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Modulation of Gut Barrier Functions in Ulcerative Colitis by Hyaluronic Acid System.

ABSTRACT: The active stages of intestinal inflammation and the pathogenesis of ulcerative colitis are associated with superficial mucosal damage and intermittent wounding that leads to epithelial barrier defects and increased permeability. The standard therapeutic interventions for colitis have focused mainly on maintaining the remission levels of the disease. Nonetheless, such treatment strategies (using anti-inflammatory, immunomodulatory agents) do not address colitis' root cause, especially the mucosal damage and dysregulated intestinal barrier functions. Restoration of barrier functionality by mucosal healing or physical barrier protecting strategies shall be considered as an initial event in the disease suppression and progression. Herein, a biphasic hyaluronan (HA) enema suspension, naïve-HA systems that protect the dysregulated gut epithelium by decreasing the inflammation, permeability, and helping in maintaining the epithelial barrier integrity in the dextran sodium sulfate-induced colitis mice model is reported. Furthermore, HA-based system modulates intestinal epithelial junctional proteins and regulatory signaling pathways, resulting in attenuation of inflammation and mucosal protection. The results suggest that HA-based system can be delivered as an enema to act as a barrier protecting system for managing distal colonic inflammatory diseases, including colitis.

SUBMITTER: Kotla NG

PROVIDER: S-EPMC8811821 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Modulation of Gut Barrier Functions in Ulcerative Colitis by Hyaluronic Acid System.

Kotla Niranjan G NG Isa Isma Liza Mohd ILM Rasala Swetha S Demir Secil S Singh Rajbir R Baby Becca V BV Swamy Samantha K SK Dockery Peter P Jala Venkatakrishna R VR Rochev Yury Y Pandit Abhay A

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20211110 4

The active stages of intestinal inflammation and the pathogenesis of ulcerative colitis are associated with superficial mucosal damage and intermittent wounding that leads to epithelial barrier defects and increased permeability. The standard therapeutic interventions for colitis have focused mainly on maintaining the remission levels of the disease. Nonetheless, such treatment strategies (using anti-inflammatory, immunomodulatory agents) do not address colitis' root cause, especially the mucosa ...[more]

PMID: 34761543

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Project description:IntroductionThe global health challenge of ulcerative colitis (UC) has been classified by the WHO as a modern refractory disease, commonly referred to as green cancer, with limited treatment options still available, highlighting the urgent need for the development of new therapeutic strategies. Recent pharmacological research has shown that traditional Chinese medicine saussurea costus (SC) possesses beneficial antibacterial and anti-inflammatory properties. Nevertheless, its underlying mechanism remains elusive.MethodsFirstly, we identified the main active components of SC through UHPLC-QTOF-MS analysis. Subsequently, UC mice were induced using DSS and administered different doses of SC to evaluate its efficacy. Additionally, the impact of SC on the repair of the intestinal mucosal barrier was evaluated through immunofluorescence and western blot. Furthermore, 16s rRNA gene sequencing was conducted to elucidate the contribution of gut microbiota to UC pathogenesis.ResultsThe primary components of SC include Proline, Phenylalanine, Isoleucine, Lucidenic acid M, and Pyroglutamic acid. The efficacy of SC was concurrently assessed, revealing its potential to ameliorate histological injury in colitis mice. Furthermore, SC was found to decrease levels of TNF-α, IL-1β, IL-8, and IL-18 while promoting the expression of IL-10 and IL-22. Similarly, we also found that the expression of ZO-1 and Occludin was reversed by SC in colitis mice. In addition, analysis of 16S rRNA gene sequencing indicated that SC reduced harmful bacterial populations, such as Proteobacteria, while simultaneously enhancing the levels of beneficial bacteria like Lactobacillus, thereby contributing to the improvement of UC pathology.ConclusionThis study highlights the therapeutic potential of SC in managing UC through its ability to attenuate inflammatory responses, restore intestinal barrier functionality, and modulate gut microbiota composition, which findings offer insights into potential strategies for advancing UC treatment.

Project description:Probiotics can effectively improve ulcerative colitis (UC), but the mechanism is still unclear. Here, shotgun metagenome and transcriptome analyses were performed to explore the therapeutic effect and the mechanism of the probiotic Lactobacillus plantarum HNU082 (Lp082) on UC. The results showed that Lp082 treatment significantly ameliorated dextran sulfate sodium (DSS)-induced UC in mice, which was manifested as increases in body weight, water intake, food intake, and colon length and decreases in disease activity index (DAI), immune organ index, inflammatory factors, and histopathological scores after Lp082 intake. An in-depth study discovered that Lp082 could improve the intestinal mucosal barrier and relieve inflammation by cooptimizing the biological barrier, chemical barrier, mechanical barrier, and immune barrier. Specifically, Lp082 rebuilt the biological barrier by regulating the intestinal microbiome and increasing the production of short-chain fatty acids (SCFAs). Lp082 improved the chemical barrier by reducing intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM) and increasing goblet cells and mucin2. Lp082 ameliorated the mechanical barrier by increasing zonula occludens-1 (ZO-1), zonula occludens-2 (ZO-2), and occludin while decreasing claudin-1 and claudin-2. Lp082 optimized the immune barrier by reducing the content of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), myeloperoxidase (MPO), and interferon-γ (IFN-γ) and increasing IL-10, transforming growth factor-β1 (TGF-β1), and TGF-β2, inhibiting the NF-κB signaling pathway. Taken together, probiotic Lp082 can play a protective role in a DSS-induced colitis mouse model by protecting the intestinal mucosal barrier, attenuating the inflammatory response, and regulating microbial imbalance. This study provides support for the development of probiotic-based microbial products as an alternative treatment strategy for UC. IMPORTANCE Many studies have focused on the therapeutic effect of probiotics on ulcerative colitis (UC), but few studies have paid attention to the mechanism of probiotics, especially the therapeutic effect. This study suggests that Lp082 has a therapeutic effect on colitis in mice. Its mechanisms of action include protecting the mucosal barrier and actively modulating the gut microbiome, modulating inflammatory pathways, and reducing neutrophil infiltration. Our study enriches the mechanism and provides a new prospect for probiotics in the treatment of colitis, helps to deepen the understanding of the intestinal mucosal barrier, and provides guidance for the future probiotic treatment of human colitis.

Project description:ObjectiveThe pathogenesis of UC relates to gut microbiota dysbiosis. We postulate that alterations in the viral community populating the intestinal mucosa play an important role in UC pathogenesis. This study aims to characterise the mucosal virome and their functions in health and UC.DesignDeep metagenomics sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on the rectal mucosa of 167 subjects from three different geographical regions in China (UC=91; healthy controls=76). Virome and bacteriome alterations in UC mucosa were assessed and correlated with patient metadata. We applied partition around medoids clustering algorithm and classified mucosa viral communities into two clusters, referred to as mucosal virome metacommunities 1 and 2.ResultsIn UC, there was an expansion of mucosa viruses, particularly Caudovirales bacteriophages, and a decrease in mucosa Caudovirales diversity, richness and evenness compared with healthy controls. Altered mucosal virome correlated with intestinal inflammation. Interindividual dissimilarity between mucosal viromes was higher in UC than controls. Escherichia phage and Enterobacteria phage were more abundant in the mucosa of UC than controls. Compared with metacommunity 1, metacommunity 2 was predominated by UC subjects and displayed a significant loss of various viral species. Patients with UC showed substantial abrogation of diverse viral functions, whereas multiple viral functions, particularly functions of bacteriophages associated with host bacteria fitness and pathogenicity, were markedly enriched in UC mucosa. Intensive transkingdom correlations between mucosa viruses and bacteria were significantly depleted in UC.ConclusionWe demonstrated for the first time that UC is characterised by substantial alterations of the mucosa virobiota with functional distortion. Enrichment of Caudovirales bacteriophages, increased phage/bacteria virulence functions and loss of viral-bacterial correlations in the UC mucosa highlight that mucosal virome may play an important role in UC pathogenesis.

Dataset Information

Modulation of Gut Barrier Functions in Ulcerative Colitis by Hyaluronic Acid System.

Publications

Modulation of Gut Barrier Functions in Ulcerative Colitis by Hyaluronic Acid System.

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