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17 pages, 2550 KiB

Open AccessArticle

Acute Stress Regulates Sex-Related Molecular Responses in the Human Jejunal Mucosa: Implications for Irritable Bowel Syndrome

by Bruno K. Rodiño-Janeiro, Marc Pigrau, Eloísa Salvo-Romero, Adoración Nieto, Elba Expósito, Ana M. González-Castro, Carmen Galán, Inés de Torres, Teodora Pribic, Laura Hernández, Beatriz Lobo, Marina Fortea, Milagros Gallart, Cristina Pardo-Camacho, Danila Guagnozzi, Javier Santos and Carmen Alonso-Cotoner

Cells 2023, 12(3), 423; https://doi.org/10.3390/cells12030423 - 27 Jan 2023

Cited by 1 | Viewed by 2126

Abstract

Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder linked to intestinal barrier dysfunction and life stress. We have previously reported that female sex per se determines an increased susceptibility to intestinal barrier dysfunction after cold pain stress (CPS). We aimed to identify [...] Read more.

Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder linked to intestinal barrier dysfunction and life stress. We have previously reported that female sex per se determines an increased susceptibility to intestinal barrier dysfunction after cold pain stress (CPS). We aimed to identify sex-related molecular differences in response to CPS in healthy subjects to understand the origin of sex bias predominance in IBS. In 13 healthy males and 21 females, two consecutive jejunal biopsies were obtained using Watson’s capsule, at baseline, and ninety minutes after CPS. Total mucosal RNA and protein were isolated from jejunal biopsies. Expression of genes related to epithelial barrier (CLDN1, CLDN2, OCLN, ZO-1, and ZO-3), mast cell (MC) activation (TPSAB1, SERPINA1), and the glucocorticoid receptor (NR3C1) were analyzed using RT-qPCR. NR3C1, ZO-1 and OCLN protein expression were evaluated through immunohistochemistry and western blot, and mucosal inflammation through MC, lymphocyte, and eosinophil numbering. Autonomic, hormonal, and psychological responses to CPS were monitored. We found an increase in jejunal MCs, a reduced CLDN1 and OCLN expression, and an increased CLDN2 and SERPINA1 expression 90 min after CPS. We also found a significant decrease in ZO-1, OCLN, and NR3C1 gene expression, and a decrease in OCLN protein expression only in females, when compared to males. CPS induced a significant increase in blood pressure, plasma cortisol and ACTH, and subjective stress perception in all participants. Specific and independent sex-related molecular responses in epithelial barrier regulation are unraveled by acute stress in the jejunum of healthy subjects and may partially explain female predominance in IBS. Full article

(This article belongs to the Special Issue Neuro-Immune Crosstalk at Mucosal Interfaces in Health and Disease)

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19 pages, 2075 KiB

Open AccessArticle

Mucosal Plasma Cell Activation and Proximity to Nerve Fibres Are Associated with Glycocalyx Reduction in Diarrhoea-Predominant Irritable Bowel Syndrome: Jejunal Barrier Alterations Underlying Clinical Manifestations

by Cristina Pardo-Camacho, John-Peter Ganda Mall, Cristina Martínez, Marc Pigrau, Elba Expósito, Mercé Albert-Bayo, Elisa Melón-Ardanaz, Adoración Nieto, Bruno Rodiño-Janeiro, Marina Fortea, Danila Guagnozzi, Amanda Rodriguez-Urrutia, Inés de Torres, Ignacio Santos-Briones, Fernando Azpiroz, Beatriz Lobo, Carmen Alonso-Cotoner, Javier Santos, Ana M. González-Castro and Maria Vicario

Cells 2022, 11(13), 2046; https://doi.org/10.3390/cells11132046 - 28 Jun 2022

Cited by 6 | Viewed by 2624

Abstract

Irritable bowel syndrome (IBS) is a disorder of brain-gut interaction characterised by abdominal pain and changes in bowel habits. In the diarrhoea subtype (IBS-D), altered epithelial barrier and mucosal immune activation are associated with clinical manifestations. We aimed to further evaluate plasma cells [...] Read more.

Irritable bowel syndrome (IBS) is a disorder of brain-gut interaction characterised by abdominal pain and changes in bowel habits. In the diarrhoea subtype (IBS-D), altered epithelial barrier and mucosal immune activation are associated with clinical manifestations. We aimed to further evaluate plasma cells and epithelial integrity to gain understanding of IBS-D pathophysiology. One mucosal jejunal biopsy and one stool sample were obtained from healthy controls and IBS-D patients. Gastrointestinal symptoms, stress, and depression scores were recorded. In the jejunal mucosa, RNAseq and gene set enrichment analyses were performed. A morphometric analysis by electron microscopy quantified plasma cell activation and proximity to enteric nerves and glycocalyx thickness. Immunoglobulins concentration was assessed in the stool. IBS-D patients showed differential expression of humoral pathways compared to controls. Activation and proximity of plasma cells to nerves and IgG concentration were also higher in IBS-D. Glycocalyx thickness was lower in IBS-D compared to controls, and this reduction correlated with plasma cell activation, proximity to nerves, and clinical symptoms. These results support humoral activity and loss of epithelial integrity as important contributors to gut dysfunction and clinical manifestations in IBS-D. Additional studies are needed to identify the triggers of these alterations to better define IBS-D pathophysiology. Full article

(This article belongs to the Special Issue Neuro-Immune Crosstalk at Mucosal Interfaces in Health and Disease)

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15 pages, 2484 KiB

Open AccessArticle

A Galactooligosaccharide Product Decreases the Rotavirus Infection in Suckling Rats

by Malén Massot-Cladera, María del Mar Rigo-Adrover, Laura Herrero, Àngels Franch, Margarida Castell, Jelena Vulevic, Francisco J. Pérez-Cano and María J. Rodríguez Lagunas

Cells 2022, 11(10), 1669; https://doi.org/10.3390/cells11101669 - 18 May 2022

Cited by 4 | Viewed by 1871

Abstract

The leading cause of gastroenteritis among young children worldwide is the Group A rotaviruses (RV), which produce a wide range of symptoms, from a limited diarrhea to severe dehydration and even death. After an RV infection, immunity is not complete and less severe [...] Read more.

The leading cause of gastroenteritis among young children worldwide is the Group A rotaviruses (RV), which produce a wide range of symptoms, from a limited diarrhea to severe dehydration and even death. After an RV infection, immunity is not complete and less severe re-infections usually occur. These infections could be ameliorated by nutritional interventions with bioactive compounds, such as prebiotics. The aim of this research was to study the impact of a particular galactooligosaccharide (B-GOS) on the RV symptomatology and immune response during two consecutive infections. Lewis neonatal rats were inoculated with SA11 (first RV infection) on day 6 of life and with EDIM (second RV infection) on day 17 of life. B-GOS group was administered by oral gavage with a daily dose of B-GOS between days three to nine of life. Clinical and immunological variables were assessed during both infective processes. In the first infection, after the prebiotic intervention with B-GOS, a lower incidence, duration, and overall severity of the diarrhea (p < 0.05) was observed. In addition, it improved another severity indicator, the fecal weight output, during the diarrhea period (p < 0.05). The second RV infection failed in provoking diarrhea in the groups studied. The immune response during first infection with SA11 was not affected by B-GOS administration and had no impact on second infection, but the prebiotic intervention significantly increased IFN-γ and TNF-α intestinal production after the second infection (p < 0.05). In summary, B-GOS supplementation is able to reduce the incidence and severity of the RV-associated diarrhea and to influence the immune response against RV infections. Full article

(This article belongs to the Special Issue Neuro-Immune Crosstalk at Mucosal Interfaces in Health and Disease)

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17 pages, 3438 KiB

Open AccessArticle

Estrogens Play a Critical Role in Stress-Related Gastrointestinal Dysfunction in a Spontaneous Model of Disorders of Gut–Brain Interaction

by Alison Accarie, Joran Toth, Lucas Wauters, Ricard Farré, Jan Tack and Tim Vanuytsel

Cells 2022, 11(7), 1214; https://doi.org/10.3390/cells11071214 - 4 Apr 2022

Cited by 6 | Viewed by 2924

Abstract

Background: Disorders of the gut–brain interaction (DGBI), such as irritable bowel syndrome and functional dyspepsia, are more prevalent in women than in men, with a ratio of 2:1. Furthermore, stressful life events have been reported as one of the triggers for symptoms in [...] Read more.

Background: Disorders of the gut–brain interaction (DGBI), such as irritable bowel syndrome and functional dyspepsia, are more prevalent in women than in men, with a ratio of 2:1. Furthermore, stressful life events have been reported as one of the triggers for symptoms in DGBI patients. Methods: Here, we studied the effect of an early-life stressor (maternal separation (MS)) on jejunal and colonic alterations, including colonic sensitivity and immune cells infiltration and activation in a validated spontaneous model of DGBI (BBDP-N), and investigated the involvement of β-estradiol on stress-worsened intestinal alterations. Results: We found that maternal separation exacerbated colonic sensitivity and mast cell and eosinophil infiltration and activation in females only. Ovariectomy partially rescued the stress phenotype by decreasing colonic sensitivity, which was restored by β-estradiol injections and did not impact immune cells infiltration and activation. Stressed males exposed to β-estradiol demonstrated similar intestinal alterations as MS females. Conclusion: Estrogen plays a direct critical role in colonic hypersensitivity in a spontaneous animal model of DGBI, while for immune activation, estrogen seems to be involved in the first step of their recruitment and activation. Our data point towards a complex interaction between stress and β-estradiol in DGBI. Full article

(This article belongs to the Special Issue Neuro-Immune Crosstalk at Mucosal Interfaces in Health and Disease)

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15 pages, 2054 KiB

Open AccessArticle

Increased Numbers of Enteric Glial Cells in the Peyer’s Patches and Enhanced Intestinal Permeability by Glial Cell Mediators in Patients with Ileal Crohn’s Disease

by Olga Biskou, Felipe Meira de-Faria, Susanna M. Walter, Martin E. Winberg, Staffan Haapaniemi, Pär Myrelid, Johan D. Söderholm and Åsa V. Keita

Cells 2022, 11(3), 335; https://doi.org/10.3390/cells11030335 - 20 Jan 2022

Cited by 14 | Viewed by 3496

Abstract

Enteric glial cells (EGC) are known to regulate gastrointestinal functions; however, their role in Crohn’s disease (CD) is elusive. Microscopic erosions over the ileal Peyer’s patches are early signs of CD. The aim of this work was to assess the localization of EGC [...] Read more.

Enteric glial cells (EGC) are known to regulate gastrointestinal functions; however, their role in Crohn’s disease (CD) is elusive. Microscopic erosions over the ileal Peyer’s patches are early signs of CD. The aim of this work was to assess the localization of EGC in the follicle and interfollicular region of the Peyer’s patches and in the lamina propria and study the effects of EGC mediators on barrier function in CD patients and non-inflammatory bowel disease (non-IBD) controls. EGC markers, glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein β (S100β) were quantified by immunofluorescence and Western blotting. Both markers showed significantly more EGC in the Peyer’s patches and lamina propria of CD patients compared to the non-IBD controls. In CD patients there were significantly more EGC in Peyer’s patches compared to lamina propria, while the opposite pattern was seen in controls. Barrier function studies using Ussing chambers showed increased paracellular permeability by EGC mediators in CD patients, whereas permeability decreased by the mediators in controls. We show the accumulation of EGC in Peyer’s patches of CD patients. Moreover, EGC mediators induced barrier dysfunction in CD patients. Thus, EGC might have harmful impacts on ongoing inflammation and contribute to the pathophysiology of the disease. Full article

(This article belongs to the Special Issue Neuro-Immune Crosstalk at Mucosal Interfaces in Health and Disease)

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16 pages, 3062 KiB

Open AccessArticle

A Distinct Faecal Microbiota and Metabolite Profile Linked to Bowel Habits in Patients with Irritable Bowel Syndrome

by Bani Ahluwalia, Cristina Iribarren, Maria K. Magnusson, Johanna Sundin, Egbert Clevers, Otto Savolainen, Alastair B. Ross, Hans Törnblom, Magnus Simrén and Lena Öhman

Cells 2021, 10(6), 1459; https://doi.org/10.3390/cells10061459 - 10 Jun 2021

Cited by 26 | Viewed by 3889

Abstract

Patients with irritable bowel syndrome (IBS) are suggested to have an altered intestinal microenvironment. We therefore aimed to determine the intestinal microenvironment profile, based on faecal microbiota and metabolites, and the potential link to symptoms in IBS patients. The faecal microbiota was evaluated [...] Read more.

Patients with irritable bowel syndrome (IBS) are suggested to have an altered intestinal microenvironment. We therefore aimed to determine the intestinal microenvironment profile, based on faecal microbiota and metabolites, and the potential link to symptoms in IBS patients. The faecal microbiota was evaluated by the GA-map^TM dysbiosis test, and tandem mass spectrometry (GC-MS/MS) was used for faecal metabolomic profiling in patients with IBS and healthy subjects. Symptom severity was assessed using the IBS Severity Scoring System and anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. A principal component analysis based on faecal microbiota (n = 54) and metabolites (n = 155) showed a clear separation between IBS patients (n = 40) and healthy subjects (n = 18). Metabolites were the main driver of this separation. Additionally, the intestinal microenvironment profile differed between IBS patients with constipation (n = 15) and diarrhoea (n = 11), while no clustering was detected in subgroups of patients according to symptom severity or anxiety. Furthermore, ingenuity pathway analysis predicted amino acid metabolism and several cellular and molecular functions to be altered in IBS patients. Patients with IBS have a distinct faecal microbiota and metabolite profile linked to bowel habits. Intestinal microenvironment profiling, based on faecal microbiota and metabolites, may be considered as a future non-invasive diagnostic tool, alongside providing valuable insights into the pathophysiology of IBS. Full article

(This article belongs to the Special Issue Neuro-Immune Crosstalk at Mucosal Interfaces in Health and Disease)

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Review

Jump to: Research

20 pages, 1582 KiB

Open AccessFeature PaperReview

Making Sense of Quorum Sensing at the Intestinal Mucosal Interface

by Friederike Uhlig and Niall P. Hyland

Cells 2022, 11(11), 1734; https://doi.org/10.3390/cells11111734 - 24 May 2022

Cited by 10 | Viewed by 3521

Abstract

The gut microbiome can produce metabolic products that exert diverse activities, including effects on the host. Short chain fatty acids and amino acid derivatives have been the focus of many studies, but given the high microbial density in the gastrointestinal tract, other bacterial [...] Read more.

The gut microbiome can produce metabolic products that exert diverse activities, including effects on the host. Short chain fatty acids and amino acid derivatives have been the focus of many studies, but given the high microbial density in the gastrointestinal tract, other bacterial products such as those released as part of quorum sensing are likely to play an important role for health and disease. In this review, we provide of an overview on quorum sensing (QS) in the gastrointestinal tract and summarise what is known regarding the role of QS molecules such as auto-inducing peptides (AIP) and acyl-homoserine lactones (AHL) from commensal, probiotic, and pathogenic bacteria in intestinal health and disease. QS regulates the expression of numerous genes including biofilm formation, bacteriocin and toxin secretion, and metabolism. QS has also been shown to play an important role in the bacteria–host interaction. We conclude that the mechanisms of action of QS at the intestinal neuro–immune interface need to be further investigated. Full article

(This article belongs to the Special Issue Neuro-Immune Crosstalk at Mucosal Interfaces in Health and Disease)

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18 pages, 2177 KiB

Open AccessReview

Eosinophils in the Gastrointestinal Tract: Key Contributors to Neuro-Immune Crosstalk and Potential Implications in Disorders of Brain-Gut Interaction

by Eloísa Salvo-Romero, Bruno K. Rodiño-Janeiro, Mercé Albert-Bayo, Beatriz Lobo, Javier Santos, Ricard Farré, Cristina Martinez and María Vicario

Cells 2022, 11(10), 1644; https://doi.org/10.3390/cells11101644 - 14 May 2022

Cited by 10 | Viewed by 5440

Abstract

Eosinophils are innate immune granulocytes actively involved in defensive responses and in local and systemic inflammatory processes. Beyond these effector roles, eosinophils are fundamental to maintaining homeostasis in the tissues they reside. Gastrointestinal eosinophils modulate barrier function and mucosal immunity and promote tissue [...] Read more.

Eosinophils are innate immune granulocytes actively involved in defensive responses and in local and systemic inflammatory processes. Beyond these effector roles, eosinophils are fundamental to maintaining homeostasis in the tissues they reside. Gastrointestinal eosinophils modulate barrier function and mucosal immunity and promote tissue development through their direct communication with almost every cellular component. This is possible thanks to the variety of receptors they express and the bioactive molecules they store and release, including cytotoxic proteins, cytokines, growth factors, and neuropeptides and neurotrophines. A growing body of evidence points to the eosinophil as a key neuro-immune player in the regulation of gastrointestinal function, with potential implications in pathophysiological processes. Eosinophil–neuron interactions are facilitated by chemotaxis and adhesion molecules, and the mediators released may have excitatory or inhibitory effects on each cell type, with physiological consequences dependent on the type of innervation involved. Of special interest are the disorders of the brain–gut interaction (DBGIs), mainly functional dyspepsia (FD) and irritable bowel syndrome (IBS), in which mucosal eosinophilia and eosinophil activation have been identified. In this review, we summarize the main roles of gastrointestinal eosinophils in supporting gut homeostasis and the evidence available on eosinophil–neuron interactions to bring new insights that support the fundamental role of this neuro-immune crosstalk in maintaining gut health and contributing to the pathophysiology of DBGIs. Full article

(This article belongs to the Special Issue Neuro-Immune Crosstalk at Mucosal Interfaces in Health and Disease)

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