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The mouse pathogen Citrobacter rodentium is utilized as a model organism for studying infections caused by the human pathogens enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and to elucidate mechanisms of mucosal immunity. In response to C. rodentium infection, innate lymphoid cells and T cells secrete interleukin (IL)-22, a cytokine that promotes mucosal barrier function. IL-22 plays a pivotal role in enabling mice to survive and recover from C. rodentium infection, although the exact mechanisms involved remain incompletely understood. Here, we investigated whether particular components of the host response downstream of IL-22 contribute to the cytokine's protective effects during C. rodentium infection. In line with previous research, mice lacking the IL-22 gene (Il22-/- mice) were highly susceptible to C. rodentium infection. To elucidate the role of specific antimicrobial proteins modulated by IL-22, we infected the following knockout mice: S100A9-/- (calprotectin), Lcn2-/- (lipocalin-2), Reg3b-/- (Reg3β), Reg3g-/- (Reg3γ), and C3-/- (C3). All knockout mice tested displayed a considerable level of resistance to C. rodentium infection, and none phenocopied the lethality observed in Il22-/- mice. By investigating another arm of the IL-22 response, we observed that C. rodentium-infected Il22-/- mice exhibited an overall decrease in gene expression related to intestinal barrier integrity as well as significantly elevated colonic inflammation, gut permeability, and pathogen levels in the spleen. Taken together, these results indicate that host resistance to lethal C. rodentium infection may depend on multiple antimicrobial responses acting in concert, or that other IL-22-regulated processes, such as tissue repair and maintenance of epithelial integrity, play crucial roles in host defense to attaching and effacing pathogens.

Emerging evidence highlights the significance of peripheral inflammation in the pathogenesis of Parkinson's disease (PD) and suggests the gut as a viable therapeutic target. This study aimed to explore the neuroprotective effects of the probiotic formulation VSL#3® and its underlying mechanism in a PD mouse model induced by MPTP. Following MPTP administration, the striatal levels of dopamine and its metabolites, as along with the survival rate of dopaminergic neurons in the substantia nigra, were significantly reduced in PD mice. MPTP also significantly increased the mRNA expression of pro-inflammatory cytokines TNF-α and IL-1β, while reducing anti-inflammation mediators, like glia cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in the striatum. These pathological changes were notably mitigated by VSL#3® treatment, suggesting its neuroprotective and anti-inflammatory effects in the brain. Additionally, VSL#3® significantly lowered the circulating levels of pro-inflammatory cytokines, and reduced TNF-α and IL-1β mRNA expression in the liver, indicating an inhibition of cytokine transfer. In the intestine, the probiotic treatment markedly decreased the mRNA expression of pro-inflammatory cytokines, (TNF-α, IL-1β, IL-6 and IL-17), and the other two key components of the NLRP3 inflammasome, caspase-1 and NLRP3, demonstrating an inhibition of VSL#3® on gut NLRP3 inflammasome. VSL#3® exerts neuroprotective effects in PD mice through the suppression of intestinal inflammation, particularly inhibiting the intestinal NLRP3 inflammasome. This study supports the therapeutic potential of targeting intestinal inflammation and utilizing probiotics in PD treatment. [ABSTRACT FROM AUTHOR]

Unaffected first-degree relatives (FDRs) from families with ≥2 affected FDRs with Crohn's disease (CD, multiplex families) have a high risk of developing CD, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between FDRs from multiplex vs simplex families and investigate the risk of future CD onset accounting for potential confounders. We assessed the Crohn's and Colitis Canada Genetic Environmental Microbial cohort of healthy FDRs of patients with CD. Genome-wide CD-polygenic risk scores, urinary fractional excretion of lactulose-to-mannitol ratio, fecal calprotectin (FCP), and fecal 16S ribosomal RNA microbiome were measured at recruitment. Associations between CD multiplex status and baseline biomarkers were determined using generalized estimating equations models. Cox models were used to assess the risk of future CD onset. There were 4051 participants from simplex families and 334 from CD multiplex families. CD multiplex status was significantly associated with higher baseline FCP (P =.026) but not with baseline CD-polygenic risk scores or the lactulose-to-mannitol ratio. Three bacterial genera were found to be differentially abundant between both groups. CD multiplex status at recruitment was independently associated with an increased risk of developing CD (adjusted hazard ratio, 3.65; 95% confidence interval, 2.18–6.11, P <.001). Within FDRs of patients with CD, participants from multiplex families had a 3-fold increased risk of CD onset, a higher FCP, and an altered bacterial composition, but not genetic burden or altered gut permeability. These results suggest that putative environmental factors might be enriched in FDRs from multiplex families. In families with multiple cases of Crohn's disease, unaffected members are 3 times more likely to develop the disease, possibly due to environmental factors rather than genetics. [ABSTRACT FROM AUTHOR]

The intestinal epithelium comprises a dynamic single cell layer in the gut that allows segregation of luminal content from the host while executing nutrient absorption, barrier maintenance, and danger signaling. Epithelial metabolism of nutrients allows for the maintenance of epithelial cell functions and host–microbe commensalism. Dietary cues, microbes and metabolites, immune cross-talk, endocrine signals, and neuronal networks control and regulate the execution of intestinal epithelial metabolism. Rewiring of epithelial metabolism constitutes a hallmark of inflammatory and malignant diseases in the gut. Extrinsic or intrinsic perturbation of intestinal epithelial metabolism promotes experimental gut inflammation and tumorigenesis. The gut epithelium protects the host from a potentially hostile environment while allowing nutrient uptake that is vital for the organism. To maintain this delicate task, the gut epithelium has evolved multilayered cellular functions ranging from mucus production to hormone release and orchestration of mucosal immunity. Here, we review the execution of intestinal epithelial metabolism in health and illustrate how perturbation of epithelial metabolism affects experimental gut inflammation and tumorigenesis. We also discuss the impact of environmental factors and host–microbe interactions on epithelial metabolism in the context of inflammatory bowel disease and colorectal cancer. Insights into epithelial metabolism hold promise to unravel mechanisms of organismal health that may be therapeutically exploited in humans in the future. [ABSTRACT FROM AUTHOR]

Background. The intestinal barrier is a crucial structure for maintaining the balance in permeability of digested food and restriction of microbial invasion from internal environment. Imbalance in these functions closely related to the initiation of intestinal epithelium reactivity and inflammation. Inflammation is the most common cause of intestinal dysfunction. Muramyl peptides (MPs) are small signaling molecules which stimulate intracellular receptors of pathogens and are potent regulators of cell response. However, molecular mechanisms of MP effect on intestinal cells remain unknown. The study of MP application to maintain viability of Caco-2 cells was aimed to explore the cytoprotective effect of MP-based probiotic on gut inflammation and intestinal barrier integrity. Materials and methods. Caco-2 cells were treated with 10–100 µg/ml lipopolysaccharide (LPS), 5–50 µg/ml MPs and combination of LPS + MPs. Cell viability was measured with MTT assay. Occludin content was detected with Western blotting. Enzyme-linked immunosorbent assay was applied to assess interleukin-8 (IL-8) production. Results. Obtained results have shown that LPS treatment with doses of 10–100 µg/ml induced in a decrease in cell viability and occludin content. On the contrary, IL-8 content was increased in LPS treatment that evidence the dose-dependent proinflammatory changes in Caco-2 cells. No significant changes were detected in the cells exposed to 5–50 µg/ml doses of MPs. However, application of 50 µg/ml of MPs inhibited IL-8 upregulation in LPS-exposed cells. Besides, MPs exhibited a dose-dependent cytoprotective effect in respect to cell viability at a dose of 20 and 50 µg/ml. Furthermore, MP dose of 50 µg/ml helped restore occludin content in LPS-exposed cells. Conclusions. Taking into the account that occludin is one of major components of tight junctions, MPs can restore epithelial barrier integrity in compromised gut. Observed results demonstrated that MPs is a promising agent in inflammation-induced intestinal injury and maintaining gut barrier function.

Aim: This study investigates changes in immune cell subsets in peripheral blood of ankylosing spondylitis (AS) patients with colitis or terminal ileitis. It aims to explore the connection between changes in lymphocyte subsets and gut inflammation, providing insights for early detection. Methods: Overall, 50 AS patients undergoing colonoscopy were enrolled. Flow cytometry was employed to analyze lymphocyte subsets, including T and B cells, in peripheral blood. Disease activity was assessed using CRP, ESR, BASDAI, ASDAS‐CRP, and ASDAS‐ESR. Results: Compared to AS patients without gut inflammation, those with colorectal inflammation showed a significant increase in total T cells (p <.05), an increase in exhausted CD4+ T cells (p <.05), and a decrease in Th2 cells and total Tc cells (p <.05). Notably, in AS patients with terminal ileitis, there was an increase in total B cells and classic switched B cells (p <.05), with a decrease in double‐positive T cells (p <.05). However, no significant differences were observed in the distribution of Tfh‐cell subpopulations (Tfh1, Tfh2, Tfh17) and Tc‐cell subpopulations (Tc1, Tc2, Tc17) between AS patients with either colorectal inflammation or terminal ileitis (p >.05). We explored the relationship between disease activity scores, ESR, CRP, and lymphocyte subsets, but found no statistically significant correlation between them. Conclusion: Distinct immune patterns may exist in AS with different types of intestinal inflammation. Colitis in AS is primarily characterized by a significant increase in exhausted CD4+ T cells, along with a decrease in Th2 cells. In contrast, terminal ileum inflammation in AS is marked by an increase in total B cells and classic switched B cells. These findings offer new insights for early detection and therapeutic intervention. [ABSTRACT FROM AUTHOR]

The fecal microbiome is identical to the gut microbial communities and provides an easy access to the gut microbiome. Therefore, fecal microbial transplantation (FMT) strategies have been used to alter dysbiotic gut microbiomes with healthy fecal microbiota, successfully alleviating various metabolic disorders, such as obesity, type 2 diabetes, and inflammatory bowel disease (IBD). However, the success of FMT treatment is donor-dependent and variations in gut microbes cannot be avoided. This problem may be overcome by using a cultured fecal microbiome. In this study, a human fecal microbiome was cultured using five different media; growth in brain heart infusion (BHI) media resulted in the highest microbial community cell count. The microbiome (16S rRNA) data demonstrated that the cultured microbial communities were similar to that of the original fecal sample. Therefore, the BHI-cultured fecal microbiome was selected for cultured FMT (cFMT). Furthermore, a dextran sodium sulfate (DSS)-induced mice-IBD model was used to confirm the impact of cFMT. Results showed that cFMT effectively alleviated IBD-associated symptoms, including improved gut permeability, restoration of the inflamed gut epithelium, decreased expression of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1, IL-6, IL-12, and IL-17), and increased expression of anti-inflammatory cytokines (IL-4 and IL-10). Thus, study's findings suggest that cFMT can be a potential alternative to nFMT. Key points: • In vitro fecal microbial communities were grown in a batch culture using five different media. • Fecal microbial transplantation was performed on DSS-treated mice using cultured and normal fecal microbes. • Cultured fecal microbes effectively alleviated IBD-associated symptoms. [ABSTRACT FROM AUTHOR]

A defining unique characteristic of the gut immune system is its ability to respond effectively to foreign pathogens while mitigating unnecessary inflammation. Intestinal macrophages serve as the cornerstone of this balancing act, acting uniquely as both the sword and shield in the gut microenvironment. The GI tract is densely innervated by the enteric nervous system (ENS), the intrinsic nervous system of the gut. Recent advances in sequencing technology have increasingly suggested neuroimmune crosstalk as a critical component for homeostasis both within the gut and in other tissues. Here, we systematically review the ENS–macrophage axis. We focus on the pertinent molecules produced by the ENS, spotlight the mechanistic contributions of intestinal macrophages to gut homeostasis and inflammation, and discuss both existing and potential strategies that intestinal macrophages use to integrate signals from the ENS. This review aims to elucidate the complex molecular basis governing ENS–macrophage signaling, highlighting their cooperative roles in sustaining intestinal health and immune equilibrium. [ABSTRACT FROM AUTHOR]

Sulforaphane is considered the bioactive metabolite of glucoraphanin after dietary consumption of broccoli sprouts. Although both molecules pass through the gut lumen to the large intestine in stable form, their biological impact on the first intestinal tract is poorly described. In celiac patients, the function of the small intestine is affected by celiac disease (CD), whose severe outcomes are controlled by gluten-free dietary protocols. Nevertheless, pathological signs of inflammation and oxidative stress may persist. The aim of this study was to compare the biological activity of sulforaphane with its precursor glucoraphanin in a cellular model of gliadin-induced inflammation. Human intestinal epithelial cells (CaCo-2) were stimulated with a pro-inflammatory combination of cytokines (IFN-γ, IL-1β) and in-vitro-digested gliadin, while oxidative stress was induced by H2O2. LC-MS/MS analysis confirmed that sulforaphane from broccoli sprouts was stable after simulated gastrointestinal digestion. It inhibited the release of all chemokines selected as inflammatory read-outs, with a more potent effect against MCP-1 (IC50 = 7.81 µM). On the contrary, glucoraphanin (50 µM) was inactive. The molecules were unable to counteract the oxidative damage to DNA (γ-H2AX) and catalase levels; however, the activity of NF-κB and Nrf-2 was modulated by both molecules. The impact on epithelial permeability (TEER) was also evaluated in a Transwell® model. In the context of a pro-inflammatory combination including gliadin, TEER values were recovered by neither sulforaphane nor glucoraphanin. Conversely, in the context of co-culture with activated macrophages (THP-1), sulforaphane inhibited the release of MCP-1 (IC50 = 20.60 µM) and IL-1β (IC50 = 1.50 µM) only, but both molecules restored epithelial integrity at 50 µM. Our work suggests that glucoraphanin should not merely be considered as just an inert precursor at the small intestine level, thus suggesting a potential interest in the framework of CD. Its biological activity might imply, at least in part, molecular mechanisms different from sulforaphane. [ABSTRACT FROM AUTHOR]

Protein hydrolysates as a feed supplement have been reported to enhance the growth of beneficial gut bacteria and improve the host's animal intestinal balance. Thus, this study evaluates the prebiotic effects of hydrolyzed squid by-products in black tiger shrimp, Penaeus monodon, diet. A 50-day feeding trial was conducted following a 4 × 2 factorial experiment in a completely randomized design. The juvenile P. monodon were fed plant-based diet (without fishmeal) supplemented with graded levels of 0, 0.5, 1.0, and 2.0% hydrolyzed squid by-products, either with or without Bacillus subtilis BF12. A control group fed a fish meal-based diet was also included. The shrimp growth, survival, nutrient retention, digestive enzyme activities, immune-related and gut pro-inflammatory gene expression, and intestine histomorphology were the evaluated biological responses. Feeding shrimp with plant-based diet containing 0.5% hydrolyzed squid by-products and B. subtilis BF12 supplement improved growth, enhanced feed conversion, improved nutrient retentions, upregulated the immune-related genes, and downregulated the gut pro-inflammatory genes. Enhanced digestive enzyme activities were observed in treatment groups with higher hydrolyzed squid by-product supplementation. Moreover, hydrolysate supplementation and probiotic application increased the shrimp's intestinal villi height and promoted the growth B. subtilis BF12 probiotics in the gut. Collectively, the present work suggests that hydrolyzed squid by-product protein supplementation at 0.5% and B. subtilis BF12 probiotics can promote growth, enhance the immunological responses, and improve the gut health of juvenile P. monodon fed a plant-based diet. [ABSTRACT FROM AUTHOR]

ABSTRACTThe mechanisms of how host-microbe mutualistic relationships are established at weaning contingently upon B-cell surveillance remain inadequately elucidated. We found that CD138+ plasmacyte (PC)-mediated promotion of IgA response regulates the symbiosis between Bacteroides uniformis (B. uniformis) and the host during the weaning period. The IgA-skewed response of CD138+ PCs is essential for B. uniformis to occupy a defined gut luminal niche, thereby fostering stable colonization. Furthermore, B. uniformis within the natural gut niche was perturbed in the absence of IgA, resulting in exacerbated gut inflammation in IgA-deficient mice and weaned piglets. Thus, we propose that the priming and maintenance of intestinal IgA response from CD138+ PCs are required for host-microbial symbiosis, whereas the perturbation of which would enhance inflammation in weaning process.

The editorial discusses the significant role of the infant gut microbiota in human health and disease. It highlights the impact of the gut microbiota on gastrointestinal, respiratory, allergic, and neurological disorders, emphasizing the importance of early colonization and its lasting effects on health. Factors such as prenatal influences, feeding methods, antibiotic use, and environmental factors can affect the infant's gut microbiota. The editorial suggests that further research is needed to understand the long-term health implications of gut microbiota colonization in infants and young children. [Extracted from the article]

Abstract Inflammatory bowel diseases (IBD) are a group of chronic inflammatory conditions of the gastrointestinal tract associated with multiple pathogenic factors, including dysregulation of the immune response. Effector CD4+ T cells and regulatory CD4+ T cells (Treg) are central players in maintaining the balance between tolerance and inflammation. Interestingly, genetic modifications in these cells have been implicated in regulating the commitment of specific phenotypes and immune functions. However, the transcriptional program controlling the pathogenic behavior of T helper cells in IBD progression is still unknown. In this study, we aimed to find master transcription regulators controlling the pathogenic behavior of effector CD4+ T cells upon gut inflammation. To achieve this goal, we used an animal model of IBD induced by the transfer of naïve CD4+ T cells into recombination-activating gene 1 (Rag1) deficient mice, which are devoid of lymphocytes. As a control, a group of Rag1 −/− mice received the transfer of the whole CD4+ T cells population, which includes both effector T cells and Treg. When gut inflammation progressed, we isolated CD4+ T cells from the colonic lamina propria and spleen tissue, and performed bulk RNA-seq. We identified differentially up- and down-regulated genes by comparing samples from both experimental groups. We found 532 differentially expressed genes (DEGs) in the colon and 30 DEGs in the spleen, mostly related to Th1 response, leukocyte migration, and response to cytokines in lamina propria T-cells. We integrated these data into Gene Regulatory Networks to identify Master Regulators, identifying four up-regulated master gene regulators (Lef1, Dnmt1, Mybl2, and Jup) and only one down-regulated master regulator (Foxo3). The altered expression of master regulators observed in the transcriptomic analysis was confirmed by qRT-PCR analysis and found an up-regulation of Lef1 and Mybl2, but without differences on Dnmt1, Jup, and Foxo3. These two master regulators have been involved in T cells function and cell cycle progression, respectively. We identified two master regulator genes associated with the pathogenic behavior of effector CD4+ T cells in an animal model of IBD. These findings provide two new potential molecular targets for treating IBD.

Chronic inflammation is epidemiologically linked to the pathogenesis of gastrointestinal diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, our understanding of the molecular mechanisms controlling gut inflammation remains insufficient, hindering the development of targeted therapies for IBD and CRC. In this study, we uncovered C15ORF48/miR-147 as a negative regulator of gut inflammation, operating through the modulation of epithelial cell metabolism. C15ORF48/miR-147 encodes two molecular products, C15ORF48 protein and miR-147-3p microRNA, which are predominantly expressed in the intestinal epithelium. C15ORF48/miR-147 ablation leads to gut dysbiosis and exacerbates chemically induced colitis in mice. C15ORF48 and miR-147-3p work together to suppress colonocyte metabolism and inflammation by silencing NDUFA4, a subunit of mitochondrial complex IV (CIV). Interestingly, the C15ORF48 protein, a structural paralog of NDUFA4, contains a unique C-terminal α-helical domain crucial for displacing NDUFA4 from CIV and its subsequent degradation. NDUFA4 silencing hinders NF-κB signaling activation and consequently attenuates inflammatory responses. Collectively, our findings have established the C15ORF48/miR-147-NDUFA4 molecular axis as an indispensable regulator of gut homeostasis, bridging mitochondrial metabolism and inflammation. [ABSTRACT FROM AUTHOR]

Background. The intestinal barrier is a crucial structure for maintaining the balance in permeability of digested food and restriction of microbial invasion from internal environment. Imbalance in these functions closely related to the initiation of intestinal epithelium reactivity and inflammation. Inflammation is the most common cause of intestinal dysfunction. Muramyl peptides (MPs) are small signaling molecules which stimulate intracellular receptors of pathogens and are potent regulators of cell response. However, molecular mechanisms of MP effect on intestinal cells remain unknown. The study of MP application to maintain viability of Caco-2 cells was aimed to explore the cytoprotective effect of MP-based probiotic on gut inflammation and intestinal barrier integrity. Materials and methods. Caco-2 cells were treated with 10–100 µg/ml lipopolysaccharide (LPS), 5–50 µg/ml MPs and combination of LPS + MPs. Cell viability was measured with MTT assay. Occludin content was detected with Western blotting. Enzyme-linked immunosorbent assay was applied to assess interleukin-8 (IL-8) production. Results. Obtained results have shown that LPS treatment with doses of 10–100 µg/ml induced in a decrease in cell viability and occludin content. On the contrary, IL-8 content was increased in LPS treatment that evidence the dose-dependent proinflammatory changes in Caco-2 cells. No significant changes were detected in the cells exposed to 5–50 µg/ml doses of MPs. However, application of 50 µg/ml of MPs inhibited IL-8 upregulation in LPS-exposed cells. Besides, MPs exhibited a dose-dependent cytoprotective effect in respect to cell viability at a dose of 20 and 50 µg/ml. Furthermore, MP dose of 50 µg/ml helped restore occludin content in LPS-exposed cells. Conclusions. Taking into the account that occludin is one of major components of tight junctions, MPs can restore epithelial barrier integrity in compromised gut. Observed results demonstrated that MPs is a promising agent in inflammation-induced intestinal injury and maintaining gut barrier function. [ABSTRACT FROM AUTHOR]

Crohn's disease is characterized by skip lesions with inflamed and adjacent non-inflamed mucosae in the small intestine and colon. Understanding the spatial organization of various regions within skip lesions can provide answers to their development and persistence. Alterations in the epithelium, lamina propria, and immune landscape have been noted in skip lesions. Host–microbiota interactions and intestinal barrier architecture are affected by inflammation, yet the measured changes are contradictory. Emerging techniques and technologies provide the foundation for uncovering spatial differences within skip lesions and applying the findings to improve candidate diagnostics, treatments, and identifying risk of recurrence. CD is characterized by enigmatic skip lesions, defined by discrete areas of inflammation demarcated from adjacent uninflamed regions. Their etiology and impact in CD might be solved by analyzing spatial analytic parameters in specific mucosal localities of inflamed and adjacent non-inflamed tissues, including microbial interactions, intestinal barrier, lamina propria, immune landscape, and mesenteric tissues. Recent technological advancements have increased our understanding of the spatial and functional changes within these lesions, including those involving host cells, mucus, and the microbiome, thus garnering a better understanding of mucosal tissue inflammation. Skip lesions are an enigmatic spatial feature characterizing Crohn's disease (CD). They comprise inflamed and adjacent non-inflamed tissue sections with a clear demarcation. Currently, spatial features of the human gastrointestinal (GI) system lack clarity regarding the organization of microbes, mucus, tissue, and host cells during inflammation. New technologies with multiplexing abilities and innovative approaches provide ways of examining the spatial organization of inflamed and non-inflamed tissues in CD, which may open new avenues for diagnosis, prognosis, and treatment. In this review, we present evidence of the relevance of spatial context in patients with CD and the methods and ideas recently published in studies of spatiality during inflammation. With this review, we aim to provide inspiration for further research to address existing gaps. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are tissue-resident immune cells distributed in all tissues and strategically located close to blood and lymphatic vessels and nerves. Thanks to the expression of a wide array of receptors, MCs act as tissue sentinels, able to detect the presence of bacteria and parasites and to respond to different environmental stimuli. MCs originate from bone marrow (BM) progenitors that enter the circulation and mature in peripheral organs under the influence of microenvironment factors, thus differentiating into heterogeneous tissue-specific subsets. Even though MC activation has been traditionally linked to IgE-mediated allergic reactions, a role for these cells in other pathological conditions including tumor progression has recently emerged. However, several aspects of MC biology remain to be clarified. The advent of single-cell RNA sequencing platforms has provided the opportunity to understand MCs' origin and differentiation as well as their phenotype and functions within different tissues, including the gut. This review recapitulates how single-cell transcriptomic studies provided insight into MC development as well as into the functional role of intestinal MC subsets in health and disease. [ABSTRACT FROM AUTHOR]

ABSTRACT Systemic inflammatory response syndrome (SIRS) is a severe inflammatory response that can lead to organ dysfunction and death. Modulating the gut microbiome is a promising therapeutic approach for managing SIRS. This study assesses the therapeutic potential of the Xuanfei Baidu (XFBD) formula in treating SIRS. The results showed that XFBD administration effectively reduced mortality rates and inflammation in SIRS mice. Using 16S rRNA sequencing and fecal microbiota transplantation (FMT), we substantiated that the therapeutic effects of XFBD are partly attributed to gut microbiota modulation. We conducted in vitro experiments to accurately assess the gut microbiome remodeling effects of 51 compounds isolated from XFBD. These compounds exhibited varying abilities to induce a microbial structure that closely resembles that of the healthy control group. By quantifying their impact on microbial structure and clustering their regulatory patterns, we devised multiple gut microbiome remodeling compound (GMRC) cocktails. GMRC cocktail C, comprising aucubin, gentiopicroside, syringic acid, gallic acid, p-hydroxybenzaldehyde, para-hydroxybenzoic acid, and isoimperatorin, demonstrated superior efficacy in treating SIRS compared to a single compound or to other cocktails. Finally, in vitro experiments showcased that GMRC cocktail C effectively rebalanced bacteria composition in SIRS patients. This study underscores XFBD’s therapeutic potential in SIRS and highlights the importance of innovative treatment approaches for this disease by targeting the gut microbiota.IMPORTANCEDeveloping effective treatment strategies for systemic inflammatory response syndrome (SIRS) is crucial due to its severe and often life-threatening nature. While traditional treatments like dexamethasone have shown efficacy, they also come with significant side effects and limitations. This study makes significant strides by demonstrating that the Xuanfei Baidu (XFBD) formula can substantially reduce mortality rates and inflammation in SIRS mice through effective modulation of the gut microbiota. By quantitatively assessing the impact of 51 compounds derived from XFBD on the gut microbiome, we developed a potent gut microbiome remodeling compound cocktail. This cocktail outperformed individual compounds and other mixtures in efficacy against SIRS. These findings highlight the potential of XFBD as a therapeutic solution for SIRS and underscore the critical role of innovative strategies targeting the gut microbiota in addressing this severe inflammatory condition.

Helicobacter pylori colonizes half of the world's population and is responsible for a significant disease burden by causing gastritis, peptic ulcers, and gastric cancer. The development of host inflammation drives these diseases, but there are still open questions in the field about how H. pylori controls this process. We characterized H. pylori inflammation using an 8-month mouse infection time course and comparison of the wild type (WT) and a previously identified mutant lacking the TlpA chemoreceptor that causes elevated inflammation. Our work shows that H. pylori chronic-stage corpus inflammation undergoes surprising fluctuations, with changes in Th17 and eosinophil numbers. The H. pylori tlpA mutant changed the inflammation temporal characteristics, resulting in different inflammation from the wild type at some time points. tlpA mutants have equivalent total and gland colonization in late-stage infections. During early infection, in contrast, they show elevated gland and total colonization compared to those by WT. Our results suggest the chronic inflammation setting is dynamic and may be influenced by colonization properties of early infection.

BackgroundCurrent assessment of dietary carbohydrates does not adequately reflect the nutritional properties and effects on gut microbial structure and function. Deeper characterization of food carbohydrate composition can serve to strengthen the link between diet and gastrointestinal health outcomes.ObjectivesThe present study aims to characterize the monosaccharide composition of diets in a healthy US adult cohort and use these features to assess the relationship between monosaccharide intake, diet quality, characteristics of the gut microbiota, and gastrointestinal inflammation.MethodsThis observational, cross-sectional study enrolled males and females across age (18-33 y, 34-49 y, and 50-65 y) and body mass index (normal, 18.5-24.99 kg/m2; overweight, 25-29.99 kg/m2; and obese, 30-44 kg/m2) categories. Recent dietary intake was assessed by the automated self-administered 24-h dietary recall system, and gut microbiota were assessed with shotgun metagenome sequencing. Dietary recalls were mapped to the Davis Food Glycopedia to estimate monosaccharide intake. Participants with >75% of carbohydrate intake mappable to the glycopedia were included (N = 180).ResultsDiversity of monosaccharide intake was positively associated with the total Healthy Eating Index score (Pearson's r = 0.520, P = 1.2 × 10-13) and negatively associated with fecal neopterin (Pearson's r = -0.247, P = 3.0 × 10-3). Comparing high with low intake of specific monosaccharides revealed differentially abundant taxa (Wald test, P < 0.05), which was associated with the functional capacity to break down these monomers (Wilcoxon rank-sum test, P < 0.05).ConclusionsMonosaccharide intake was associated with diet quality, gut microbial diversity, microbial metabolism, and gastrointestinal inflammation in healthy adults. As specific food sources were rich in particular monosaccharides, it may be possible in the future to tailor diets to fine-tune the gut microbiota and gastrointestinal function. This trial is registered at www.Clinicaltrialsgov as NCT02367287.

Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the gastrointestinal tract and profound alterations to the gut microbiome. Adherent-invasive Escherichia coli (AIEC) is a mucosa-associated pathobiont that colonizes the gut of patients with Crohn's disease, a form of IBD. Because AIEC exacerbates gut inflammation, strategies to reduce the AIEC bloom during colitis are highly desirable. To thrive in the inflamed gut, Enterobacteriaceae acquire the essential metal nutrient iron by producing and releasing siderophores. Here, we implemented an immunization-based strategy to target the siderophores enterobactin and its glucosylated derivative salmochelin to reduce the AIEC bloom in the inflamed gut. Using chemical (dextran sulfate sodium) and genetic (Il10-/- mice) IBD mouse models, we showed that immunization with enterobactin conjugated to the mucosal adjuvant cholera toxin subunit B potently elicited mucosal and serum antibodies against these siderophores. Siderophore-immunized mice exhibited lower AIEC gut colonization, diminished AIEC association with the gut mucosa, and reduced colitis severity. Moreover, Peyer's patches and the colonic lamina propria harbored enterobactin-specific B cells that could be identified by flow cytometry. The beneficial effect of siderophore immunization was primarily B cell-dependent because immunized muMT-/- mice, which lack mature B lymphocytes, were not protected during AIEC infection. Collectively, our study identified siderophores as a potential therapeutic target to reduce AIEC colonization and its association with the gut mucosa, which ultimately may reduce colitis exacerbation. Moreover, this work provides the foundation for developing monoclonal antibodies against siderophores, which could provide a narrow-spectrum strategy to target the AIEC bloom in Crohn's disease patients. IMPORTANCE Adherent-invasive Escherichia coli (AIEC) is abnormally prevalent in patients with ileal Crohn's disease and exacerbates intestinal inflammation, but treatment strategies that selectively target AIEC are unavailable. Iron is an essential micronutrient for most living organisms, and bacterial pathogens have evolved sophisticated strategies to capture iron from the host environment. AIEC produces siderophores, small, secreted molecules with a high affinity for iron. Here, we showed that immunization to elicit antibodies against siderophores promoted a reduction of the AIEC bloom, interfered with AIEC association with the mucosa, and mitigated colitis in experimental mouse models. We also established a flow cytometry-based approach to visualize and isolate siderophore-specific B cells, a prerequisite for engineering monoclonal antibodies against these molecules. Together, this work could lead to a more selective and antibiotic-sparing strategy to target AIEC in Crohn's disease patients.

ObjectiveTuft cells residing in the intestinal epithelium have diverse functions. In the small intestine, they provide protection against inflammation, combat against helminth and protist infections, and serve as entry portals for enteroviruses. In the colon, they had been implicated in tumourigenesis. Commitment of intestinal progenitor cells to the tuft cell lineage requires Rho GTPase Cell Division Cycle 42 (CDC42), a Rho GTPase that acts downstream of the epidermal growth factor receptor and wingless-related integration site signalling cascades, and the master transcription factor POU class 2 homeobox 3 (POU2F3). This study investigates how this pathway is regulated by the DEAD box containing RNA binding protein DDX5 in vivo.DesignWe assessed the role of DDX5 in tuft cell specification and function in control and epithelial cell-specific Ddx5 knockout mice (DDX5ΔIEC) using transcriptomic approaches.ResultsDDX5ΔIEC mice harboured a loss of intestinal tuft cell populations, modified microbial repertoire, and altered susceptibilities to ileal inflammation and colonic tumourigenesis. Mechanistically, DDX5 promotes CDC42 protein synthesis through a post-transcriptional mechanism to license tuft cell specification. Importantly, the DDX5-CDC42 axis is parallel but distinct from the known interleukin-13 circuit implicated in tuft cell hyperplasia, and both pathways augment Pou2f3 expression in secretory lineage progenitors. In mature tuft cells, DDX5 not only promotes integrin signalling and microbial responses, it also represses gene programmes involved in membrane transport and lipid metabolism.ConclusionRNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine.

The gut microbiota plays an important role in the disease progression of inflammatory bowel disease. Although probiotics are effective against IBD, not many studies have investigated their effects on gut microbiota composition and immunomodulation in mouse colitis models. Our study aimed at the therapeutic effects of Lacticaseibacillus paracasei BNCC345679 for the first time and explored its impact on gut microbiome dysbiosis, inflammatory cytokines, related miRNAs, VCAM-1, oxidative stress, intestinal integrity, and mucus barrier. We found that oral intervention of L. paracasei BNCC345679 affects recovering beneficial microbial taxa, including lactobacillus spp. and akkermansia spp., followed by improved body weight, DAI score, and inflammatory cytokines. L. paracasei BNCC345679 mitigated oxidative stress and increased the expression of intestinal integrity proteins MUC2 and ZO-1. These results suggested that L. paracasei BNCC345679 has the capacity to reduce DSS-induced colitis and has the potential as a supplement for the mitigation of IBD. [ABSTRACT FROM AUTHOR]

Foods prepared using microbial conversion of major and minor food components, which are otherwise known as fermented foods continue to impact human health. The live microorganisms and transformed metabolites can also have a deep influence on the gut microbiota, the multifaceted population of microorganisms dwelling inside the gut play a key role in wellbeing of an individual. The probiotic strains delivered through the consumption of fermented food and other bioactive components such as polyphenolic metabolites, bioactive peptides, short‐chain fatty acids and others including those produced via gut microbiota mediated transformations have been proposed to balance the gut microbiota diversity and activity, and also to regulate the inflammation in the gut. However, little is known about such effects and only a handful of fermented foods have been explored to date. We herein review the recent knowledge on the dysbiotic gut microbiota linking to major gut inflammatory diseases. Also, evidences that fermented food consumption modulates the gut microbiota, and its impact on the gut inflammation and inflammatory diseases have been discussed. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Abstract Background Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma. Methods Sox10 iCreERT2 /Rpl22 HA/+ mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH+ sympathetic neurons and glial-restricted Sox10 iCreERT2 /JellyOP fl/+ /Rpl22 HA/+ mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI. Results With ~ 4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glial reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic–driven enteric glial reactivity. Conclusions Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development.

BackgroundIntestinal inflammation disrupts the microbiota composition leading to an expansion of Enterobacteriaceae family members (dysbiosis). Associated with this shift in microbiota composition is a profound change in the metabolic landscape of the intestine. It is unclear how changes in metabolite availability during gut inflammation impact microbial and host physiology.ResultsWe investigated microbial and host lactate metabolism in murine models of infectious and non-infectious colitis. During inflammation-associated dysbiosis, lactate levels in the gut lumen increased. The disease-associated spike in lactate availability was significantly reduced in mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells. Commensal E. coli and pathogenic Salmonella, representative Enterobacteriaceae family members, utilized lactate via the respiratory L-lactate dehydrogenase LldD to increase fitness. Furthermore, mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells exhibited lower levels of inflammation in a model of non-infectious colitis.ConclusionsThe release of lactate by intestinal epithelial cells during gut inflammation impacts the metabolism of gut-associated microbial communities. These findings suggest that during intestinal inflammation and dysbiosis, changes in metabolite availability can perpetuate colitis-associated disturbances of microbiota composition. Video Abstract.

The gut microbiota plays an important role in the disease progression of inflammatory bowel disease. Although probiotics are effective against IBD, not many studies have investigated their effects on gut microbiota composition and immunomodulation in mouse colitis models. Our study aimed at the therapeutic effects of Lacticaseibacillus paracasei BNCC345679 for the first time and explored its impact on gut microbiome dysbiosis, inflammatory cytokines, related miRNAs, VCAM-1, oxidative stress, intestinal integrity, and mucus barrier. We found that oral intervention of L. paracasei BNCC345679 affects recovering beneficial microbial taxa, including lactobacillus spp. and akkermansia spp., followed by improved body weight, DAI score, and inflammatory cytokines. L. paracasei BNCC345679 mitigated oxidative stress and increased the expression of intestinal integrity proteins MUC2 and ZO-1. These results suggested that L. paracasei BNCC345679 has the capacity to reduce DSS-induced colitis and has the potential as a supplement for the mitigation of IBD.

Characterization of the interleukin (IL)‐10 knockout (KO) mouse with chronic gut inflammation, cardiovascular dysfunction, and bone loss suggests a critical role for this cytokine in interorgan communication within the gut, bone, and cardiovascular axis. We sought to understand the role of IL‐10 in the cross‐talk between these systems. Six‐week‐old IL‐10 KO mice and their wild type (WT) counterparts were maintained on a standard rodent diet for 3 or 6 months. Gene expression of proinflammatory markers and Fgf23, serum 17β‐estradiol (E2), and cardiac protein expression were assessed. Ileal Il17a and Tnf mRNA increased while Il6 mRNA increased in the bone and heart by at least 2‐fold in IL‐10 KO mice. Bone Dmp1 and Phex mRNA were repressed at 6 months in IL‐10 KO mice, resulting in increased Fgf23 mRNA (~4‐fold) that contributed to increased fibrosis. In the IL‐10 KO mice, gut bacterial β‐glucuronidase activity and ovarian Cyp19a1 mRNA were lower (p < 0.05), consistent with reduced serum E2 and reduced cardiac pNOS3 (Ser1119) in these mice. Treatment of ileal lymphocytes with E2 reduced gut inflammation in WT but not IL‐10 KO mice. In conclusion, our data suggest that diminished estrogen and defective bone mineralization increased FGF23 which contributed to cardiac fibrosis in the IL‐10 KO mouse. [ABSTRACT FROM AUTHOR]

Obesity has become a worldwide concern because of its rapidly increasing prevalence, which affects not only individuals but also society. Recently, the gut microbiota has been reported as a new path to obesity treatment. Probiotics have become the most recognized method to improve the gut microbiota and treat dysbiosis. This study was conducted to review the effect of oral probiotics on body mass index and gut inflammation in individuals with obesity. Systematic literature research was conducted in PubMed, Scopus, and ScienceDirect databases up to June 23, 2023, to identify eligible articles. The "Advanced Search" option and "All fields" were selected for the following search terms: "obese" AND "probiotic" AND "gut inflammation". The research from the databases resulted in 136 literature sources, from which only 3 literature sources were included in this review. From the included literature, it was found that the supplementation of oral probiotics in adults, adolescents, and children had no significant effect on the BMI level. The gut inflammation biomarkers also showed a lack of significant change after probiotic consumption compared to the placebo group. Further studies are needed to review the effectiveness of the strain used in the probiotic, the difference in the exact dosage, the duration of intervention, and the side effects of oral probiotic consumption for overweight and obesity. [ABSTRACT FROM AUTHOR]

Background: Alterations in resting state functional connectivity (rs-FC) in Crohn's Disease (CD) have been documented in default mode network (DMN) and frontal parietal network (FPN) areas, visual, cerebellar, salience and attention restingstate-networks (RSNs), constituting a CD specific neural phenotype. To date, most studies are in patients in remission, with limited studies in active disease. Methods: Twenty five active CD cases and 25 age-, BMI- and gender-matched healthy controls (HC) were recruited to a resting-state-functional Magnetic Resonance Imaging (rs-fMRI) study. Active disease was defined as C-reactive protein>5 mg/dL, faecal calprotectin>250 µg/g, or through ileocolonoscopy or MRE. rs-fMRI data were analysed using independent component analysis (ICA) and dual regression. Differences in RSNs between HCs and active CD were assessed, and rs-FC was associated with disease duration and abdominal pain. Results: Increased connectivity in the FPN (fusiform gyrus, thalamus, caudate, posterior cingulate cortex, postcentral gyrus) and visual RSN (orbital frontal cortex) were observed in CD versus HC. Decreased activity was observed in the salience network (cerebellum, postcentral gyrus), DMN (parahippocampal gyrus, cerebellum), and cerebellar network (occipital fusiform gyrus, cerebellum) in CD versus HCs. Greater abdominal pain scores were associated with lower connectivity in the precuneus (visual network) and parietal operculum (salience network), and higher connectivity in the cerebellum (frontal network). Greater disease duration was associated with greater connectivity in the middle temporal gyrus and planum temporale (visual network). Conclusion: Alterations in rs-FC in active CD in RSNs implicated in cognition, attention, emotion, and pain may represent neural correlates of chronic systemic inflammation, abdominal pain, disease duration, and severity. [ABSTRACT FROM AUTHOR]

Introduction: The gastrointestinal and immune systems of premature infants are not fully developed, rendering them more vulnerable to severe complications like necrotizing enterocolitis. Human milk offers a rich array of bioactive factors that collectively contribute to reducing the incidence of gut infections and inflammatory conditions. When a mother's milk is unavailable, preterm infants are often provided with donor human milk processed in Human Milk Banks. However, it remains uncertain whether pasteurized milk confers the same level of risk reduction as unprocessed milk. This uncertainty may stem from the well-documented adverse effects of heat treatment on milk composition. Yet, our understanding of the comprehensive impact on protective mechanisms is limited. Methods: In this study, we conducted a comparative analysis of the effects of raw versus pasteurized milk and colostrum versus mature milk on cellular functions associated with the gut epithelial barrier and responses to inflammatory stimuli. We utilized THP-1 and HT-29 cell lines, representing monocyte/macrophages and gut epithelial cells, respectively. Results: Our observations revealed that all milk types stimulated epithelial cell proliferation. However, only raw colostrum increased cell migration and interfered with the interaction between E. coli and epithelial cells. Furthermore, the response of epithelial and macrophage cells to lipopolysaccharide (LPS) was enhanced solely by raw colostrum, with a milder effect observed with mature milk. In contrast, both raw and pasteurized milk diminished the LPS induced response in monocytes. Lastly, we examined how milk affected the differentiation of monocytes into macrophages, finding that milk reduced the subsequent inflammatory response of macrophages to LPS. Discussion: Our study sheds light on the impact of human milk on certain mechanisms that potentially account for its protective effects against necrotizing enterocolitis, highlighting the detrimental influence of pasteurization on some of these mechanisms. Our findings emphasize the urgency of developing alternative pasteurization methods to better preserve milk properties. Moreover, identifying the key components critically affected by these protective mechanisms could enable their inclusion in donor milk or formula, thereby enhancing immunological benefits for vulnerable newborns. [ABSTRACT FROM AUTHOR]

Background: Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma. Methods: Sox10iCreERT2/Rpl22HA/+ mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH+ sympathetic neurons and glial-restricted Sox10iCreERT2/JellyOPfl/+/Rpl22HA/+ mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI. Results: With ~ 4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glial reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic–driven enteric glial reactivity. Conclusions: Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development. [ABSTRACT FROM AUTHOR]

Probiotic bacteria belonging to Lactobacillus spp. are important producers of bioactive molecules, known as postbiotics, that play essential roles in the immunological support of the intestinal mucosa. In this study, the system of co-culture of intestinal epithelial cells with macrophage cells in vitro was used to study the potential effect of postbiotic fractions of L. rhamonosus and L. plantarum on the modulation of the immune response induced by pro-inflammatory stimuli. This study's results revealed that the presence of probiotic bacterial components on the mucosal surface in the early and late stage of inflammatory conditions is based on cellular interactions that control inflammation and consequent damage to the intestinal epithelium. In our studies, heat killed fractions of probiotic bacteria and their extracted proteins showed a beneficial effect on controlling inflammation, regardless of the strain tested, consequently protecting intestinal barrier damage. In conclusion, the presented results emphasize that the fractions of probiotic bacteria of L. plantarum and L. rhamnosus may play a significant role in the regulation of LPS-mediated cytotoxic activity in intestinal epithelial cells. The fractions of probiotic strains of L. rhamnosus and L. plantarum showed the potential to suppress inflammation, effectively activating the anti-inflammatory cytokine IL-10 and modulating the IL-18-related response. [ABSTRACT FROM AUTHOR]

Abstract Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a classical exogenous synthetic ligand of AHR that has significant immunotoxic effects. Activation of AHR has beneficial effects on intestinal immune responses, but inactivation or overactivation of AHR can lead to intestinal immune dysregulation and even intestinal diseases. Sustained potent activation of AHR by TCDD results in impairment of the intestinal epithelial barrier. However, currently, AHR research has been more focused on elucidating physiologic AHR function than on dioxin toxicity. The appropriate level of AHR activation plays a role in maintaining gut health and protecting against intestinal inflammation. Therefore, AHR offers a crucial target to modulate intestinal immunity and inflammation. Herein, we summarize our current understanding of the relationship between AHR and intestinal immunity, the ways in which AHR affects intestinal immunity and inflammation, the effects of AHR activity on intestinal immunity and inflammation, and the effect of dietary habits on intestinal health through AHR. Finally, we discuss the therapeutic role of AHR in maintaining gut homeostasis and relieving inflammation. Graphical Abstract

5-Aminosalicylic acid (5-ASA), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is a widely used first-line medication for the treatment of ulcerative colitis, but its anti-inflammatory mechanism is not fully resolved. Here, we show that 5-ASA ameliorates colitis in dextran sulfate sodium (DSS)-treated mice by activating PPAR-γ signaling in the intestinal epithelium. DSS-induced colitis was associated with a loss of epithelial hypoxia and a respiration-dependent luminal expansion of Escherichia coli, which could be ameliorated by treatment with 5-ASA. However, 5-ASA was no longer able to reduce inflammation, restore epithelial hypoxia, or blunt an expansion of E. coli in DSS-treated mice that lacked Pparg expression specifically in the intestinal epithelium. These data suggest that the anti-inflammatory activity of 5-ASA requires activation of epithelial PPAR-γ signaling, thus pointing to the intestinal epithelium as a potential target for therapeutic intervention in ulcerative colitis.IMPORTANCE An expansion of Enterobacterales in the fecal microbiota is a microbial signature of dysbiosis that is linked to many noncommunicable diseases, including ulcerative colitis. Here, we used Escherichia coli, a representative of the Enterobacterales, to show that its dysbiotic expansion during colitis can be remediated by modulating host epithelial metabolism. Dextran sulfate sodium (DSS)-induced colitis reduced mitochondrial activity in the colonic epithelium, thereby increasing the amount of oxygen available to fuel an E. coli expansion through aerobic respiration. Activation of epithelial peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling with 5-aminosalicylic acid (5-ASA) was sufficient to restore mitochondrial activity and blunt a dysbiotic E. coli expansion. These data identify the host's epithelial metabolism as a potential treatment target to remediate microbial signatures of dysbiosis, such as a dysbiotic E. coli expansion in the fecal microbiota.

BackgroundAlterations in resting state functional connectivity (rs-FC) in Crohn’s Disease (CD) have been documented in default mode network (DMN) and frontal parietal network (FPN) areas, visual, cerebellar, salience and attention resting-state-networks (RSNs), constituting a CD specific neural phenotype. To date, most studies are in patients in remission, with limited studies in active disease.MethodsTwenty five active CD cases and 25 age-, BMI- and gender-matched healthy controls (HC) were recruited to a resting-state-functional Magnetic Resonance Imaging (rs-fMRI) study. Active disease was defined as C-reactive protein>5 mg/dL, faecal calprotectin>250 μg/g, or through ileocolonoscopy or MRE. rs-fMRI data were analysed using independent component analysis (ICA) and dual regression. Differences in RSNs between HCs and active CD were assessed, and rs-FC was associated with disease duration and abdominal pain.ResultsIncreased connectivity in the FPN (fusiform gyrus, thalamus, caudate, posterior cingulate cortex, postcentral gyrus) and visual RSN (orbital frontal cortex) were observed in CD versus HC. Decreased activity was observed in the salience network (cerebellum, postcentral gyrus), DMN (parahippocampal gyrus, cerebellum), and cerebellar network (occipital fusiform gyrus, cerebellum) in CD versus HCs. Greater abdominal pain scores were associated with lower connectivity in the precuneus (visual network) and parietal operculum (salience network), and higher connectivity in the cerebellum (frontal network). Greater disease duration was associated with greater connectivity in the middle temporal gyrus and planum temporale (visual network).ConclusionAlterations in rs-FC in active CD in RSNs implicated in cognition, attention, emotion, and pain may represent neural correlates of chronic systemic inflammation, abdominal pain, disease duration, and severity.

IntroductionThe gastrointestinal and immune systems of premature infants are not fully developed, rendering them more vulnerable to severe complications like necrotizing enterocolitis. Human milk offers a rich array of bioactive factors that collectively contribute to reducing the incidence of gut infections and inflammatory conditions. When a mother's milk is unavailable, preterm infants are often provided with donor human milk processed in Human Milk Banks. However, it remains uncertain whether pasteurized milk confers the same level of risk reduction as unprocessed milk. This uncertainty may stem from the well-documented adverse effects of heat treatment on milk composition. Yet, our understanding of the comprehensive impact on protective mechanisms is limited.MethodsIn this study, we conducted a comparative analysis of the effects of raw versus pasteurized milk and colostrum versus mature milk on cellular functions associated with the gut epithelial barrier and responses to inflammatory stimuli. We utilized THP-1 and HT-29 cell lines, representing monocyte/macrophages and gut epithelial cells, respectively.ResultsOur observations revealed that all milk types stimulated epithelial cell proliferation. However, only raw colostrum increased cell migration and interfered with the interaction between E. coli and epithelial cells. Furthermore, the response of epithelial and macrophage cells to lipopolysaccharide (LPS) was enhanced solely by raw colostrum, with a milder effect observed with mature milk. In contrast, both raw and pasteurized milk diminished the LPS induced response in monocytes. Lastly, we examined how milk affected the differentiation of monocytes into macrophages, finding that milk reduced the subsequent inflammatory response of macrophages to LPS.DiscussionOur study sheds light on the impact of human milk on certain mechanisms that potentially account for its protective effects against necrotizing enterocolitis, highlighting the detrimental influence of pasteurization on some of these mechanisms. Our findings emphasize the urgency of developing alternative pasteurization methods to better preserve milk properties. Moreover, identifying the key components critically affected by these protective mechanisms could enable their inclusion in donor milk or formula, thereby enhancing immunological benefits for vulnerable newborns.

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.

Background & aimsHow benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH-HCC progression, as well as regression.MethodsHyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development.ResultsFoz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment.ConclusionsThe Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH-associated HCC, chronic kidney injury, and heart failure.