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18 pages, 2817 KiB

Open AccessArticle

Microbe–Immune–Stress Interactions Impact Behaviour during Postnatal Development

by Cassandra Francella, Miranda Green, Giorgia Caspani, Jonathan K. Y. Lai, Kelly C. Rilett and Jane A. Foster

Int. J. Mol. Sci. 2022, 23(23), 15064; https://doi.org/10.3390/ijms232315064 - 1 Dec 2022

Cited by 6 | Viewed by 2221

Abstract

Decades of research have established the role of microbiota–brain communication in behaviour and brain function. Studies have shown that microbiota composition and diversity are influenced by a variety of factors including host genetics, diet, and other environmental exposures, with implications for the immunological [...] Read more.

Decades of research have established the role of microbiota–brain communication in behaviour and brain function. Studies have shown that microbiota composition and diversity are influenced by a variety of factors including host genetics, diet, and other environmental exposures, with implications for the immunological and neurobiological development of the host organism. To further understand early-life interactions between environment, genetic factors, the microbiome and the central nervous system, we investigated the impact of postnatal stress in C57Bl/6 wild type and T-cell deficient mice on microbe–brain interactions and behaviour. Mice were exposed to immune challenge with lipopolysaccharide (LPS) at postnatal day (P) 3 and maternal separation at P9 (16 h overnight). Behavioural assessment of growth and development as well as behaviour (righting reflex, ultrasonic vocalizations in response to brief maternal separation, open field, sociability, and grooming) was conducted. Microbiota diversity and composition of fecal samples collected at P24 revealed reduced alpha diversity in T-cell-deficient mice as well as genotype- and stress-related taxa. Notably, integrated analyses of microbiota and behaviour in the context of immunocompromise revealed key behavioural related taxa that may be important to brain development. These findings are important to determining the influence of genetic and environmental factors on gut microbiota and advances our understanding microbiome–brain signaling pathways on neurodevelopment and behaviour. Full article

(This article belongs to the Special Issue Molecular Mechanisms in the Microbiome–Brain–Gut Axis)

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19 pages, 4347 KiB

Open AccessArticle

Shotgun Metagenomics Study Suggests Alteration in Sulfur Metabolism and Oxidative Stress in Children with Autism and Improvement after Microbiota Transfer Therapy

by Khemlal Nirmalkar, Fatir Qureshi, Dae-Wook Kang, Juergen Hahn, James B. Adams and Rosa Krajmalnik-Brown

Int. J. Mol. Sci. 2022, 23(21), 13481; https://doi.org/10.3390/ijms232113481 - 3 Nov 2022

Cited by 12 | Viewed by 5371

Abstract

Links between gut microbiota and autism spectrum disorder (ASD) have been explored in many studies using 16S rRNA gene amplicon and shotgun sequencing. Based on these links, microbiome therapies have been proposed to improve gastrointestinal (GI) and ASD symptoms in ASD individuals. Previously, [...] Read more.

Links between gut microbiota and autism spectrum disorder (ASD) have been explored in many studies using 16S rRNA gene amplicon and shotgun sequencing. Based on these links, microbiome therapies have been proposed to improve gastrointestinal (GI) and ASD symptoms in ASD individuals. Previously, our open-label microbiota transfer therapy (MTT) study provided insight into the changes in the gut microbial community of children with ASD after MTT and showed significant and long-term improvement in ASD and GI symptoms. Using samples from the same study, the objective of this work was to perform a deeper taxonomic and functional analysis applying shotgun metagenomic sequencing. Taxonomic analyses revealed that ASD Baseline had many bacteria at lower relative abundances, and their abundance increased after MTT. The relative abundance of fiber consuming and beneficial microbes including Prevotella (P. dentalis, P. enoeca, P. oris, P. meloninogenica), Bifidobacterium bifidum, and a sulfur reducer Desulfovibrio piger increased after MTT-10wks in children with ASD compared to Baseline (consistent at genus level with the previous 16S rRNA gene study). Metabolic pathway analysis at Baseline compared to typically developing (TD) children found an altered abundance of many functional genes but, after MTT, they became similar to TD or donors. Important functional genes that changed included: genes encoding enzymes involved in folate biosynthesis, sulfur metabolism and oxidative stress. These results show that MTT treatment not only changed the relative abundance of important genes involved in metabolic pathways, but also seemed to bring them to a similar level to the TD controls. However, at a two-year follow-up, the microbiota and microbial genes shifted into a new state, distinct from their levels at Baseline and distinct from the TD group. Our current findings suggest that microbes from MTT lead to initial improvement in the metabolic profile of children with ASD, and major additional changes at two years post-treatment. In the future, larger cohort studies, mechanistic in vitro experiments and metatranscriptomics studies are recommended to better understand the role of these specific microbes, functional gene expression, and metabolites relevant to ASD. Full article

(This article belongs to the Special Issue Molecular Mechanisms in the Microbiome–Brain–Gut Axis)

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16 pages, 1911 KiB

Open AccessArticle

Effects of Two Distinct Psychoactive Microbes, Lacticaseibacillus rhamnosus JB-1 and Limosilactobacillus reuteri 6475, on Circulating and Hippocampal mRNA in Male Mice

by Sandor Haas-Neill, Eiko Iwashita, Anna Dvorkin-Gheva and Paul Forsythe

Int. J. Mol. Sci. 2022, 23(17), 9653; https://doi.org/10.3390/ijms23179653 - 25 Aug 2022

Cited by 4 | Viewed by 2347

Abstract

Discovery of the microbiota-gut–brain axis has led to proposed microbe-based therapeutic strategies in mental health, including the use of mood-altering bacterial species, termed psychobiotics. However, we still have limited understanding of the key signaling pathways engaged by specific organisms in modulating brain function, [...] Read more.

Discovery of the microbiota-gut–brain axis has led to proposed microbe-based therapeutic strategies in mental health, including the use of mood-altering bacterial species, termed psychobiotics. However, we still have limited understanding of the key signaling pathways engaged by specific organisms in modulating brain function, and evidence suggests that bacteria with broadly similar neuroactive and immunomodulatory actions can drive different behavioral outcomes. We sought to identify pathways distinguishing two psychoactive bacterial strains that seemingly engage similar gut–brain signaling pathways but have distinct effects on behaviour. We used RNAseq to identify mRNAs differentially expressed in the blood and hippocampus of mice following Lacticaseibacillus rhamnosus JB-1, and Limosilactobacillus reuteri 6475 treatment and performed Gene Set Enrichment Analysis (GSEA) to identify enrichment in pathway activity. L. rhamnosus, but not L. reuteri treatment altered several pathways in the blood and hippocampus, and the rhamnosus could be clearly distinguished based on mRNA profile. In particular, L. rhamnosus treatment modulated the activity of interferon signaling, JAK/STAT, and TNF-alpha via NF-KB pathways. Our results highlight that psychobiotics can induce complex changes in host gene expression, andin understanding these changes, we may help fine-tune selection of psychobiotics for treating mood disorders. Full article

(This article belongs to the Special Issue Molecular Mechanisms in the Microbiome–Brain–Gut Axis)

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16 pages, 2822 KiB

Open AccessArticle

Bacteria-Derived Protein Aggregates Contribute to the Disruption of Host Proteostasis

by Alyssa C. Walker, Rohan Bhargava, Autumn S. Dove, Amanda S. Brust, Ali A. Owji and Daniel M. Czyż

Int. J. Mol. Sci. 2022, 23(9), 4807; https://doi.org/10.3390/ijms23094807 - 27 Apr 2022

Cited by 4 | Viewed by 3083

Abstract

Neurodegenerative protein conformational diseases are characterized by the misfolding and aggregation of metastable proteins encoded within the host genome. The host is also home to thousands of proteins encoded within exogenous genomes harbored by bacteria, fungi, and viruses. Yet, their contributions to host [...] Read more.

Neurodegenerative protein conformational diseases are characterized by the misfolding and aggregation of metastable proteins encoded within the host genome. The host is also home to thousands of proteins encoded within exogenous genomes harbored by bacteria, fungi, and viruses. Yet, their contributions to host protein-folding homeostasis, or proteostasis, remain elusive. Recent studies, including our previous work, suggest that bacterial products contribute to the toxic aggregation of endogenous host proteins. We refer to these products as bacteria-derived protein aggregates (BDPAs). Furthermore, antibiotics were recently associated with an increased risk for neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis—possibly by virtue of altering the composition of the human gut microbiota. Other studies have shown a negative correlation between disease progression and antibiotic administration, supporting their protective effect against neurodegenerative diseases. These contradicting studies emphasize the complexity of the human gut microbiota, the gut–brain axis, and the effect of antibiotics. Here, we further our understanding of bacteria’s effect on host protein folding using the model Caenorhabditis elegans. We employed genetic and chemical methods to demonstrate that the proteotoxic effect of bacteria on host protein folding correlates with the presence of BDPAs. Furthermore, the abundance and proteotoxicity of BDPAs are influenced by gentamicin, an aminoglycoside antibiotic that induces protein misfolding, and by butyrate, a short-chain fatty acid that we previously found to affect host protein aggregation and the associated toxicity. Collectively, these results increase our understanding of host–bacteria interactions in the context of protein conformational diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms in the Microbiome–Brain–Gut Axis)

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17 pages, 2514 KiB

Open AccessArticle

Fecal Microbiota Transplantation Derived from Alzheimer’s Disease Mice Worsens Brain Trauma Outcomes in Wild-Type Controls

by Sirena Soriano, Kristen Curry, Qi Wang, Elsbeth Chow, Todd J. Treangen and Sonia Villapol

Int. J. Mol. Sci. 2022, 23(9), 4476; https://doi.org/10.3390/ijms23094476 - 19 Apr 2022

Cited by 14 | Viewed by 5612

Abstract

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration, both of which increase the risk and accelerate the progression of Alzheimer’s disease (AD). The gut microbiome is an essential modulator of the immune system, impacting the brain. AD has been related with reduced diversity [...] Read more.

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration, both of which increase the risk and accelerate the progression of Alzheimer’s disease (AD). The gut microbiome is an essential modulator of the immune system, impacting the brain. AD has been related with reduced diversity and alterations in the community composition of the gut microbiota. This study aimed to determine whether the gut microbiota from AD mice exacerbates neurological deficits after TBI in control mice. We prepared fecal microbiota transplants from 18 to 24 month old 3×Tg-AD (FMT-AD) and from healthy control (FMT-young) mice. FMTs were administered orally to young control C57BL/6 (wild-type, WT) mice after they underwent controlled cortical impact (CCI) injury, as a model of TBI. Then, we characterized the microbiota composition of the fecal samples by full-length 16S rRNA gene sequencing analysis. We collected the blood, brain, and gut tissues for protein and immunohistochemical analysis. Our results showed that FMT-AD administration stimulates a higher relative abundance of the genus Muribaculum and a decrease in Lactobacillus johnsonii compared to FMT-young in WT mice. Furthermore, WT mice exhibited larger lesion, increased activated microglia/macrophages, and reduced motor recovery after FMT-AD compared to FMT-young one day after TBI. In summary, we observed gut microbiota from AD mice to have a detrimental effect and aggravate the neuroinflammatory response and neurological outcomes after TBI in young WT mice. Full article

(This article belongs to the Special Issue Molecular Mechanisms in the Microbiome–Brain–Gut Axis)

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19 pages, 1997 KiB

Open AccessArticle

Microbe-Immune Crosstalk: Evidence That T Cells Influence the Development of the Brain Metabolome

by Giorgia Caspani, Miranda Green, Jonathan R. Swann and Jane A. Foster

Int. J. Mol. Sci. 2022, 23(6), 3259; https://doi.org/10.3390/ijms23063259 - 17 Mar 2022

Cited by 6 | Viewed by 2881

Abstract

Cross-talk between the immune system and the brain is essential to neuronal development, neuronal excitability, neuroplasticity, and neurotransmission. Gut microbiota are essential to immune system development and immune function; hence, it is essential to consider more broadly the microbiota-immune-brain axis in neurodevelopment. The [...] Read more.

Cross-talk between the immune system and the brain is essential to neuronal development, neuronal excitability, neuroplasticity, and neurotransmission. Gut microbiota are essential to immune system development and immune function; hence, it is essential to consider more broadly the microbiota-immune-brain axis in neurodevelopment. The gut, brain, and microbial metabolomes obtained from C57Bl/6 and T-cell-deficient mice across four developmental timepoints (postnatal day 17, 24, 28, and 84) were studied by ¹H NMR spectroscopy. 16S rRNA gene sequencing was performed on cecal and fecal samples. In the absence of T-cells, the developmental trajectory of the gut microbiota and of the host’s metabolic profile was altered. The novel insights from this work include (1) the requirement of functional T-cells for the normal trajectory of microbiotal development and the metabolic maturation of the supra-organism, (2) the potential role for Muribaculaceae taxa in modulating the cecal availability of metabolites previously implicated with a role in the gut-brain axis in T-cell deficient mice, and (3) the impact of T-cell-deficiency on central levels of neuroactive metabolites. Full article

(This article belongs to the Special Issue Molecular Mechanisms in the Microbiome–Brain–Gut Axis)

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Review

Jump to: Research

35 pages, 2188 KiB

Open AccessReview

Mucosal Immunity and the Gut-Microbiota-Brain-Axis in Neuroimmune Disease

by Kathryn G. Sterling, Griffin Kutler Dodd, Shatha Alhamdi, Peter G. Asimenios, Ruben K. Dagda, Kenny L. De Meirleir, Dorothy Hudig and Vincent C. Lombardi

Int. J. Mol. Sci. 2022, 23(21), 13328; https://doi.org/10.3390/ijms232113328 - 1 Nov 2022

Cited by 12 | Viewed by 6118

Abstract

Recent advances in next-generation sequencing (NGS) technologies have opened the door to a wellspring of information regarding the composition of the gut microbiota. Leveraging NGS technology, early metagenomic studies revealed that several diseases, such as Alzheimer’s disease, Parkinson’s disease, autism, and myalgic encephalomyelitis, [...] Read more.

Recent advances in next-generation sequencing (NGS) technologies have opened the door to a wellspring of information regarding the composition of the gut microbiota. Leveraging NGS technology, early metagenomic studies revealed that several diseases, such as Alzheimer’s disease, Parkinson’s disease, autism, and myalgic encephalomyelitis, are characterized by alterations in the diversity of gut-associated microbes. More recently, interest has shifted toward understanding how these microbes impact their host, with a special emphasis on their interactions with the brain. Such interactions typically occur either systemically, through the production of small molecules in the gut that are released into circulation, or through signaling via the vagus nerves which directly connect the enteric nervous system to the central nervous system. Collectively, this system of communication is now commonly referred to as the gut-microbiota-brain axis. While equally important, little attention has focused on the causes of the alterations in the composition of gut microbiota. Although several factors can contribute, mucosal immunity plays a significant role in shaping the microbiota in both healthy individuals and in association with several diseases. The purpose of this review is to provide a brief overview of the components of mucosal immunity that impact the gut microbiota and then discuss how altered immunological conditions may shape the gut microbiota and consequently affect neuroimmune diseases, using a select group of common neuroimmune diseases as examples. Full article

(This article belongs to the Special Issue Molecular Mechanisms in the Microbiome–Brain–Gut Axis)

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17 pages, 4883 KiB

Open AccessReview

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

by Kazunori Suda and Kazunori Matsuda

Int. J. Mol. Sci. 2022, 23(3), 1172; https://doi.org/10.3390/ijms23031172 - 21 Jan 2022

Cited by 44 | Viewed by 13503

Abstract

Accumulating evidence suggests that the gut microbiome influences the brain functions and psychological state of its host via the gut–brain axis, and gut dysbiosis has been linked to several mental illnesses, including major depressive disorder (MDD). Animal experiments have shown that a depletion [...] Read more.

Accumulating evidence suggests that the gut microbiome influences the brain functions and psychological state of its host via the gut–brain axis, and gut dysbiosis has been linked to several mental illnesses, including major depressive disorder (MDD). Animal experiments have shown that a depletion of the gut microbiota leads to behavioral changes, and is associated with pathological changes, including abnormal stress response and impaired adult neurogenesis. Short-chain fatty acids such as butyrate are known to contribute to the up-regulation of brain-derived neurotrophic factor (BDNF), and gut dysbiosis causes decreased levels of BDNF, which could affect neuronal development and synaptic plasticity. Increased gut permeability causes an influx of gut microbial components such as lipopolysaccharides, and the resultant systemic inflammation may lead to neuroinflammation in the central nervous system. In light of the fact that gut microbial factors contribute to the initiation and exacerbation of depressive symptoms, this review summarizes the current understanding of the molecular mechanisms involved in MDD onset, and discusses the therapeutic potential of probiotics, including butyrate-producing bacteria, which can mediate the microbiota–gut–brain axis. Full article

(This article belongs to the Special Issue Molecular Mechanisms in the Microbiome–Brain–Gut Axis)

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18 pages, 394 KiB

Open AccessReview

The Role of Gut Dysbiosis in Acute-on-Chronic Liver Failure

by Sung-Eun Kim, Ji Won Park, Hyung Su Kim, Myoung-Kuk Jang, Ki Tae Suk and Dong Joon Kim

Int. J. Mol. Sci. 2021, 22(21), 11680; https://doi.org/10.3390/ijms222111680 - 28 Oct 2021

Cited by 9 | Viewed by 2475

Abstract

Acute-on-chronic liver failure (ACLF) is an important syndrome of liver failure that has a high risk of short-term mortality in patients with chronic liver disease. The development of ACLF is associated with proinflammatory precipitating events, such as infection, alcoholic hepatitis, and intense systemic [...] Read more.

Acute-on-chronic liver failure (ACLF) is an important syndrome of liver failure that has a high risk of short-term mortality in patients with chronic liver disease. The development of ACLF is associated with proinflammatory precipitating events, such as infection, alcoholic hepatitis, and intense systemic inflammation. Recently, the role of the gut microbiome has increasingly emerged in human health and disease. Additionally, the gut microbiome might have a major role in the development of liver disease. In this review, we examine evidence to support the role of gut dysbiosis in cirrhosis and ACLF. Additionally, we explore the mechanism by which the gut microbiome contributes to the development of ACLF, with a focus on alcohol-induced liver disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms in the Microbiome–Brain–Gut Axis)

27 pages, 1564 KiB

Open AccessReview

The Gut-Brain Axis in Autism Spectrum Disorder: A Focus on the Metalloproteases ADAM10 and ADAM17

by Yuanpeng Zheng, Tessa A. Verhoeff, Paula Perez Pardo, Johan Garssen and Aletta D. Kraneveld

Int. J. Mol. Sci. 2021, 22(1), 118; https://doi.org/10.3390/ijms22010118 - 24 Dec 2020

Cited by 17 | Viewed by 5409

Abstract

Autism Spectrum Disorder (ASD) is a spectrum of disorders that are characterized by problems in social interaction and repetitive behavior. The disease is thought to develop from changes in brain development at an early age, although the exact mechanisms are not known yet. [...] Read more.

Autism Spectrum Disorder (ASD) is a spectrum of disorders that are characterized by problems in social interaction and repetitive behavior. The disease is thought to develop from changes in brain development at an early age, although the exact mechanisms are not known yet. In addition, a significant number of people with ASD develop problems in the intestinal tract. A Disintegrin And Metalloproteases (ADAMs) include a group of enzymes that are able to cleave membrane-bound proteins. ADAM10 and ADAM17 are two members of this family that are able to cleave protein substrates involved in ASD pathogenesis, such as specific proteins important for synapse formation, axon signaling and neuroinflammation. All these pathological mechanisms are involved in ASD. Besides the brain, ADAM10 and ADAM17 are also highly expressed in the intestines. ADAM10 and ADAM17 have implications in pathways that regulate gut permeability, homeostasis and inflammation. These metalloproteases might be involved in microbiota-gut–brain axis interactions in ASD through the regulation of immune and inflammatory responses in the intestinal tract. In this review, the potential roles of ADAM10 and ADAM17 in the pathology of ASD and as targets for new therapies will be discussed, with a focus on the gut–brain axis. Full article

(This article belongs to the Special Issue Molecular Mechanisms in the Microbiome–Brain–Gut Axis)

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