The gut homeostasis-immune system axis: novel insights into rheumatoid arthritis pathogenesis and treatment.

Rheumatoid arthritis is a widely prevalent autoimmune bone disease that imposes a significant burden on global healthcare systems due to its increasing incidence. In recent years, attention has focused on the interaction between gut homeostasis and the immune system, particularly in relation to bone health. Dysbiosis, which refers to an imbalance in the composition and function of the gut microbiota, has been shown to drive immune dysregulation through mechanisms such as the release of pro-inflammatory metabolites, increased gut permeability, and impaired regulatory T cell function. These factors collectively contribute to immune system imbalance, promoting the onset and progression of Rheumatoid arthritis. Dysbiosis induces both local and systemic inflammatory responses, activating key pro-inflammatory cytokines such as tumor necrosis factor-alpha, Interleukin-6, and Interleukin-17, which exacerbate joint inflammation and damage. Investigating the complex interactions between gut homeostasis and immune regulation in the context of Rheumatoid arthritis pathogenesis holds promise for identifying new therapeutic targets, revealing novel mechanisms of disease progression, and offering innovative strategies for clinical treatment.

New Role of the Serotonin as a Biomarker of Gut-Brain Interaction.

Serotonin (5-hydroxytryptamine: 5-HT), a neurotransmitter that regulates mood in the brain and signaling in the gut, has receptors throughout the body that serve various functions, especially in the gut and brain. Selective serotonin reuptake inhibitors (SSRIs) are used to treat depression, but their efficacy is uncertain. Depression is often associated with early gastrointestinal symptoms. Gut disorders such as functional dyspepsia (FD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are linked to elevated serotonin levels. In this review, we would like to discuss the approach of using serotonin as a biomarker for gut-brain, and body-wide organ communication may lead to the development of preventive and innovative treatments for gut-brain disorders, offering improved visibility and therapeutic monitoring. It could also be used to gauge stress intensity for self-care and mental health improvement.

Changes in Digestive Health, Satiety and Overall Well-Being after 14 Days of a Multi-Functional GI Primer Supplement.

A recent review proposed a role for multi-functional food or supplement products in priming the gut to support both digestive and systemic health. Accordingly, we designed and eva-luated the effect of a multi-functional gastrointestinal (GI) primer supplement on participant-reported measures for digestive health, quality-of-life (e.g., energy/vitality and general health), and reasons for satiation (e.g., attitudes towards food and eating). In this single-arm clinical trial, 68 participants with mild digestive symptoms consumed the GI primer supplement daily for 14 days. Digestive symptoms were evaluated daily from baseline (Day 0) through Day 14. At baseline and Day 14, participants reported their stool consistency, reasons for satiation, and quality-of-life measures using validated questionnaires. At Day 14, participants reported significant improvements in all (13/13) digestive symptom parameters (p-values < 0.05) and an increase in % of stools with normal consistencies. There were significant improvements (p-values < 0.05) in energy/vitality and general health, and in specific attitudes towards food and eating (e.g., physical satisfaction, planned amount, decreased eating priority, decreased food appeal, and self-consciousness). Results suggest the GI primer supplement promotes digestive health, improves quality of life, and impacts attitudes towards food/eating. This study provides preliminary support for the gut priming hypothesis through which multi-functional digestive products may improve GI health.

GSK3ß Substrate-competitive Inhibitors Regulate the gut Homeostasis and Barrier Function to Inhibit Neuroinflammation in Scopolamine-induced Alzheimer's Disease Model Mice.

Alzheimer's disease (AD) is a neurodegenerative disease mainly characterized by cognitive impairment. Glycogen synthase kinase 3 (GSK3ß) is a potential therapeutic target against AD. Isoorientin (ISO), a GSK3ß substrate competitive inhibitor, plays anti-AD effects in in vitro and in vivo AD model. TFGF-18 is an ISO synthetic analog with improved potency, but its neuroprotective effect in vivo remains to be elucidated, and the underlying mechanisms of GSK3ß inhibitor against AD need to be clarified. This study investigated the TFGF-18 and ISO effects on gut homeostasis and neuroinflammation in scopolamine (SCOP)-induced AD mice. And the protection on barrier function was observed in in vitro blood-brain barrier (BBB) model of mouse brain microvascular endothelial cells (bEnd.3). The results show that TFGF-18 and ISO improved cognitive function in SCOP-induced mice, and inhibited cholinergic system disorders and inflammation in the brain and intestine, decreased the level of lipopolysaccharides (LPS) in serum and intestine, protected the diversity and balance of intestinal microbiome, increased the expressions of tight junction protein (ZO-1, occludin), brain derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the mouse brain and intestine. In addition, TFGF-18 and ISO protected against barrier damage in LPS-stimulated BBB model of bEnd.3 cells in vitro. TFGF-18 and ISO increased the ratio of p-GSK3ß/GSK3ß, suppressed toll-like receptors 4 (TLR-4) expression and nuclear factor kappa-B (NF-κB) activation in vivo and in vitro, and increased the expressions of ß-catenin, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in vitro. In conclusion, The GSK3ß inhibitors TFGF-18 and ISO modulate the gut homeostasis and barrier function to inhibit neuroinflammation and attenuate cognitive impairment by regulating NF-κB, ß-catenin and Nrf2/HO-1 pathways.

The microbiota: a crucial mediator in gut homeostasis and colonization resistance.

The gut microbiota is a complex and diverse community of microorganisms that colonizes the human gastrointestinal tract and influences various aspects of human health. These microbes are closely related to enteric infections. As a foreign entity for the host, commensal microbiota is restricted and regulated by the barrier and immune system in the gut and contributes to gut homeostasis. Commensals also effectively resist the colonization of pathogens and the overgrowth of indigenous pathobionts by utilizing a variety of mechanisms, while pathogens have developed strategies to subvert colonization resistance. Dysbiosis of the microbial community can lead to enteric infections. The microbiota acts as a pivotal mediator in establishing a harmonious mutualistic symbiosis with the host and shielding the host against pathogens. This review aims to provide a comprehensive overview of the mechanisms underlying host-microbiome and microbiome-pathogen interactions, highlighting the multi-faceted roles of the gut microbiota in preventing enteric infections. We also discuss the applications of manipulating the microbiota to treat infectious diseases in the gut.

Prophylactic supplementation with selenium nanoparticles protects against foodborne toxin zearalenone-induced intestinal barrier dysfunction.

Selenium nanoparticles (SeNPs) have been used as a potential alternative to other forms of selenium in nutritional supplements for the treatment and prevention of inflammatory and oxidative stress-related diseases. Zearalenone (ZEA) is a foodborne mycotoxin present in grains that poses a health threat. Here, we investigated the adverse impacts of ZEA on intestinal homeostasis and explored the protective effects of probiotic-synthesized SeNPs against its damage. Results showed that ZEA reduced mucin and tight junction proteins expression in jejunum, induced inflammatory process and oxidative stress which in turn increased intestinal permeability in mice. ZEA-induced intestinal toxicity was further verified in vitro. Intracellular redox imbalance triggered endoplasmic reticulum (ER) stress in intestinal epithelial cells, which caused structural damage to the ER. Remarkably, SeNPs exhibited a counteractive effect by inducing a decrease in intracellular levels of Inositol 1,4,5-trisphosphate (IP3) and Ca2+, along with a reduction in the expression level of IP3 receptor. SeNPs effectively mitigated ZEA-induced ER stress was related to the increased activity of selenium-dependent antioxidant enzymes and the expression of ER-resident selenoproteins. Furthermore, SeNPs significantly inhibited the activation of PERK/eIF2α/ATF4/CHOP pathway in vitro and in vivo. In addition, SeNPs effectively reversed ZEA-induced gut microbiota dysbiosis and increased the abundance of short-chain fatty acid-producing beneficial bacteria (Alloprevotella and Muribaculaceae). The Spearman correlation analysis suggested that the structure of gut microbiota was closely related to the SeNPs attenuation of ZEA-induced intestinal toxicity. This study provides new insights into ZEA-induced intestinal toxicity and identifies a novel potential nutrient SeNPs to overcome adverse effects.

Gut microbiota regulates gut homeostasis, mucosal immunity and influences immune-related diseases.

The intestinal microbiome constitutes a sophisticated and massive ecosystem pivotal for maintaining gastrointestinal equilibrium and mucosal immunity via diverse pathways. The gut microbiota is continuously reshaped by multiple environmental factors, thereby influencing overall wellbeing or predisposing individuals to disease state. Many observations reveal an altered microbiome composition in individuals with autoimmune conditions, coupled with shifts in metabolic profiles, which has spurred ongoing development of therapeutic interventions targeting the microbiome. This review delineates the microbial consortia of the intestine, their role in sustaining gastrointestinal stability, the association between the microbiome and immune-mediated pathologies, and therapeutic modalities focused on microbiome modulation. We emphasize the entire role of the intestinal microbiome in human health and recommend microbiome modulation as a viable strategy for disease prophylaxis and management. However, the application of gut microbiota modification for the treatment of immune-related diseases, such as fecal microbiota transplantation and probiotics, remain quite challenging. Therefore, more research is needed into the role and mechanisms of these therapeutics.

Gut microbial metalloproteins and its role in xenobiotics degradation and ROS scavenging.

The gut microbial metalloenzymes play an important role in maintaining the balance between gut microbial ecosystem, human physiologically processes and immune system. The metals coordinated into active site contribute in various detoxification and defense strategies to avoid unfavourable environment and ensure bacterial survival in human gut. Metallo-ß-lactamase is a potent degrader of antibiotics present in periplasmic space of both commensals and pathogenic bacteria. The resistance to anti-microbial agents developed in this enzyme is one of the global threats for human health. The organophosphorus eliminator, organophosphorus hydrolases have evolved over a course of time to hydrolyze toxic organophosphorus compounds and decrease its effect on human health. Further, the redox stress responders namely superoxide dismutase and catalase are key metalloenzymes in reducing both endogenous and exogenous oxidative stress. They hold a great importance for pathogens as they contribute in pathogenesis in human gut along with reduction of oxidative stress. The in-silico study on these enzymes reveals the importance of point mutation for the evolution of these enzymes in order to enhance their enzyme activity and stability. Various mutation studies were conducted to investigate the catalytic activity of these enzymes. By using the "directed evolution" method, the enzymes involved in detoxification and defense system can be engineered to produce new variants with enhance catalytic features, which may be used to predict the severity due to multi-drug resistance and degradation pattern of organophosphorus compounds in human gut.

Viral infection disrupts intestinal homeostasis via Sting-dependent NF-κB signaling in Drosophila.

Host-microbe interactions influence intestinal stem cell (ISC) activity to modulate epithelial turnover and composition. Here, we investigated the functional impacts of viral infection on intestinal homeostasis and the mechanisms by which viral infection alters ISC activity. We report that Drosophila A virus (DAV) infection disrupts intestinal homeostasis in Drosophila by inducing sustained ISC proliferation, resulting in intestinal dysplasia, loss of gut barrier function, and reduced lifespan. We found that additional viruses common in laboratory-reared Drosophila also promote ISC proliferation. The mechanism of DAV-induced ISC proliferation involves progenitor-autonomous epidermal growth factor receptor (EGFR) signaling, c-Jun N-terminal kinase (JNK) activity in enterocytes, and requires Sting-dependent nuclear factor κB (NF-κB) (Relish) activity. We further demonstrate that activating Sting-Relish signaling is sufficient to induce ISC proliferation, promote intestinal dysplasia, and reduce lifespan in the absence of infection. Our results reveal that viral infection can significantly disrupt intestinal physiology, highlight a novel role for Sting-Relish signaling, and support a role for viral infection in aging.

Host-microbiota interaction in intestinal stem cell homeostasis.

Intestinal stem cells (ISCs) play a pivotal role in gut physiology by governing intestinal epithelium renewal through the precise regulation of proliferation and differentiation. The gut microbiota interacts closely with the epithelium through myriad of actions, including immune and metabolic interactions, which translate into tight connections between microbial activity and ISC function. Given the diverse functions of the gut microbiota in affecting the metabolism of macronutrients and micronutrients, dietary nutrients exert pronounced effects on host-microbiota interactions and, consequently, the ISC fate. Therefore, understanding the intricate host-microbiota interaction in regulating ISC homeostasis is imperative for improving gut health. Here, we review recent advances in understanding host-microbiota immune and metabolic interactions that shape ISC function, such as the role of pattern-recognition receptors and microbial metabolites, including lactate and indole metabolites. Additionally, the diverse regulatory effects of the microbiota on dietary nutrients, including proteins, carbohydrates, vitamins, and minerals (e.g. iron and zinc), are thoroughly explored in relation to their impact on ISCs. Thus, we highlight the multifaceted mechanisms governing host-microbiota interactions in ISC homeostasis. Insights gained from this review provide strategies for the development of dietary or microbiota-based interventions to foster gut health.

Maintenance of caecal homeostasis by diverse adaptive immune cells in the rhesus macaque.

Objectives: The caecum bridges the small and large intestine and plays a front-line role in discriminating gastrointestinal antigens. Although dysregulated in acute and chronic conditions, the tissue is often overlooked immunologically. Methods: To address this issue, we applied single-cell transcriptomic-V(D)J sequencing to FACS-isolated CD45+ caecal patch/lamina propria leukocytes from a healthy (5-year-old) female rhesus macaque ex vivo and coupled these data to VDJ deep sequencing reads from haematopoietic tissues. Results: We found caecal NK cells and ILC3s to co-exist with a spectrum of effector T cells partially derived from SOX4 + recent thymic emigrants. Tolerogenic Vγ8Vδ1-T cells, plastic CD4+ T helper cells and GZMK + EOMES + and TMIGD2 + tissue-resident memory CD8+ T cells were present and differed metabolically. An IL13 + GATA3 + Th2 subset expressing eicosanoid pathway enzymes was accompanied by IL1RL1 + GATA3 + regulatory T cells and a minor proportion of IgE+ plasma cells (PCs), illustrating tightly regulated type 2 immunity devoid of ILC2s. In terms of B lymphocyte lineages, caecal patch antigen-presenting memory B cells sat alongside germinal centre cells undergoing somatic hypermutation and differentiation into IGF1 + PCs. Prototypic gene expression signatures decreased across PC clusters, and notably, expanded IgA clonotypes could be traced in VDJ deep sequencing reads from additional compartments, including the bone marrow, supporting that these cells contribute a steady stream of systemic antibodies. Conclusions: The data advance our understanding of caecal immunological function, revealing processes involved in barrier maintenance and molecular networks relevant to disease.

Whole-genome sequencing of Chromobacterium subtsugae strains exhibiting toxicity to Drosophila melanogaster.

Chromobacterium subtsugae exhibits toxicity to Drosophila melanogaster, providing a new infection model to study host homeostasis. Previous studies using pathogen models have proven to be a useful tool to understand host physiology. Here, we report on the whole-genome sequences of these microbes obtained from short and long reads.

Two human milk-like synthetic bacterial communities displayed contrasted impacts on barrier and immune responses in an intestinal quadricellular model.

The human milk (HM) microbiota, a highly diverse microbial ecosystem, is thought to contribute to the health benefits associated with breast-feeding, notably through its impact on infant gut microbiota. Our objective was to further explore the role of HM bacteria on gut homeostasis through a "disassembly/reassembly" strategy. HM strains covering the diversity of HM cultivable microbiota were first characterized individually and then assembled in synthetic bacterial communities (SynComs) using two human cellular models, peripheral blood mononuclear cells and a quadricellular model mimicking intestinal epithelium. Selected HM bacteria displayed a large range of immunomodulatory properties and had variable effects on epithelial barrier, allowing their classification in functional groups. This multispecies characterization of HM bacteria showed no clear association between taxonomy and HM bacteria impacts on epithelial immune and barrier functions, revealing the entirety and complexity of HM bacteria potential. More importantly, the assembly of HM strains into two SynComs of similar taxonomic composition but with strains exhibiting distinct individual properties, resulted in contrasting impacts on the epithelium. These impacts of SynComs partially diverged from the predicted ones based on individual bacteria. Overall, our results indicate that the functional properties of the HM bacterial community rather than the taxonomic composition itself could play a crucial role in intestinal homeostasis of infants.

Dietary polyphenols regulate appetite mechanism via gut-brain axis and gut homeostasis.

Nowadays, due to the rise of fast-food consumption, the metabolic diseases are increasing as a result of high-sugar and high-fat diets. Therefore, there is an urgent need for natural, healthy and side-effect-free diets in daily life. Whole grain supplementation can enhance satiety and regulate energy metabolism, effects that have been attributed to polyphenol content. Dietary polyphenols interact with gut microbiota to produce intermediate metabolites that can regulate appetite while also enhancing prebiotic effects. This review considers how interactions between gut metabolites and dietary polyphenols might regulate appetite by acting on the gut-brain axis. In addition, further advances in the study of dietary polyphenols and gut microbial metabolites on energy metabolism and gut homeostasis are summarized. This review contributes to a better understanding of how dietary polyphenols regulate appetite via the gut-brain axis, thereby providing nutritional references for citizens' dietary preferences.

Unlocking the potential of Rosa roxburghii Tratt polyphenol: a novel approach to treating acute lung injury from a perspective of the lung-gut axis.

Introduction: Acute lung injury (ALI) is a serious respiratory disease characterized by progressive respiratory failure with high morbidity and mortality. It is becoming increasingly important to develop functional foods from polyphenol-rich medicinal and dietary plants in order to prevent or alleviate ALI by regulating intestinal microflora. Rosa roxburghii Tratt polyphenol (RRTP) has significant preventive and therapeutic effects on lipopolysaccharide-induced ALI mice, but its regulatory effects on gut homeostasis in ALI mice remains unclear. Methods: This study aims to systematically evaluate the ameliorative effects of RRTP from the perspective of "lung-gut axis" on ALI mice by intestine histopathological assessment, oxidative stress indicators detection and short-chain fatty acids (SCFAs) production, and then explore the modulatory mechanisms of RRTP on intestinal homeostasis by metabolomics and gut microbiomics of cecal contents. Results: The results showed that RRTP can synergistically exert anti-ALI efficacy by significantly ameliorating intestinal tissue damage, inhibiting oxidative stress, increasing SCFAs in cecal contents, regulating the composition and structure of intestinal flora, increasing Akkermansia muciniphila and modulating disordered intestinal endogenous metabolites. Discussion: This study demonstrated that RRTP has significant advantages in adjuvant therapy of ALI, and systematically clarified its comprehensive improvement mechanism from a new perspective of "lung-gut axis", which provides a breakthrough for the food and healthcare industries to develop products from botanical functional herbs and foods to prevent or alleviate ALI by regulating intestinal flora.

Dissecting Maillard reaction production in fried foods: Formation mechanisms, sensory characteristic attribution, control strategy, and gut homeostasis regulation.

Foods rich in carbohydrates or fats undergo the Maillard reaction during frying, which promotes the color, flavor and sensory characteristics formation. In the meanwhile, Maillard reaction intermediates and advanced glycation end products (AGEs) have a negative impact on food sensory quality and gut homeostasis. This negative effect can be influenced by food composition and other processing factors. Whole grain products are rich in polyphenols, which can capture carbonyl compounds in Maillard reaction, and reduce the production of AGEs during frying. This review summarizes the Maillard reaction production intermediates and AGEs formation mechanism in fried food and analyzes the factors affecting the sensory formation of food. In the meanwhile, the effects of Maillard reaction intermediates and AGEs on gut homeostasis were summarized. Overall, the innovative processing methods about the Maillard reaction are summarized to optimize the sensory properties of fried foods while minimizing the formation of AGEs.

Replacing dietary sodium selenite with biogenic selenium nanoparticles improves the growth performance and gut health of early-weaned piglets.

Selenium nanoparticles (SeNPs) are proposed as a safer and more effective selenium delivery system than sodium selenite (Na2SeO3). Here, we investigated the effects of replacing dietary Na2SeO3 with SeNPs synthesized by Lactobacillus casei ATCC 393 on the growth performance and gut health of early-weaned piglets. Seventy-two piglets (Duroc × Landrace × Large Yorkshire) weaned at 21 d of age were divided into the control group (basal diet containing 0.3 mg Se/kg from Na2SeO3) and SeNPs group (basal diet containing 0.3 mg Se/kg from SeNPs) during a 14-d feeding period. The results revealed that SeNPs supplementation increased the average daily gain (P = 0.022) and average daily feed intake (P = 0.033), reduced (P = 0.056) the diarrhea incidence, and improved (P = 0.013) the feed conversion ratio compared with Na2SeO3. Additionally, SeNPs increased jejunal microvilli height (P = 0.006) and alleviated the intestinal barrier dysfunction by upregulating (P < 0.05) the expression levels of mucin 2 and tight junction proteins, increasing (P < 0.05) Se availability, and maintaining mitochondrial structure and function, thereby improving antioxidant capacity and immunity. Furthermore, metabolomics showed that SeNPs can regulate lipid metabolism and participate in the synthesis, secretion and action of parathyroid hormone, proximal tubule bicarbonate reclamation and tricarboxylic acid cycle. Moreover, SeNPs increased (P < 0.05) the abundance of Holdemanella and the levels of acetate and propionate. Correlation analysis suggested that Holdemanella was closely associated with the regulatory effects of SeNPs on early-weaned piglets through participating in lipid metabolism. Overall, replacing dietary Na2SeO3 with biogenic SeNPs could be a potential nutritional intervention strategy to prevent early-weaning syndrome in piglets.

The signaling pathway of hypoxia inducible factor in regulating gut homeostasis.

Hypoxia represent a condition in which an adequate amount of oxygen supply is missing in the body, and it could be caused by a variety of diseases, including gastrointestinal disorders. This review is focused on the role of hypoxia in the maintenance of the gut homeostasis and related treatment of gastrointestinal disorders. The effects of hypoxia on the gut microbiome and its role on the intestinal barrier functionality are also covered, together with the potential role of hypoxia in the development of gastrointestinal disorders, including inflammatory bowel disease and irritable bowel syndrome. Finally, we discussed the potential of hypoxia-targeted interventions as a novel therapeutic approach for gastrointestinal disorders. In this review, we highlighted the importance of hypoxia in the maintenance of the gut homeostasis and the potential implications for the treatment of gastrointestinal disorders.

The potential role of gut microbiota outer membrane vesicles in colorectal cancer.

Colorectal cancer (CRC) is a common malignant digestive tract tumor in colorectal regions. Considerable evidence now shows that the gut microbiota have essential roles in CRC occurrence and development. Most Gram-negative bacteria release outer membrane vesicles (OMVs) via outer membrane blistering, which contain specific cargoes which interact with host cells via intercellular communications, host immune regulation, and gut microbiota homeostasis. Studies have also shown that OMVs selectively cluster near tumor cells, thus cancer treatment strategies based on OMVs have attracted considerable research attention. However, little is known about the possible impact of gut microbiota OMVs in CRC pathophysiology. Therefore, in this review, we summarize the research progress on molecular composition and function of OMV, and review the microbial dysbiosis in CRC. We then focus on the potential role of gut microbiota OMVs in CRC. Finally, we examine the clinical potential of OMVs in CRC treatment, and their main advantages and challenges in tumor therapy.

The Eph/ephrin system symphony of gut inflammation.

The extent of gut inflammation depends largely on the gut barrier's integrity and enteric neuroimmune interactions. However, the factors and molecular mechanisms that regulate inflammation-related changes in the enteric nervous system (ENS) remain largely unexplored. Eph/ephrin signaling is critical for inflammatory response, neuronal activation, and synaptic plasticity in the brain, but its presence and function in the ENS have been largely unknown to date. This review discusses the critical role of Eph/ephrin in regulating gut homeostasis, inflammation, neuroimmune interactions, and pain pathways. Targeting the Eph/ephrin system offers innovative treatments for gut inflammation disorders, offering hope for enhanced patient prognosis, pain management, and overall quality of life.