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The Gut–Liver–Brain Axis: From Head to Feet

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 26932

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Prof. Dr. Rita Moretti

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Guest Editor

Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
Interests: small vessel disease; neurovascular coupling; liver–brain axis; NAFLD and brain; bilirubin and antioxidative properties; neuroinflammation
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Dr. Mauro Giuffrè

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Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
Interests: liver cirrhosis; HCC; portal hypertension; esophageal varices; liver elastography; spleen elastography
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Dear Colleagues,

The gastrointestinal tract digests and absorbs food and forms a barrier against harmful agents, but it also is an immune–hormonal system, regulated by an intrinsic network of neuronal ganglia known as the enteric nervous system (ENS). In 2013, the National Institute of Mental Health launched a project focused on exploring the mechanism involved in gut–brain communication; however, the exact mechanisms by which the gut and brain communicate and influence each other are not fully understood.

The ENS provides motor excitatory neurons, which innervate muscle layers, secretory glands, and the lymphatic vascular system. The ENS forms a complete sensory–motor reflex composed of intrinsic primary afferent neurons, interneurons, and motor neurons, differentiated by the expression of neuropeptides. The ENS also features enteroglial cells (EGCs). These produce specific proteins, such as glial fibrillar acid protein (GFAP), vimentin, and S-100, and show receptors for cytokines, neuropeptides, and neurotrophins. The critical interactive communications between the gut and brain are the sympathetic system and the vagus nervus (VN) of the autonomic nervous system, while the site of interactive communication occurs in the spinal cord, proceeding through the tractus solitaires nucleus in the brain stem and the dorsal motor nucleus of VN. The afferent fibers ascend towards the thalamus, enter the gracile nucleus and cuneate nucleus, and project to the thalamus through the lemniscus medialis. These fibers arrive diffusively in the lobus limbicus, which is the insular cortex, through the parabrachial nucleus. Interestingly enough, the VN does not directly interact with the gut luminal content but is indirectly involved in its absorption process through entero-endocrine cells in the gut epithelium; neural communications arrive directly into the brain through glutamatergic transmission. VN fibers are enriched with receptors such as 5-HT3, Toll-like receptor 4, and free fatty acid receptors, and their final projections end in the brain. Substance P (SP), neurokinin A, and neurokinin B are neuromodulators of tachykinin, and the action of SP on neurotransmission occurs in the non-adrenergic/non-cholinergic system, which is directly involved in the perception of painful stimuli. The vasoactive intestinal peptide (VIP) induces vasodilation and modulates mucin secretion and participates in the relaxation of intestinal smooth muscles and modulates functions of the lymphocyte component of the immune system. Cholecystokinin (CCK) is a major mediator of gastrointestinal feedback to the central nervous system through the afferent component of the VN. Histamine and serotonin modulate the function of a variety of intestinal cells, including neurons, EGCs, muscle cells, and the immune system. Somatostatin, which lies behind the regulation of the growth of intestinal cells, inhibits the secretion of gastrin, insulin, glucagon, and cytokines. The liver by itself has been widely related to the brai, through the indirect accumulation of ammonium in so-called hepatic encephalopathy. Nevertheless, more recent data involve the specific medical condition of non-alcoholic fatty liver disease (NAFLD) in a direct general status-related condition. NAFLD is associated with high cardiovascular morbidity and mortality, which is usually considered to be related to cardiac involvement, asymptomatic brain lesions, alterations in cerebral perfusion and activity, cognitive impairment, and brain aging, with increased risk and severity of both ischemic and hemorrhagic stroke. Besides known metabolic risk factors, NAFLD is characterized by a pro-inflammatory state, which contributes to atherosclerosis and microglia activation, endothelial dysfunction, pro-coagulant state, and platelets activation, which, in turn, promote both micro and macrovascular damage. This Special Issue aims to expand knowledge and current findings regarding the inter-relationships between ENS, microbiota, liver, and brain, expanding the modern triad-axis to the entire body system.

Prof. Dr. Rita Moretti
Dr. Mauro Giuffrè
Guest Editors

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Keywords

enteric nervous system (ENS)
microbiota
microbiome
gut–brain axis
liver
inflammation
blood–brain barrier
blood–brain-barrier leakage
astrocytes
atherosclerosis
nutrition

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Published Papers (7 papers)

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Editorial

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3 pages, 213 KiB

Open AccessEditorial

The Gut-Liver-Brain Axis: From the Head to the Feet

by Mauro Giuffrè and Rita Moretti

Int. J. Mol. Sci. 2023, 24(21), 15662; https://doi.org/10.3390/ijms242115662 - 27 Oct 2023

Cited by 5 | Viewed by 2162

Abstract

The gut-liver-brain axis, a multifaceted network of communication, intricately connects the enteric, hepatic, and central nervous systems [...] Full article

(This article belongs to the Special Issue The Gut–Liver–Brain Axis: From Head to Feet)

Research

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13 pages, 2938 KiB

Open AccessArticle

The Bacterial DNA Profiling of Chorionic Villi and Amniotic Fluids Reveals Overlaps with Maternal Oral, Vaginal, and Gut Microbiomes

by Giuseppina Campisciano, Nunzia Zanotta, Mariachiara Quadrifoglio, Annalisa Careri, Alessandra Torresani, Carolina Cason, Francesco De Seta, Giuseppe Ricci, Manola Comar and Tamara Stampalija

Int. J. Mol. Sci. 2023, 24(3), 2873; https://doi.org/10.3390/ijms24032873 - 2 Feb 2023

Cited by 4 | Viewed by 2033

Abstract

The in utero microbiome hypothesis has been long debated. This hypothesis will change our comprehension of the pioneer human microbiome if proved correct. In 60 uncomplicated pregnancies, we profiled the microbiome of chorionic villi (CV) and amniotic fluids (AF) in relation to maternal saliva, rectum, and vagina and the soluble cytokines cascade in the vagina, CV and AF. In our series, 12/37 (32%) AF and 10/23 (44%) CV tested positive for bacterial DNA. CV and AF harbored bacterial DNA of Streptococcus and Lactobacillus, overlapping that of the matched oral and vaginal niches, which showed a dysbiotic microbiome. In these pregnant women, the immune profiling revealed an immune hyporesponsiveness in the vagina and a high intraamniotic concentration of inflammatory cytokines. To understand the eventual role of bacterial colonization of the CV and AF and the associated immune response in the pregnancy outcome, further appropriate studies are needed. In this context, further studies should highlight if the hematogenous route could justify the spread of bacterial DNA from the oral microbiome to the placenta and if vaginal dysbiosis could favor the likelihood of identifying CV and AF positive for bacterial DNA. Full article

(This article belongs to the Special Issue The Gut–Liver–Brain Axis: From Head to Feet)

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14 pages, 440 KiB

Open AccessArticle

Gut Microbiota Changes during Dimethyl Fumarate Treatment in Patients with Multiple Sclerosis

by Caterina Ferri, Massimiliano Castellazzi, Nicola Merli, Michele Laudisi, Elisa Baldin, Eleonora Baldi, Leonardo Mancabelli, Marco Ventura and Maura Pugliatti

Int. J. Mol. Sci. 2023, 24(3), 2720; https://doi.org/10.3390/ijms24032720 - 1 Feb 2023

Cited by 12 | Viewed by 3043

Abstract

The gut microbiota is involved in the development of the immune system and can modulate the risk for immune-mediated disorders such as multiple sclerosis (MS). Dysbiosis has been demonstrated in MS patients and its restoration by disease-modifying treatments (DMTs) is hypothesized. We aimed to study the changes in gut microbiota composition during the first 6 months of treatment with dimethyl fumarate (DMF), an oral DMT, and to identify the microorganisms associated with DMF side effects. We collected and analyzed the gut microbiota of 19 MS patients at baseline and after 1, 3, and 6 months of DMF treatment. We then cross-sectionally compared gut microbiota composition according to the presence of gastrointestinal (GI) symptoms and flushing. Overall, the gut microbiota biodiversity showed no changes over the 6-month follow-up. At the genus level, DMF was associated with decreased Clostridium abundance after 6 months. In subjects reporting side effects, a higher abundance of Streptococcus, Haemophilus, Clostridium, Lachnospira, Blautia, Subdoligranulum, and Tenericutes and lower of Bacteroidetes, Barnesiella, Odoribacter, Akkermansia, and some Proteobacteria families were detected. Our results suggest that gut microbiota may be involved in therapeutic action and side effects of DMF, representing a potential target for improving disease course and DMT tolerability. Full article

(This article belongs to the Special Issue The Gut–Liver–Brain Axis: From Head to Feet)

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23 pages, 4508 KiB

Open AccessArticle

Modulation of the Gut Microbiota in Memory Impairment and Alzheimer’s Disease via the Inhibition of the Parasympathetic Nervous System

by Sunmin Park and Xuangao Wu

Int. J. Mol. Sci. 2022, 23(21), 13574; https://doi.org/10.3390/ijms232113574 - 5 Nov 2022

Cited by 22 | Viewed by 3362

Abstract

The gut microbiota has been demonstrated to play a critical role in maintaining cognitive function via the gut-brain axis, which may be related to the parasympathetic nervous system (PNS). However, the exact mechanism remains to be determined. We investigated that patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) could exhibit an altered gut microbiota through the suppression of the PNS, compared to the healthy individuals, using the combined gut microbiota data from previous human studies. The hypothesis was validated in rats to suppress the PNS by scopolamine injections. The human fecal bacterial FASTA/Q files were selected and combined from four different AD studies (n = 410). All rats had a high-fat diet and treatments for six weeks. The MD rats had memory impairment by scopolamine injection (2 mg/kg body weight; MD, Control) or no memory impairment by saline injection. The scopolamine-injected rats had a donepezil intake as the positive group. In the optimal model generated from the XGboost analysis, Blautia luti, Pseudomonas mucidoiens, Escherichia marmotae, and Gemmiger formicillis showed a positive correlation with MCI while Escherichia fergusonii, Mycobacterium neglectum, and Lawsonibacter asaccharolyticus were positively correlated with AD in the participants with enterotype Bacteroides (ET-B, n = 369). The predominant bacteria in the AD group were negatively associated in the networking analysis with the bacteria in the healthy group of ET-B participants. From the animal study, the relative abundance of Bacteroides and Bilophilia was lower, and that of Escherichia, Blautia, and Clostridium was higher in the scopolamine-induced memory deficit (MD) group than in the normal group. These results suggest that MCI was associated with the PNS suppression and could progress to AD by exacerbating the gut dysbiosis. MCI increased Clostridium and Blautia, and its progression to AD elevated Escherichia and Pseudomonas. Therefore, the modulation of the PNS might be linked to an altered gut microbiota and brain function, potentially through the gut-brain axis. Full article

(This article belongs to the Special Issue The Gut–Liver–Brain Axis: From Head to Feet)

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21 pages, 4516 KiB

Open AccessArticle

Acute Colon Inflammation Triggers Primary Motor Cortex Glial Activation, Neuroinflammation, Neuronal Hyperexcitability, and Motor Coordination Deficits

by Livia Carrascal, María D. Vázquez-Carretero, Pablo García-Miranda, Ángela Fontán-Lozano, María L. Calonge, Anunciación A. Ilundáin, Carmen Castro, Pedro Nunez-Abades and María J. Peral

Int. J. Mol. Sci. 2022, 23(10), 5347; https://doi.org/10.3390/ijms23105347 - 11 May 2022

Cited by 3 | Viewed by 2597

Abstract

Neuroinflammation underlies neurodegenerative diseases. Herein, we test whether acute colon inflammation activates microglia and astrocytes, induces neuroinflammation, disturbs neuron intrinsic electrical properties in the primary motor cortex, and alters motor behaviors. We used a rat model of acute colon inflammation induced by dextran sulfate sodium. Inflammatory mediators and microglial activation were assessed in the primary motor cortex by PCR and immunofluorescence assays. Electrophysiological properties of the motor cortex neurons were determined by whole-cell patch-clamp recordings. Motor behaviors were examined using open-field and rotarod tests. We show that the primary motor cortex of rats with acute colon inflammation exhibited microglial and astrocyte activation and increased mRNA abundance of interleukin-6, tumor necrosis factor-alpha, and both inducible and neuronal nitric oxide synthases. These changes were accompanied by a reduction in resting membrane potential and rheobase and increased input resistance and action potential frequency, indicating motor neuron hyperexcitability. In addition, locomotion and motor coordination were impaired. In conclusion, acute colon inflammation induces motor cortex microglial and astrocyte activation and inflammation, which led to neurons’ hyperexcitability and reduced motor coordination performance. The described disturbances resembled some of the early features found in amyotrophic lateral sclerosis patients and animal models, suggesting that colon inflammation might be a risk factor for developing this disease. Full article

(This article belongs to the Special Issue The Gut–Liver–Brain Axis: From Head to Feet)

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Review

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19 pages, 598 KiB

Open AccessReview

Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation

by Mauro Giuffrè, Silvia Gazzin, Caterina Zoratti, John Paul Llido, Giuseppe Lanza, Claudio Tiribelli and Rita Moretti

Int. J. Mol. Sci. 2022, 23(24), 15564; https://doi.org/10.3390/ijms232415564 - 8 Dec 2022

Cited by 22 | Viewed by 6994

Abstract

Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression. However, the mechanisms behind the neurological involvement in CD remain controversial. Recent evidence shows these can be related to gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and in severe cases, vitamins or nutrients deficiency. Here, we have summarized new evidence related to gut microbiota and the so-called “gut-liver-brain axis” involved in CD-related neurological manifestations. Additionally, there has yet to be an agreement on whether serological or neurophysiological findings can effectively early diagnose and properly monitor CD-associated neurological involvement; notably, most of them can revert to normal with a rigorous gluten-free diet. Moving from a molecular level to a symptom-based approach, clinical, serological, and neurophysiology data might help to disentangle the many-faceted interactions between the gut and brain in CD. Eventually, the identification of multimodal biomarkers might help diagnose, monitor, and improve the quality of life of patients with “neuroCD”. Full article

(This article belongs to the Special Issue The Gut–Liver–Brain Axis: From Head to Feet)

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Other

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8 pages, 682 KiB

Open AccessOpinion

Gut Microbes Meet Machine Learning: The Next Step towards Advancing Our Understanding of the Gut Microbiome in Health and Disease

by Mauro Giuffrè, Rita Moretti and Claudio Tiribelli

Int. J. Mol. Sci. 2023, 24(6), 5229; https://doi.org/10.3390/ijms24065229 - 9 Mar 2023

Cited by 11 | Viewed by 5511

Abstract

The human gut microbiome plays a crucial role in human health and has been a focus of increasing research in recent years. Omics-based methods, such as metagenomics, metatranscriptomics, and metabolomics, are commonly used to study the gut microbiome because they provide high-throughput and high-resolution data. The vast amount of data generated by these methods has led to the development of computational methods for data processing and analysis, with machine learning becoming a powerful and widely used tool in this field. Despite the promising results of machine learning-based approaches for analyzing the association between microbiota and disease, there are several unmet challenges. Small sample sizes, disproportionate label distribution, inconsistent experimental protocols, or a lack of access to relevant metadata can all contribute to a lack of reproducibility and translational application into everyday clinical practice. These pitfalls can lead to false models, resulting in misinterpretation biases for microbe–disease correlations. Recent efforts to address these challenges include the construction of human gut microbiota data repositories, improved data transparency guidelines, and more accessible machine learning frameworks; implementation of these efforts has facilitated a shift in the field from observational association studies to experimental causal inference and clinical intervention. Full article

(This article belongs to the Special Issue The Gut–Liver–Brain Axis: From Head to Feet)

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