflammation in this clinical setting. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

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30 pages, 2726 KiB

Open AccessReview

Modulatory Effect of Gut Microbiota on the Gut-Brain, Gut-Bone Axes, and the Impact of Cannabinoids

by Iddrisu Ibrahim, Soumyakrishnan Syamala, Joseph Atia Ayariga, Junhuan Xu, Boakai K. Robertson, Sreepriya Meenakshisundaram and Olufemi S. Ajayi

Metabolites 2022, 12(12), 1247; https://doi.org/10.3390/metabo12121247 - 10 Dec 2022

Cited by 16 | Viewed by 2949

Abstract

The gut microbiome is a collection of microorganisms and parasites in the gastrointestinal tract. Many factors can affect this community’s composition, such as age, sex, diet, medications, and environmental triggers. The relationship between the human host and the gut microbiota is crucial for [...] Read more.

The gut microbiome is a collection of microorganisms and parasites in the gastrointestinal tract. Many factors can affect this community’s composition, such as age, sex, diet, medications, and environmental triggers. The relationship between the human host and the gut microbiota is crucial for the organism’s survival and development, whereas the disruption of this relationship can lead to various inflammatory diseases. Cannabidiol (CBD) and tetrahydrocannabinol (THC) are used to treat muscle spasticity associated with multiple sclerosis. It is now clear that these compounds also benefit patients with neuroinflammation. CBD and THC are used in the treatment of inflammation. The gut is a significant source of nutrients, including vitamins B and K, which are gut microbiota products. While these vitamins play a crucial role in brain and bone development and function, the influence of gut microbiota on the gut-brain and gut-bone axes extends further and continues to receive increasing scientific scrutiny. The gut microbiota has been demonstrated to be vital for optimal brain functions and stress suppression. Additionally, several studies have revealed the role of gut microbiota in developing and maintaining skeletal integrity and bone mineral density. It can also influence the development and maintenance of bone matrix. The presence of the gut microbiota can influence the actions of specific T regulatory cells, which can lead to the development of bone formation and proliferation. In addition, its metabolites can prevent bone loss. The gut microbiota can help maintain the bone’s equilibrium and prevent the development of metabolic diseases, such as osteoporosis. In this review, the dual functions gut microbiota plays in regulating the gut-bone axis and gut-brain axis and the impact of CBD on these roles are discussed. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

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28 pages, 1434 KiB

Open AccessReview

Microbiome and Metabolome Insights into the Role of the Gastrointestinal–Brain Axis in Parkinson’s and Alzheimer’s Disease: Unveiling Potential Therapeutic Targets

by Helena U. Zacharias, Christoph Kaleta, François Cossais, Eva Schaeffer, Henry Berndt, Lena Best, Thomas Dost, Svea Glüsing, Mathieu Groussin, Mathilde Poyet, Sebastian Heinzel, Corinna Bang, Leonard Siebert, Tobias Demetrowitsch, Frank Leypoldt, Rainer Adelung, Thorsten Bartsch, Anja Bosy-Westphal, Karin Schwarz and Daniela Berg

Metabolites 2022, 12(12), 1222; https://doi.org/10.3390/metabo12121222 - 05 Dec 2022

Cited by 6 | Viewed by 3195

Abstract

Neurodegenerative diseases such as Parkinson’s (PD) and Alzheimer’s disease (AD), the prevalence of which is rapidly rising due to an aging world population and westernization of lifestyles, are expected to put a strong socioeconomic burden on health systems worldwide. Clinical trials of therapies [...] Read more.

Neurodegenerative diseases such as Parkinson’s (PD) and Alzheimer’s disease (AD), the prevalence of which is rapidly rising due to an aging world population and westernization of lifestyles, are expected to put a strong socioeconomic burden on health systems worldwide. Clinical trials of therapies against PD and AD have only shown limited success so far. Therefore, research has extended its scope to a systems medicine point of view, with a particular focus on the gastrointestinal–brain axis as a potential main actor in disease development and progression. Microbiome and metabolome studies have already revealed important insights into disease mechanisms. Both the microbiome and metabolome can be easily manipulated by dietary and lifestyle interventions, and might thus offer novel, readily available therapeutic options to prevent the onset as well as the progression of PD and AD. This review summarizes our current knowledge on the interplay between microbiota, metabolites, and neurodegeneration along the gastrointestinal–brain axis. We further illustrate state-of-the art methods of microbiome and metabolome research as well as metabolic modeling that facilitate the identification of disease pathomechanisms. We conclude with therapeutic options to modulate microbiome composition to prevent or delay neurodegeneration and illustrate potential future research directions to fight PD and AD. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

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34 pages, 2748 KiB

Open AccessReview

Dysbiosis of Gut Microbiota from the Perspective of the Gut–Brain Axis: Role in the Provocation of Neurological Disorders

by Meenakshi Kandpal, Omkar Indari, Budhadev Baral, Shweta Jakhmola, Deeksha Tiwari, Vasundhra Bhandari, Rajan Kumar Pandey, Kiran Bala, Avinash Sonawane and Hem Chandra Jha

Metabolites 2022, 12(11), 1064; https://doi.org/10.3390/metabo12111064 - 03 Nov 2022

Cited by 24 | Viewed by 5986

Abstract

The gut–brain axis is a bidirectional communication network connecting the gastrointestinal tract and central nervous system. The axis keeps track of gastrointestinal activities and integrates them to connect gut health to higher cognitive parts of the brain. Disruption in this connection may facilitate [...] Read more.

The gut–brain axis is a bidirectional communication network connecting the gastrointestinal tract and central nervous system. The axis keeps track of gastrointestinal activities and integrates them to connect gut health to higher cognitive parts of the brain. Disruption in this connection may facilitate various neurological and gastrointestinal problems. Neurodegenerative diseases are characterized by the progressive dysfunction of specific populations of neurons, determining clinical presentation. Misfolded protein aggregates that cause cellular toxicity and that aid in the collapse of cellular proteostasis are a defining characteristic of neurodegenerative proteinopathies. These disorders are not only caused by changes in the neural compartment but also due to other factors of non-neural origin. Mounting data reveal that the majority of gastrointestinal (GI) physiologies and mechanics are governed by the central nervous system (CNS). Furthermore, the gut microbiota plays a critical role in the regulation and physiological function of the brain, although the mechanism involved has not yet been fully interpreted. One of the emerging explanations of the start and progression of many neurodegenerative illnesses is dysbiosis of the gut microbial makeup. The present understanding of the literature surrounding the relationship between intestinal dysbiosis and the emergence of certain neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, is the main emphasis of this review. The potential entry pathway of the pathogen-associated secretions and toxins into the CNS compartment has been explored in this article at the outset of neuropathology. We have also included the possible mechanism of undelaying the synergistic effect of infections, their metabolites, and other interactions based on the current understanding. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

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Other

Jump to: Research, Review

14 pages, 561 KiB

Open AccessSystematic Review

What Has Longitudinal ‘Omics’ Studies Taught Us about Irritable Bowel Syndrome? A Systematic Review

by Qin Xiang Ng, Chun En Yau, Clyve Yu Leon Yaow, Ryan Ian Houe Chong, Nicolette Zy-Yin Chong, Seth En Teoh, Yu Liang Lim, Alex Yu Sen Soh, Wee Khoon Ng and Julian Thumboo

Metabolites 2023, 13(4), 484; https://doi.org/10.3390/metabo13040484 - 28 Mar 2023

Cited by 7 | Viewed by 2191

Abstract

Irritable bowel syndrome is a prototypical disorder of the brain–gut–microbiome axis, although the underlying pathogenesis and mechanisms remain incompletely understood. With the recent advances in ‘omics’ technologies, studies have attempted to uncover IBS-specific variations in the host–microbiome profile and function. However, no biomarker [...] Read more.

Irritable bowel syndrome is a prototypical disorder of the brain–gut–microbiome axis, although the underlying pathogenesis and mechanisms remain incompletely understood. With the recent advances in ‘omics’ technologies, studies have attempted to uncover IBS-specific variations in the host–microbiome profile and function. However, no biomarker has been identified to date. Given the high inter-individual and day-to-day variability of the gut microbiota, and a lack of agreement across the large number of microbiome studies, this review focused on omics studies that had sampling at more than one time point. A systematic literature search was performed using various combinations of the search terms “Irritable Bowel Syndrome” and “Omics” in the Medline, EMBASE, and Cochrane Library up to 1 December 2022. A total of 16 original studies were reviewed. These multi-omics studies have implicated Bacteroides, Faecalibacterium prausnitzii, Ruminococcus spp., and Bifidobacteria in IBS and treatment response, found altered metabolite profiles in serum, faecal, or urinary samples taken from IBS patients compared to the healthy controls, and revealed enrichment in the immune and inflammation-related pathways. They also demonstrated the possible therapeutic mechanisms of diet interventions, for example, synbiotics and low fermentable oligosaccharides, disaccharides, monosaccharides, and polyol (FODMAP) diets on microbial metabolites. However, there was significant heterogeneity among the studies and no uniform characteristics of IBS-related gut microbiota. There is a need to further study these putative mechanisms and also ensure that they can be translated to therapeutic benefits for patients with IBS. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

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15 pages, 323 KiB

Open AccessStudy Protocol

The Influence of Probiotic Supplementation on the Severity of Anxiety and Depressive Symptoms; Function and Composition of Gut Microbiota; and Metabolic, Inflammation, and Oxidative Stress Markers in Patients with Depression—A Study Protocol

by Anna Skowrońska, Oliwia Gawlik-Kotelnicka, Aleksandra Margulska and Dominik Strzelecki

Metabolites 2023, 13(2), 182; https://doi.org/10.3390/metabo13020182 - 25 Jan 2023

Cited by 3 | Viewed by 1916

Abstract

This article aims to present the theoretical basis, methodology, and design of a clinical trial we will conduct. The study will be prospective, randomized, placebo-controlled, and double-blind. Each intervention period will last 8 weeks and the trial will be conducted on 100 patients [...] Read more.

This article aims to present the theoretical basis, methodology, and design of a clinical trial we will conduct. The study will be prospective, randomized, placebo-controlled, and double-blind. Each intervention period will last 8 weeks and the trial will be conducted on 100 patients in total, who will be randomly divided into two groups consisting of 50 patients each. We plan to investigate the impact of Lactobacillus helveticus Rosell and Bifidobacterium longum Rosell on the depressive, anxiety, and stress levels in patients with depressive disorders with possible comorbid anxiety. In addition to assessing the influence of probiotics on the clinical condition, we also plan to study the clinical and biochemical parameters of metabolic syndrome, which often coexists with depression. Both depressive and metabolic issues may have part of their etiopathology in common, e.g., inflammation, oxidative stress, and dysbiosis. This is why we will additionally investigate the parameters related to gut microbiota, inflammatory, and oxidative statuses. Thus, the primary endpoint of the study will be the change in depression score measured with the Montgomery–Åsberg Depression Rating Scale. The secondary endpoints will include changes in anxiety and stress levels, as well as metabolic, inflammation, and oxidative stress parameters. Full article

(This article belongs to the Special Issue The Microbiota–Gut–Brain Axis: Role of Metabolism)

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