Gut bacteria play key roles in intestinal physiology, via the secretion of diversified bacterial effectors. Many of these effectors remodel the host proteome, either by altering transcription or by regulating protein post-translational modifications. SUMOylation, a ubiquitin-like post-translational modification playing key roles in intestinal physiology, is a target of gut bacteria. Mutualistic gut bacteria can promote SUMOylation, via the production of short- or branched-chain fatty acids (SCFA/BCFA). In contrast, several pathogenic bacteria were shown to dampen SUMOylation in order to promote infection. Here, we demonstrate that Staphylococcus warneri, a natural member of the human gut microbiota, decreases SUMOylation in intestinal cells. We identify that Warnericin RK, a hemolytic toxin secreted by S. warneri, targets key components of the host SUMOylation machinery, leading to the loss of SUMO-conjugated proteins. We further demonstrate that Warnericin RK promotes inflammation in intestinal and immune cells using both SUMO-dependent and SUMO-independent mechanisms. We finally show that Warnericin RK regulates the expression of genes involved in intestinal tight junctions. Together, these results highlight the diversity of mechanisms used by bacteria from the gut microbiota to manipulate host SUMOylation. They further highlight that changes in gut microbiota composition may impact intestinal inflammation, by altering the equilibrium between bacterial effectors promoting or dampening SUMOylation.

Tongfu Xiexia Decoction (TFXXD), a traditional Chinese medicine formula, comprises six herbs: semen raphani, Rehmannia glutinosa, rhubarb, Magnolia officinalis, trifoliate orange, and mirabilite. The aim of this study was to investigate the effects of TFXXD on its biotransformation and microbial abundance in the gut of constipated rats.

Ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) was used to analyze the biotransformation of TFXXD in the colonic contents, and 16S rRNA sequencing was used to assess the structure and diversity of the gut microbiota across various rat groups.

We identified and analyzed 25 biotransformations of TFXXD in the colonic contents, which undergo various reactions such as deglycosylation, ring opening, and hydration in intestinal bacteria, with 14 originating from trifoliate orange, six from rhubarb, three from Rehmannia glutinosa, one from Semen raphani, and one from M. officinalis. 16S rRNA analysis revealed that TFXXD significantly enhanced the relative abundance of beneficial bacteria, such as Lactobacillus and Bacteroides while significantly reducing Oscillospira abundance. Moreover, TFXXD considerably affected the carbohydrate and amino acid metabolism. Correlation analyses revealed a significant negative correlation between Bacteroides and ACH (Acetylcholine), NO (nitric oxide), D-Lac (D-Lactate), IL-6 (Interleukin-6), TNF-α (tumor necrosis factor-α), and IL-1β (Interleukin-1β) and a significant positive correlation between Bacteroides, hesperetin, and rhein.

In conclusion, our findings indicate that TFXXD can modulate the structure and diversity of the gut microbiota and enhance the metabolic balance in constipated rats.

This review and commentary outline the strong rationale for normalizing the abnormal microbiota of patients with ulcerative colitis, Crohn's disease, and pouchitis and focus on strategies to improve current variable outcomes of fecal microbial transplant (FMT) in ulcerative colitis. Applying lessons from successful FMT therapy of recurrent Clostridioides difficile and insights from basic scientific understanding of host/microbial interactions provide strategies to enhance clinical outcomes in IBD. We outline promising approaches to develop novel-defined consortia of live biotherapeutic products and combination treatments to improve current results and to optimize and personalize treatment approaches in individual patients and disease subsets.

The intestinal barrier is a critical defense against external pathogens and plays a central role in immune regulation and nutrient absorption. Oxidative stress and chronic inflammation in high-altitude environments can exacerbate the damage to the intestinal barrier in Baimei ternary pigs. Anthocyanin extract of Lycium ruthenicum Murray (AEL), has garnered widespread attention due to its rich anthocyanin flavonoid content, which exhibits antioxidant and anti-inflammatory properties. These properties help alleviate inflammation and oxidative stress, thereby enhancing gut function in animals. Based on this, the study employed Bamei ternary pigs and supplemented their basic diet with varying concentrations of AEL to investigate its impact on gut barrier function. The results demonstrated that AEL inhibited key factors of the intestinal Toll-like receptor pathway, including Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated protein 6 (TRAF6), and nuclear factor kappa B (NF-κB), affecting gene transcription and protein expression levels. This led to a reduction in pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), an increase in anti-inflammatory IL-10 production, and improved antioxidant capacity by enhancing total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity, while decreasing malondialdehyde (MDA) production. Additionally, AEL improved intestinal morphology and facilitated the transcription and expression of tight junction proteins, including zonula occludens-1 (ZO-1), claudin-1 (CLDN-1), and occludin (OCLN). AEL also elevated the transcription levels of mucin 1 (MUC1) and mucin 2 (MUC2), as well as the secretion levels of polymeric immunoglobulin receptor (pIgR) and secretory immunoglobulin A (SIgA), while increased the number of intestinal goblet cells. Furthermore, dietary supplementation with AEL altered the structure of the intestinal microbiota, enhancing the abundance of beneficial bacterial genera such as Verrucomicrobiaceae, Rikenellaceae, Butyricicoccaceae, UCG-005、Rikenellaceae_RC9_gut_group、norank_f_Ruminococcaceae、Eubacterium_oxidoreducens_group, thereby promoting the production of intestinal short-chain fatty acids (SCFAs). In conclusion, AEL inhibits the Toll-like receptor pathway, reduces the production of inflammatory factors, enhances antioxidant levels, improves intestinal morphology and microbiota structure,, thereby reinforcing intestinal barrier function.

Mucosal microbial communities (MMCs) are complex ecosystems near the mucosal layers of the gut essential for maintaining health and modulating disease states. Despite advances in high-throughput omics technologies, current methodologies struggle to capture the dynamic metabolic interactions and spatiotemporal variations within MMCs. In this work, we present MetaBiome, a multiscale model integrating agent-based modeling (ABM), finite volume methods, and constraint-based models to explore the metabolic interactions within these communities. Integrating ABM allows for the detailed representation of individual microbial agents each governed by rules that dictate cell growth, division, and interactions with their surroundings. Through a layered approach-encompassing microenvironmental conditions, agent information, and metabolic pathways-we simulated different communities to showcase the potential of the model. Using our in-silico platform, we explored the dynamics and spatiotemporal patterns of MMCs in the proximal small intestine and the cecum, simulating the physiological conditions of the two gut regions. Our findings revealed how specific microbes adapt their metabolic processes based on substrate availability and local environmental conditions, shedding light on spatial metabolite regulation and informing targeted therapies for localized gut diseases. MetaBiome provides a detailed representation of microbial agents and their interactions, surpassing the limitations of traditional grid-based systems. This work marks a significant advancement in microbial ecology, as it offers new insights into predicting and analyzing microbial communities.IMPORTANCEOur study presents a novel multiscale model that combines agent-based modeling, finite volume methods, and genome-scale metabolic models to simulate the complex dynamics of mucosal microbial communities in the gut. This integrated approach allows us to capture spatial and temporal variations in microbial interactions and metabolism that are difficult to study experimentally. Key findings from our model include the following: (i) prediction of metabolic cross-feeding and spatial organization in multi-species communities, (ii) insights into how oxygen gradients and nutrient availability shape community composition in different gut regions, and (iii) identification of spatiallyregulated metabolic pathways and enzymes in E. coli. We believe this work represents a significant advance in computational modeling of microbial communities and provides new insights into the spatial regulation of gut microbiome metabolism. The multiscale modeling approach we have developed could be broadly applicable for studying other complex microbial ecosystems.

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves fat buildup in the liver and is connected to a disruption in gut microbiota and a reduction in beneficial microbiota. Lactobacillus is an important probiotic that can grow in anaerobic or low-oxygen environment and is widely used in food industry and health fields. In recent years, the improvement of MASLD by Lactobacillus has been extensively studied. However, the detailed mechanisms by which different species of Lactobacillus improve MASLD have not been summarized. In this review, we present the potential of Lactobacillus as a non-drug approach to mitigate MASLD. We will discuss the preclinical and clinical research backing this method and the ways these probiotics improve MASLD. This review mainly presents the different species of Lactobacillus that improve MASLD, and various mechanisms by which Lactobacillus strains alleviate MASLD, including improving intestinal permeability and inflammation, reducing oxidative stress, and restoring of gut metabolites. Future research into mechanisms and larger clinical trials will help confirm the effectiveness of using Lactobacillus and related genera in the treatment of MASLD.

The immature gastrointestinal development of infants and young animals made them more vulnerable to stress-related damage, which affected the gut-liver axis and consequently impaired their health and growth. This study used weaned piglets as a model to investigate how dietary sesamin regulated the gut-liver axis and impacted young animal health. We assessed gut-liver tissue morphology, measured key indicators of intestinal barrier damage, mucosal repair, antioxidant and immune pathways in the gut-liver system and serum, and analyzed microbial composition. We further explored the interactions between sesamin and the gut-liver axis through PLS-PM and molecular docking analysis. Results showed that sesamin enhanced intestinal barrier function, reduced liver damage, decreased oxidative stress, promoted anti-inflammatory immune responses, and enriched beneficial microbes, thereby promoting overall growth. Sesamin can enhance the health of young animals by regulating the function of the gut-liver axis.

This pilot study investigated the effects of a reduced sulfur (RS) diet on the gut microbiome composition and fecal metabolome in individuals with remitted or active ulcerative colitis (UC). Thirteen participants maintained their habitual diet (control), while nine followed an RS diet for eight weeks (Wk8). Stool and plasma samples were collected at the baseline and Wk8. The sulfur intake decreased in the RS group (-28 g/1000 kcal) versus the control group (-1.7 g/1000 kcal; p < 0.001). The RS group exhibited a significant decrease in lipopolysaccharide-binding protein (-5280 ng/mL), while these levels increased in the control group (620 ng/mL; p < 0.05). The microbiome analysis showed an increased alpha diversity at Wk8 (p < 0.01), suggesting a microbial shift with a RS intake. The metabolic alterations indicated enhanced nitrogen disposal (increased uric acid, methyluric acid, N-acetyl-L-glutamate) and a higher energy demand (elevated ubiquinol and glucose-pyruvate). The RS diet increased beneficial microbes Collinsella stercoris, Asaccharobacter celatus, and Alistipes finegoldii, while decreasing pathobionts Eggerthella lenta and Romboutsia ilealis. Methyluric acid correlated positively with C. stercoris (β = 0.70) and negatively with E. lenta (β = -0.77) suggesting these microbes utilized this metabolite and influenced the microbiome composition. In conclusion, a RS diet promoted microbial diversity, metabolic adaptations, and reduced inflammation, highlighting its potential as a novel strategy for UC management.

Red wine grape pomace (RWGP), a winemaking by-product rich in phenolics, flavonoids, and dietary fiber, has shown promise in mitigating cardiovascular disease (CVD), however, its mechanisms of action remain incompletely understood. This study comprehensively profiled the phenolic composition of RWGP-including free, esterified, etherified, and insoluble-bound fractions-and evaluated the effects of RWGP dietary supplementation on gut barrier integrity, inflammation, oxidative stress, and survival in SR-B1-/-ApoE-R61h/h mice, a model of diet-induced lethal ischemic heart disease. RWGP supplementation significantly improved survival rates and restored gut barrier function, as evidenced by lower plasma FITC-dextran and LPS levels, increased circulating ZO-1 levels, and reduced histopathological colon damage. In addition, RWGP reduced pro-inflammatory cytokines (IL-1β) and showed a trend toward attenuating systemic oxidative stress (TBARS). Analysis of phenolic compounds indicated a significant presence of insoluble-bound phenolics. Nevertheless, the beneficial effects observed are likely attributable to the synergistic actions of RWGP's complex phytochemical and fiber composition. These results highlight RWGP's potential as a sustainable, gut-targeted functional food ingredient for CVD prevention and management.

Pesticides can modulate gut microbiota composition, but their specific effects on it remain largely elusive. In our study, we show that pesticides inhibit or promote the growth of various gut microbial species and can be accumulated to prolong their presence in the host. Pesticide exposure also induces significant alterations in gut bacterial metabolism, as reflected by changes in hundreds of metabolites. We generate a pesticide-gut microbiota-metabolite network that not only reveals pesticide-sensitive gut bacteria species but also reports specific metabolic changes in 306 pesticide-gut microbiota pairs. Using an in vivo mouse model, we further demonstrate the interactions of a representative pesticide-gut microbiota pair and verify the inflammation-inducing effects of pesticide exposure on the host, mediated by microbially dysregulated lipid metabolism. Taken together, our findings generate a comprehensive atlas of pesticide-gut microbiota-metabolite interactions atlas and shed light on the molecular mechanisms by which pesticides affect host health via gut microbiota-modulated metabolism.

Dogs are cherished companions, and in today's world, pets are increasingly regarded as family members. Pet owners are placing growing emphasis on their animals' health, particularly for dogs. Probiotics, which are living bacteria that benefit the host when given in sufficient quantities, have drawn a lot of interest in the veterinary nutrition community due to their beneficial effects on companion animals, including dogs. This study emphasizes the advantages of adding probiotics to canine diets in order to enhance the health of the gut flora and the technologies used to incorporate probiotics into canine feed. It looks at the best ways to deal with common dog health problems, highlighting probiotics as a helpful substitute for antibiotics, which can have serious adverse effects, encourage bacterial resistance, and disturb the gut's microbial ecology, which is necessary for digesting. Such disruptions are linked to chronic inflammatory enteropathy and obesity in dogs. This paper also examines biotechnological advancements in probiotic incorporation methods in dog feed, aiming to optimize their health benefits. Probiotic feed supplements may thus represent a promising approach to advancing canine health care, providing a natural adjunct to conventional treatments and preventive measures.

Depression, a major global health issue, is closely associated with imbalances in gut microbiota and altered intestinal functions. This study investigates the antidepressant potential of a composite of Geniposide (GP) and Nanocrystalline Cellulose (NCC), focusing on its effects on the gut-brain axis. Utilizing network pharmacology, GP was identified as a key compound targeting the BCL2 gene in depression management. Experimental approaches, including a chronic unpredictable mild stress (CUMS) model in mice, cellular assays, and fecal microbiota transplantation (FMT), were used to evaluate the composite's effectiveness. Results indicate that GP activates the adenosine monophosphate-activated protein kinase (AMPK) pathway by upregulating BCL2, enhancing intestinal barrier integrity, and balancing gut flora. These mechanisms contribute to its positive effects on hippocampal function and depressive-like behaviors in mice, suggesting that the GP-NCC composite could be a promising avenue for developing depression therapies that target gut health.

Graves' disease (GD) is a common autoimmune thyroid disease with limited treatment efficacy, high relapse rates, and severe adverse effects. Gut microbiota dysbiosis is thought to play a critical role in GD, with the potential for microbiota-based therapies in GD treatment. However, experimental evidence is needed to validate this hypothesis. In this study, we evaluated the therapeutic effects of the commensal bacterium B. fragilis and its metabolite, propionate, in a GD mouse model. We found that oral supplementation with B. fragilis or propionate significantly reduced serum levels of inflammatory cytokines, total thyroxine (TT4), and TSH receptor antibodies (TRAb). It also decreased the proportion of circulating Th17 cells while increasing the proportion of circulating regulatory T cells (Tregs), thus mitigating systemic inflammation, hyperthyroidism, and the autoimmune response against TSHR. In addition, B. fragilis and propionate significantly decreased the levels of inflammatory cytokines and the proportion of M1 macrophages in thyroid tissue, while increasing the proportions of Treg cells and M2 macrophages, thereby reducing thyroid inflammation and size. Notably, the combination of B. fragilis or propionate with methimazole (MMI) significantly ameliorated pathological changes in GD mice and markedly reduced MMI dosage requirements, demonstrating a synergistic therapeutic effect. Our findings suggest that B. fragilis and propionate could serve as effective adjuvant agents in combination with MMI, thereby enhancing therapeutic efficacy while reducing drug dosage and minimizing side effects. This study opens a new avenue for microbiota-based treatments in managing GD.IMPORTANCEThis study explores a new approach to treat Graves' disease (GD), a major type of hyperthyroidism. Traditional treatments for GD often come with significant side effects and high relapse rates. Researchers found that Bacteroides fragilis, a gut commensal bacterium, and its metabolite propionate can improve the condition of GD mice. When combined with methimazole, a conventional medication for GD treatment, these natural agents demonstrated enhanced therapeutic efficacy, enabling dose reduction of methimazole and consequently reducing adverse effects. This research suggests that combining gut microbiota-based treatments with standard therapies may offer a more effective and safer way to manage GD.

Systemic hypertension is a major risk factor for cardiovascular disease and remains challenging to manage despite the widespread use of antihypertensive medications and lifestyle modifications. This review explores the role of gut microbiota in hypertension development and regulation, highlighting key mechanisms such as inflammation, gut-brain axis modulation, and bioactive metabolite production. We also assess the potential of microbiota-targeted therapies for hypertension management.

Emerging evidence indicates that microbial dysbiosis, high-salt diets, and gut-derived metabolites such as short-chain fatty acids (SCFAs) and bile acids significantly influence blood pressure regulation. Preclinical and early clinical studies suggest that interventions targeting gut microbiota, including probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), and dietary modifications, may help modulate hypertension. However, variability in gut microbiota composition among individuals and limited human trial data pose challenges to translating these findings into clinical practice. While microbiota-based therapies show promise for hypertension management, further research is needed to establish their efficacy and long-term effects. Large-scale, standardized clinical trials are crucial for understanding the therapeutic potential and limitations of gut microbiota interventions. A deeper understanding of the gut-hypertension axis could lead to novel, personalized treatment strategies for hypertension.

In the present study, we comprehensively investigated the impacts of the infusion of three short-chain fatty acids (SCFAs), sodium acetate (SA), propionate (SP), and butyrate (SB), to examine their respective roles in the gastrointestinal tract (GIT) health and innate immunity of twenty adult Guanzhong milk goats of 1.5 years of age. Infusion of SCFAs resulted in upregulating the activity of certain antioxidant enzymes in comparison with the control group. The SA group significantly (p < 0.05) increased the activity of the catalase (CAT) in the liver, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in the colon, and maleic dialdehyde (MDA) in the jejunum. SP significantly (p < 0.05) upregulated the activity of the total antioxidant capacity (T-AOC) in the ileum, CAT and MDA in the jejunum, CAT in the colon, and SOD in the liver. SB was significantly (p < 0.05) upregulated the activity of the T-AOC in the ileum, CAT in the jejunum, and T-AOC, CAT, SOD, and GSH-Px in the colon. Infusion of SCFAs resulted in significant (p < 0.05) increases in pro-inflammatory and anti-inflammatory cytokines in the intestine compared to the control group. We found that the SA group significantly (p < 0.05) upregulated the level of interleukin-1 beta (IL-1β) in the ileum and jejunum, as well as the levels of IL-6 and TNF-α in the colon, while the SP group significantly (p < 0.05) increased the level of IL-1β in the jejunum and the level of interleukin-10 (IL-10) in the colon. Furthermore, the SB group significantly (p < 0.05) upregulated levels of IL-1β in the jejunum, interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) in the colon, and IL-10 in the cecum. Furthermore, some intestinal tight-junction proteins were significantly increased by SCFA infusion. SA significantly (p < 0.05) increased the claudin level in the ileum and occludin in the colon, while the SP group significantly (p < 0.05) upregulated the level of occludin in the jejunum and the claudin level in the ileum. Moreover, SB significantly (p < 0.05) increased the occludin level in the jejunum, claudin level in the ileum, and zonula occludens-1 (ZO-1) level in the colon and cecum. There are many positive associations among antioxidant, inflammatory cytokine, and tight-junction protein indexes in the liver and intestine. In conclusion, our results suggest that the gastric infusion of SA, SP, and SB might improve goat intestinal health through the positive influence on the antioxidant capacity, pro-inflammatory and anti-inflammatory cytokines, and tight-junction proteins.

This study investigated the longitudinal effects of acute (7-day) and prolonged (3-month) high-altitude exposure on gut microbiota in healthy adult males, addressing the limited data available in human populations. A cohort of 406 healthy adult males was followed, and fecal samples were collected at three time points: baseline at 800 m (406 samples), 7 days after ascending to 4,500 m (406 samples), and 2 weeks post-return to 800 m following 3 months at high altitude (186 samples). High-throughput 16S ribosomal DNA sequencing was employed to analyze microbiota composition and diversity. Results revealed significant changes in alpha- and beta-diversity, with acute high-altitude exposure inducing more pronounced effects compared to prolonged exposure. Specifically, acute exposure increased opportunistic pathogens (Ruminococcus and Oscillibacter) but decreased beneficial short-chain fatty acid producers (Faecalibacterium and Bifidobacterium). Notably, these changes in microbiota persisted even after returning to low altitude, indicating long-term remodeling. Functional analyses revealed substantial changes in metabolic pathways, suggesting microbiota-driven adaptations to energy utilization under high-altitude hypoxic conditions. In summary, acute high-altitude exposure caused dramatic changes in gut microbiota, while prolonged exposure led to structural and functional reshaping. These findings enhance our understanding of how high-altitude environments reshape gut microbiota.

This study is the first to investigate the impact of high-altitude exposure on gut microbiota adaptation in a large-scale longitudinal cohort. It seeks to enhance understanding of how high-altitude environments reshape gut microbiota. Acute exposure to high altitude significantly affected both α-diversity and β-diversity of gut microbiota, with acute exposure causing more pronounced changes than prolonged adaptation, indicating temporary disruptions in microbial communities. Notable shifts in microbial abundance were observed, including increased levels of genera linked to hypoxic stress (e.g., Gemmiger, Ruminococcus, and Parabacteroides) and decreased levels of beneficial bacteria (e.g., Faecalibacterium, Roseburia, and Bifidobacterium), suggesting possible adverse health effects. Functional analysis indicated changes in metabolism-related pathways post-exposure, supporting the idea that high-altitude adaptations involve metabolic adjustments for energy management. These findings enhance understanding of high-altitude physiology, illustrating the role of gut microbiota in hypoxic health.

Spinal cord injury (SCI) affects millions of people worldwide annually, presenting significant challenges in functional recovery despite therapeutic advancements. Current treatment strategies predominantly focus on stabilizing the spinal cord and facilitating neural repair, yet their effectiveness remains uncertain and controversial. Recent scientific investigations have explored the potential of probiotics and postbiotics to modulate inflammation, influence neurotransmitters, and aid in tissue repair, marking a potential paradigm shift in SCI management. This review critically evaluates these innovative approaches, emphasizing their ability to harness the natural properties of microorganisms within the body to potentially enhance outcomes in SCI treatment. By analyzing the latest research findings, this review provides valuable insights into how probiotics and postbiotics can revolutionize inflammation management and neurological recovery following SCI, underscoring their promising role in future therapeutic strategies aimed at improving the quality of life of SCI patients globally.

Background: Critical illness induces profound metabolic alterations, characterized by a hypermetabolic state, insulin resistance, protein catabolism, and gut barrier dysfunction, which contribute to increased morbidity and mortality. Emerging evidence highlights the role of the gut microbiome and its metabolites in modulating systemic inflammation and immune responses during critical illness. This narrative review explores the metabolic evolution of critically ill patients, the impact of gut dysbiosis on disease progression, and the potential role of nutrition in modulating metabolism and improving patient outcomes. Methods: A comprehensive literature search was conducted across PubMed and Google Scholar for articles published up to February 2025. Search terms included "critical illness", "metabolism", "gut microbiota", "nutrition", and related keywords. Articles published in English addressing metabolic alterations, microbiome changes, and nutritional strategies in critically ill patients were included. After screening for eligibility, relevant articles were synthesized to outline current knowledge and identify gaps. Results: Metabolic changes in critical illness progress through distinct phases, from catabolism-driven hypermetabolism to gradual recovery. Gut dysbiosis, characterized by a loss of microbial diversity and increased gut permeability, contributes to systemic inflammation and organ dysfunction. Nutritional strategies, including enteral nutrition, probiotics, prebiotics, and metabolomics-driven interventions, may help restore microbial balance, preserve gut barrier integrity, and modulate immune and metabolic responses. Future nutrition therapy should focus on metabolic modulation rather than solely addressing nutrient deficits. Conclusions: Advances in gut microbiome research and metabolomics offer new avenues for personalized nutrition strategies tailored to the metabolic demands of critically ill patients. Integrating these approaches may improve clinical and functional recovery while mitigating the long-term consequences of critical illness.

Previous observational studies have indicated a correlation between the skin microbiome and Type 2 diabetes (T2DM). It is hypothesized that this causal relationship may be influenced by inflammatory responses. However, these factors as determinants of T2DM remain largely unexplored.

This study incorporated data from the GWAS database on the skin microbiome, 91 types of inflammatory cytokines, and T2DM. We employed two-sample MR and multivariable MR methods to assess the correlation between the skin microbiome and T2DM, and to investigate whether this correlation is affected by inflammatory cytokines.

The results of the two-sample MR analysis indicate that within the skin microbiome, genetically predicted genus: Acinetobacter, class: Alphaproteobacteria, genus: Bacteroides, ASV005[Propionibacterium granulosum], and ASV072[Rothia mucilaginosa] are associated with an increased risk of T2DM, while phylum: Proteobacteria, genus: Enhydrobacter, family: Clostridiales, ASV006[Staphylococcus hominis] serve as protective factors against T2DM. Among the inflammatory cytokines, levels of Macrophage colony-stimulating factor 1, Tumor necrosis factor receptor superfamily member 9, Urokinase-type plasminogen activator, and C-C motif chemokine 28 are associated with an increased risk of T2DM. Multivariable MR analysis further revealed that Macrophage colony-stimulating factor 1 levels act as a mediating factor between ASV072[Rothia mucilaginosa] and T2DM.

In this study, we found a connection between the skin microbiome and T2DM, with inflammatory cytokines playing a key role in this relationship. This research helps us better understand this complex link and shows that addressing inflammation is important for preventing and treating diabetes. This could greatly benefit public health by reducing the impact of diabetes and its complications. Our results suggest that future studies should explore the specific biological interactions between the skin microbiome and diabetes to develop more effective risk management and treatment strategies from a microbial perspective.

Metabolic dysfunction leading to non-alcoholic fatty liver disease (NAFLD) exhibits distinct molecular and immune signatures that are influenced by factors like gut microbiota. The gut microbiome interacts with the liver via a bidirectional relationship with the gut-liver axis. Microbial metabolites, sirtuins, and immune responses are pivotal in different metabolic diseases. This extensive review explores the complex and multifaceted interrelationship between sirtuins and gut microbiota, highlighting their importance in health and disease, particularly metabolic dysfunction and hepatocellular carcinoma (HCC). Sirtuins (SIRTs), classified as a group of NAD+-dependent deacetylases, serve as crucial modulators of a wide spectrum of cellular functions, including metabolic pathways, the inflammatory response, and the process of senescence. Their subcellular localization and diverse functions link them to various health conditions, including NAFLD and cancer. Concurrently, the gut microbiota, comprising diverse microorganisms, significantly influences host metabolism and immune responses. Recent findings indicate that sirtuins modulate gut microbiota composition and function, while the microbiota can affect sirtuin activity. This bidirectional relationship is particularly relevant in metabolic disorders, where dysbiosis contributes to disease progression. The review highlights recent findings on the roles of specific sirtuins in maintaining gut health and their implications in metabolic dysfunction and HCC development. Understanding these interactions offers potential therapeutic avenues for managing diseases linked to metabolic dysregulation and liver pathology.

Infectious complications (ICs) in acute pancreatitis (AP) are primarily driven by intestinal bacterial translocation, significantly increasing mortality and hospital stays. Despite this, the role of the gut microenvironment, particularly its metabolic aspects, in AP remains poorly understood. In this study, we investigated a cohort of patients with AP, and conducted supplemental murine studies, to explore the relationship between the gut metabolome and the development of ICs. Metabolomic analysis revealed that disruptions in gut tryptophan metabolism - especially reductions in serotonin and indole pathways - are key features associated with IC occurrence. Additionally, elevated plasma levels of tryptophan metabolites within the kynurenine pathway were identified as valuable predictive biomarkers for ICs. Mechanistic studies in murine models demonstrated that an impaired intestinal Th17 response, modulated by these tryptophan metabolites, plays a critical role in IC development. Serotonin supplementation enhanced Th17 responses, reducing IC incidence, while administration of kynurenic acid, a kynurenine metabolite, exacerbated pancreatic infections, potentially through immunosuppressive effects. These findings highlight the pivotal role of tryptophan metabolites in AP pathogenesis, emphasizing their potential as both predictive markers and therapeutic targets in IC management.

Inflammatory bowel disease (IBD) is a chronic condition associated with elevated rates of anxiety and depression and ultimately reduces the quality of life. Thus, preventive care addressing both physical and psychological health is essential. In this study we aimed to explore the protective effects of Indoleacrylic Acid (IA) against lipopolysaccharide (LPS)-induced inflammation using human colorectal adenocarcinoma cells (HT-29) and dextran sulfate sodium (DSS)-induced zebrafish to assess its potential as a novel therapeutic agent for IBD. IA exhibited substantial anti-inflammatory properties in HT-29 cells and zebrafish models. It significantly reduced the production of pro-inflammatory mediators, including PGE2, TNF-α, IL-6, and IL-8, while upregulating MUC2, AhR, and tight junction proteins (ZO-1, occludin, and claudin-1), thereby enhancing mucosal barrier integrity. In zebrafish larvae, IA improved survival rates, boosted mucin production, and reduced macrophage infiltration and heartbeat rate. Behavioral analyses of adult zebrafish revealed that IA alleviated anxiety-like behaviors, as shown by increased locomotion and improved performance in zone preference and light-dark transition tests. By targeting inflammation and anxiety-like symptoms, IA demonstrates a dual benefit by addressing both intestinal inflammation and the psychological burden of IBD. These findings highlight IA's potential as a novel therapeutic agent for managing IBD, offering a comprehensive approach to improving patient outcomes.

Inflammatory bowel disease (IBD) is a severe chronic intestinal disorder with a rising global incidence. Current therapies, including the delivery of anti-inflammatory drugs and probiotics, face significant challenges in terms of safety, stability, and efficacy. In IBD patients, the activity of antioxidant enzymes (e.g., superoxide dismutase, glutathione peroxidase, and glutathione reductase) is reduced at the site of intestinal inflammation, leading to the accumulation of reactive oxygen species (ROS). This accumulation damages the intestinal mucosa, disrupts tight junctions between cells, and compromises the integrity of the intestinal barrier, exacerbating IBD symptoms. Therefore, nanoparticles responsive to ROS and capable of mimicking antioxidant enzyme activity, such as boronates, polydopamine, sulfides, and metal nanozymes, have emerged as promising tools. These nanoparticles can respond to elevated ROS levels in inflamed intestinal regions and release drugs to effectively neutralize ROS, making them ideal candidates for IBD treatment. This review discusses the application of various ROS-responsive nanomaterial delivery systems in IBD therapy, highlights current challenges, and outlines future research directions. Furthermore, we explore the "layered programmable delivery" strategy, which combines ROS-responsive nanoparticles with pH-responsive and cell membrane-targeted nanoparticles. This strategy has the potential to overcome the limitations of single-mechanism targeted drug delivery, enabling multi-range and multi-functional treatment approaches that significantly enhance delivery efficiency, providing new insights for the future of localized IBD treatment.

Ulcerative colitis (UC) is a chronic inflammatory disorder, and its incidence is experiencing an upward trend worldwide. UC can result in gut microbiota dysbiosis, impaired intestinal epithelial barrier, and systemic inflammation, for all of which there is presently no definitive treatment available. Lactobacillus is known to regulate gut microbiota and related metabolites to intervene in the development of UC. The objective of this study was to explore the underlying mechanism through which a novel probiotic, Lactobacillus vaginalis, alleviates DSS-induced colitis. Specifically, L. vaginalis were found to ameliorate the DSS-induced UC phenotype, restore intestinal microbiota balance and intestinal barrier function, and elevate the levels of 3-indoleacrylic acid (IAA) in mouse feces. Furthermore, fecal microbiota transplantation and fecal filtrate transplantation provide additional evidence that L. vaginalis alleviate DSS-induced colitis through metabolic products. Additionally, IAA has been shown to alleviate DSS-induced colitis symptoms, decrease inflammatory responses, and enhance intestinal barrier function. Finally, our findings confirm that L. vaginal and metabolites possess the capability to regulate the immune microenvironment in mice with colitis. And the RNA-seq analysis suggests that L. vaginal may play a pivotal role in alleviating colitis by modulating the PPAR signaling pathway. In conclusion, our findings suggest that oral administration of L. vaginalis alleviates DSS induced colonic inflammation by increasing the levels of IAA. L. vaginalis, as an emerging probiotic, provides a potential therapeutic strategy for clinical UC.

Glycyrrhiza, a legume native to the Mediterranean region, has a long history of ethnomedicinal use in China. Due to its antiviral, antibacterial, anti-inflammatory, antioxidant, antitumor, anti-ulcer, and hepatoprotective properties, Glycyrrhiza is widely utilized in the treatment of gastrointestinal disorders.

The specific mechanisms of the main active constituents of glycyrrhiza in the treatment of inflammatory bowel disease, precancerous lesions and colorectal cancer at all stages of the colitis-associated colon cancer "Inflammation-Dysplasia-Cancer" sequence, as well as its pharmacokinetics, toxicology, formulation improvements, and application studies, are reviewed to provide new insights and perspectives on glycyrrhiza as a dietary supplement to treat and prevent colitis-associated colon cancer.

Information on Glycyrrhiza was retrieved from electronic databases, including PubMed and Web of Science.

Glycyrrhiza is a well-established medicinal plant with significant potential for applications in both the food and pharmaceutical industries. Over 400 active constituents have been identified in Glycyrrhiza, including terpenoids, flavonoids, isoflavones, coumarins, and polyphenols. Numerous studies have demonstrated that Glycyrrhiza and its active compounds can inhibit the "Inflammation-Dysplasia-Cancer" progression of colitis-associated colon cancer by mitigating inflammatory bowel disease, reducing the number of intestinal precancerous lesions, and counteracting colorectal cancer. Furthermore, derivatives and nanocarriers are crucial for the effective treatment of colitis-associated colon cancer using Glycyrrhiza and its active constituents.

In conclusion, Glycyrrhiza is a plant with both medicinal and nutritional value, making it a potential food ingredient and dietary supplement for the treatment of colitis-associated colon cancer.

The liver regenerative capacity is crucial for patients with end-stage liver disease following partial hepatectomy (PHx). The specific bacteria and mechanisms regulating liver regeneration post-PHx remain unclear. This study demonstrated dynamic changes in the abundance of Parabacteroides distasonis (P. distasonis) post-PHx, correlating with hepatocyte proliferation. Treatment with live P. distasonis significantly promoted hepatocyte proliferation and liver regeneration after PHx. Targeted metabolomics revealed a significant positive correlation between P. distasonis and β-hydroxybutyric acid (BHB), as well as hyodeoxycholic acid and 3-hydroxyphenylacetic acid in the gut after PHx. Notably, treatment with BHB, but not hyodeoxycholic acid or 3-hydroxyphenylacetic acid, significantly promoted hepatocyte proliferation and liver regeneration in mice after PHx. Moreover, STAT3 inhibitor Stattic attenuated the promotive effects of BHB on cell proliferation and liver regeneration both in vitro and in vivo. Mechanistically, P. distasonis upregulated the expression of fatty acid oxidation-related proteins, and increased BHB levels in the liver, and then BHB activated the STAT3 signaling pathway to promote liver regeneration. This study, for the first time, identifies the involvement of P. distasonis and its associated metabolite BHB in promoting liver regeneration after PHx, providing new insights for considering P. distasonis and BHB as potential strategies for promoting hepatic regeneration.

The human immune system is closely linked to microbiota such as a complex symbiotic relationship during the coevolution of vertebrates and microorganisms. The transfer of microorganisms from the mother's microbiota to the newborn begins before birth during gestation and is considered the initial phase of the intestinal microbiota (IM). The gut is an important site where microorganisms can establish colonies. The IM contains polymicrobial communities, which show complex interactions with diet and host immunity. The tendency towards dysbiosis of the intestinal microbiota is influenced by local but also extra-intestinal factors such as inflammatory processes, infections, or a septic state that can aggravate it. Pathogens could trigger an immune response, such as proinflammatory responses. In addition, changes in the host immune system also influence the intestinal community and structure with additional translocation of pathogenic and non-pathogenic bacteria. Finally, local intestinal inflammation has been found to be an important factor in the growth of pathogenic microorganisms, particularly in its role in sepsis. The aim of this article is to be able to detect the current knowledge of the mechanisms that can lead to dysbiosis of the intestinal microbiota and that can cause bacterial translocation with a risk of infection or septic state and vice versa.

Exercise perturbs various aspects of gastrointestinal integrity and function, which may lead to performance impeding gastrointestinal symptoms (GIS) and/or precipitate clinical issues warranting medical management. This study aimed to determine the impact of prebiotic supplementation on gastrointestinal integrity and functional status in response to exertional heat stress (EHS). Sixteen endurance athletes completed two trials of 3-hr running at 60% V˙O2max in 30 °C at baseline (T1) and following an 8-week supplementation period (T2), with 16 g/day prebiotic (PREBIOTIC) or matched placebo (PLACEBO). Blood samples were collected pre-EHS and post-EHS and in recovery for determination of stress response (cortisol), intestinal epithelial injury (intestinal fatty acid binding protein), bacterial endotoxemia (sCD14), and systemic inflammation (C-reactive protein). GIS and feeding tolerance variables were assessed throughout the EHS. Orocecal transit time was determined via a lactulose challenge given at 2.5 hr into EHS. Plasma cortisol (combined mean: +252 ng/ml), intestinal fatty acid binding protein (+800 pg/ml), and sCD14 (+487 ng/ml) concentrations increased in response to EHS in T1 (p ≤ .05), but not for C-reactive protein (+0.8 μg/ml; p > .05), in both PREBIOTIC and PLACEBO. PREBIOTIC supplementation resulted in a blunted intestinal fatty acid binding protein response on T2 (+316 pg/ml) compared with an increase (+1,001 ng/ml) in PLACEBO (p = .005). Lower sCD14 was observed at T2 (2,799 ng/ml) versus T1 (3,246 ng/ml) in PREBIOTIC only (p = .039). No intervention effects were observed for C-reactive protein. No difference within or between PREBIOTIC and PLACEBO at T1 and T2 was observed for orocecal transit time, GIS, and feeding tolerance. In conclusion, 8 weeks of prebiotic supplementation modestly attenuates EHS associated perturbations to intestinal integrity, but does not further impair gastrointestinal transit and/or exacerbate EHS associated GIS or feeding tolerance.

Cohort studies consistently show that a high intake of cereal fiber and whole-grain products is associated with a decreased risk of type 2 diabetes (T2DM), cancer, and cardiovascular diseases. Similar findings are also reported for infectious and chronic inflammatory disorders. All these disorders are at least partially caused by inflammaging, a chronic state of inflammation associated with aging and Metabolic Syndrome. Surprisingly, insoluble (cereal) fiber intake consistently shows stronger protective associations with most long-term health outcomes than soluble fiber. Most humans consume soluble fiber mainly from sweet fruits, which usually come with high levels of sugar, counteracting the potentially beneficial effects of fiber. In both observational and interventional studies, high-fiber diets show a beneficial impact on inflammation, which can be attributed to a variety of nutrients apart from dietary fiber. These confounders need to be considered when evaluating the effects of fiber as part of complex dietary patterns. When assessing specific types of fiber, inulin and resistant starch clearly elicit anti-inflammatory short-term effects, while results for pectins, beta-glucans, or psyllium turn out to be less convincing. For insoluble fiber, promising but sparse data have been published so far. Hypotheses on putative mechanisms of anti-inflammatory fiber effects include a direct impact on immune cells (e.g., for pectin), fermentation to pleiotropic short-chain fatty acids (for fermentable fiber only), modulation of the gut microbiome towards higher levels of diversity, changes in bile acid metabolism, a differential release of gut hormones (such as the glucose-dependent insulinotropic peptide (GIP)), and an improvement of insulin resistance via the mTOR/S6K1 signaling cascade. Moreover, the contribution of phytate-mediated antioxidative and immune-modulatory means of action needs to be considered. In this review, we summarize the present knowledge on the impact of fiber-rich diets and dietary fiber on the human inflammatory system. However, given the huge heterogeneity of study designs, cohorts, interventions, and outcomes, definite conclusions on which fiber to recommend to whom cannot yet be drawn.

Background: Type 1 diabetes (T1D) is a severe chronic T-cell mediated autoimmune disease that attacks the insulin-producing beta cells of the pancreas. The multifactorial nature of T1D involves both genetic and environmental components, with recent research focusing on the gut microbiome as a crucial environmental factor in T1D pathogenesis. The gut microbiome and its metabolites play an important role in modulating immunity and autoimmunity. In recent years, studies have revealed significant alterations in the taxonomic and functional composition of the gut microbiome associated with the development of islet autoimmunity and T1D. These changes include reduced production of short-chain fatty acids, altered bile acid and tryptophan metabolism, and increased intestinal permeability with consequent perturbations of host (auto)immune responses. Methods/Results: In this review, we summarize and discuss recent observational, mechanistic and etiological studies investigating the gut microbiome in T1D and elucidating the intricate role of gut microbes in T1D pathogenesis. Moreover, we highlight the recent advances in intervention studies targeting the microbiota for the prevention or treatment of human T1D. Conclusions: A deeper understanding of the evolution of the gut microbiome before and after T1D onset and of the microbial signals conditioning host immunity may provide us with essential insights for exploiting the microbiome as a prognostic and therapeutic tool.

Background: Microplastics (MPs) are small plastic fragments with diameters less than 5 mm in size and are prevalent in everyday essentials and consumables. Large global plastic production has now led to a flooding of MPs in our natural environment. Due to their detrimental impacts on the planet's ecosystems and potentially our health, MPs have emerged as a significant public health concern. In this pilot study, we hypothesize that MPs exposure will negatively affect gut microbiota composition and function, in which metabolic reprogramming plays an important role. Methods: Using in vitro experiments, three bacterial strains (Escherichia coli MG1655, Nissle 1917, and Lactobacillus rhamnosus) were selected to investigate the impacts of MPs exposure. The bacterial strains were individually cultured in an anaerobic chamber and exposed to 1 µm polystyrene MPs at various concentrations (0, 10, 20, 50, 100, and 500 µg/mL) in the culture medium. Results: MPs exposure reduced the growth of all three bacterial strains in a dose-dependent manner. Liquid chromatography mass spectrometry (LC-MS)-based untargeted metabolomics revealed significant differences in multiple metabolic pathways, such as sulfur metabolism and amino sugar and nucleotide sugar metabolism. In addition, we extracted gut microbiota from C57BL/6 mice, and 16S rRNA sequencing results showed a significant upregulation of Lactobacillales and a significant reduction in Erysipelotrichales due to MPs exposure. Furthermore, targeted and untargeted metabolomics corroborated the in vitro results and revealed alterations in microbial tryptophan metabolism and energy producing pathways, such as glycolysis/gluconeogenesis and the pentose phosphate pathway. Conclusions: These findings provide evidence that MPs exposure causes comprehensive changes to healthy gut microbiota, which may also provide insights into the mechanistic effects of MPs exposure in humans.

Short-chain fatty acids (SCFAs), produced through fermentation of dietary fibers by gut bacteria, play a central role in modulating cardiovascular function and heart failure (HF) development. The progression of HF is influenced by intestinal barrier dysfunction and microbial translocation, where SCFAs serve as key mediators in the gut-heart axis. This review examines the complex metabolic interactions between SCFAs and other gut microbiota metabolites in HF, including their relationships with trimethylamine N-oxide (TMAO), aromatic amino acids (AAAs), B vitamins, and bile acids (BAs). We analyze the associations between SCFA production and clinical parameters of HF, such as left ventricular ejection fraction (LVEF), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and glomerular filtration rate (GFR). Gaining insights into metabolic networks offers new potential therapeutic targets and prognostic markers for managing heart failure, although their clinical significance needs further exploration.

Individuals with inflammatory bowel disease (IBD) are at a higher risk of developing mental disorders, such as anxiety and depression. The imbalance between the intestinal microbiota and its host, known as dysbiosis, is one of the factors, disrupting the balance of metabolite production and their signaling pathways, leading to disease progression. A metabolomics approach can help identify the role of gut microbiota in mental disorders associated with IBD by evaluating metabolites and their signaling comprehensively. This narrative review focuses on metabolomics studies that have comprehensively elucidated the altered gut microbial metabolites and their signaling pathways underlying mental disorders in IBD patients. The information was compiled by searching PubMed, Web of Science, Scopus, and Google Scholar from 2005 to 2023. The findings indicated that intestinal microbial dysbiosis in IBD patients leads to mental disorders such as anxiety and depression through disturbances in the metabolism of carbohydrates, sphingolipids, bile acids, neurotransmitters, neuroprotective, inflammatory factors, and amino acids. Furthermore, the reduction in the production of neuroprotective factors and the increase in inflammation observed in these patients can also contribute to the worsening of psychological symptoms. Analyzing the metabolite profile of the patients and comparing it with that of healthy individuals using advanced technologies like metabolomics, aids in the early diagnosis and prevention of mental disorders. This approach allows for the more precise identification of the microbes responsible for metabolite production, enabling the development of tailored dietary and pharmaceutical interventions or targeted manipulation of microbiota.

Lactiplantibacillus plantarum can activate aryl hydrocarbon receptor (AHR) signaling in the gut by metabolizing tryptophan, thereby counteracting inflammation. However, the tryptophan metabolic characteristics of microorganisms are strain-specific and significantly influence their AHR-activating effects. In this study, four strains with different tryptophan metabolic profiles were screened, and a dextran sulfate sodium-induced colitis model was established in C57BL/6 mice. The key tryptophan metabolic characteristics of L. plantarum involved in AHR downstream signaling activation to alleviate colitis were explored. The results showed that strain SFFI50, characterized by poor tryptophan metabolism, and strain SFFI175, which produced high levels of IAA and ICA, did not alleviate colitis. Strain SFFI118, capable of metabolizing tryptophan to produce IAA, ICA, and ILA, could slightly restore mouse body weight, DAI, and IL-22 expression. L. plantarum SFFI23 significantly restored body weight, colon length, histopathological damage, and cytokine expression in mice. Moreover, it activated the downstream signaling of AHR, specifically CYP1A1, and repairs the intestinal barrier function. Targeted metabolomic analysis revealed a significant increase in indole-3-lactic acid (ILA) in the mouse intestine. Correlation analysis revealed a significant positive correlation between high ILA production of L. plantarum, CYP1A1 expression, intestinal barrier function restoration, ILA levels in vivo, and colitis alleviation. Therefore, we inferred that high ILA production is a key tryptophan metabolic characteristic of L. plantarum which activated AHR downstream signaling (such as CYP1A1, IL-22, and STAT3) to alleviate colitis. This study provides a theoretical basis for the development of personalized dietary interventions to improve gut health.

Microorganisms in the gut play a pivotal role in human health, influencing various pathophysiological processes. Certain microorganisms are particularly essential for maintaining intestinal homeostasis, reducing inflammation, supporting nervous system function, and regulating metabolic processes. Short-chain fatty acids (SCFAs) are a subset of fatty acids produced by the gut microbiota (GM) during the fermentation of indigestible polysaccharides. The interaction between GM and SCFAs is inherently bidirectional: the GM not only shapes SCFAs composition and metabolism but SCFAs also modulate microbiota's diversity, stability, growth, proliferation, and metabolism. Recent research has shown that GM and SCFAs communicate through various pathways, mainly involving mechanisms related to inflammation and immune responses, intestinal barrier function, the gut-brain axis, and metabolic regulation. An imbalance in GM and SCFA homeostasis can lead to the development of several chronic diseases, including inflammatory bowel disease, colorectal cancer, systemic lupus erythematosus, Alzheimer's disease, and type 2 diabetes mellitus. This review explores the synergistic interactions between GM and SCFAs, and how these interactions directly or indirectly influence the onset and progression of various diseases through the regulation of the mechanisms mentioned above.

Xiangsha Liujunzi Wan (LJZW) is a traditional Chinese medicine (TCM) formula containing a variety of traditional Chinese herb components. Its principal components are often used in the treatment of gastrointestinal diseases and contribute to the treatment of Crohn's disease (CD).

To explore the therapeutic potential of LJZW in CD through network pharmacology, bioinformatics, molecular docking, and experimental verification.

The principal bioactive components and corresponding targets of LJZW were ascertained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Potential targets for CD were identified in GeneCards, OMIM, DrugBank, DisGeNET, CTD, and Gene Expression Omnibus (GEO) databases. Intersection targets of LJZW and CD were identified using a Venn diagram and visualized using Cytoscape 3.8.0 to construct a protein-protein interaction (PPI) network. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to assess the function of intersection targets. AutoDockTools and PyMOL were used for molecular docking to recognize the association between the core ingredients of LJZW and the core targets of CD. Subsequently, a series of experiments were conducted for validation.

The network pharmacology results indicated that there were 156 bioactive components and 268 corresponding targets for LJZW, 3023 primary relevant targets for CD, and 169 intersection targets for LJZW and CD. The PPI network was employed to identify five hub genes and six clusters. The GO functional analysis indicated that intersection targets are primarily correlated with oxidative stress and inflammatory responses. KEGG pathway analysis revealed that these targets were primarily associated with the phosphotylinosital 3 kinase (PI3K)-protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways. The molecular docking results showed that the core ingredients of LJZW had good binding ability with the core targets of CD. A series of experiments demonstrated that LJZW could effectively attenuate TNBS-induced colitis symptoms, inhibit the inflammatory response, and protect intestinal barrier function by inhibiting the PI3K-AKT and MAPK signaling pathways, thus preventing and treating CD.

LJZW has the characteristics of multi-component, multi-target, and multi-pathway treatment, which helps to improve the treatment of CD, protect the intestinal barrier, and exert the effect of anti-inflammatory therapy by inhibiting PI3K-AKT and MAPK signaling pathways.