The interplay between the gut microbiota and gastrointestinal hormones plays a pivotal role in the health of the host and the development of diseases. As a vital component of the intestinal microecosystem, the gut microbiota influences the synthesis and release of many gastrointestinal hormones through mechanisms such as modulating the intestinal environment, producing metabolites, impacting mucosal barriers, generating immune and inflammatory responses, and releasing neurotransmitters. Conversely, gastrointestinal hormones exert feedback regulation on the gut microbiota by modulating the intestinal environment, nutrient absorption and utilization, and the bacterial biological behavior and composition. The distributions of the gut microbiota and gastrointestinal hormones are anatomically intertwined, and close interactions between the gut microbiota and gastrointestinal hormones are crucial for maintaining gastrointestinal homeostasis. Interventions leveraging the interplay between the gut microbiota and gastrointestinal hormones have been employed in the clinical management of metabolic diseases and inflammatory bowel diseases, such as bariatric surgery and fecal microbiota transplantation, offering promising targets for the treatment of dysbiosis-related diseases.

Type 1 diabetes (T1D) results from T cell-mediated destruction of pancreatic β-cells, requiring lifelong insulin therapy and glycemic monitoring. While genetic risk, particularly HLA class II, is well established, rising T1D incidence and earlier onset suggest environmental modifiers. Mouse models show that microbiome alterations influence β-cell autoimmunity, and human studies link microbiome composition to T1D, though specific microbial regulators remain unidentified. We examine host-microbiome interactions, including studies implicating enteroviruses in modulating islet autoimmunity. Mechanistic discoveries of microbial effects on diabetes have emerged from mouse model studies. We consider clinical applications, including microbiota-targeted therapies and biomarkers of microbiome-immune crosstalk. Future research should integrate microbial, genetic, environmental, and immune data using multi-omic approaches. Collaborative efforts combining immunology, microbiology, and clinical metadata will drive discovery and precision medicine in T1D.

The gut microbiota plays a pivotal role in human life and undergoes dynamic changes throughout the human lifespan, from infancy to old age. During our life, the gut microbiota influences health and disease across life stages. This review summarizes the discussions and presentations from the symposium "Gut microbiota development from infancy to old age" held in collaboration with the Journal of Internal Medicine. In early infancy, microbial colonization is shaped by factors such as mode of delivery, antibiotic exposure, and milk-feeding practices, laying the foundation for subsequent increased microbial diversity and maturation. Throughout childhood and adolescence, microbial maturation continues, influencing immune development and metabolic health. In adulthood, the gut microbiota reaches a relatively stable state, influenced by genetics, diet, and lifestyle. Notably, disruptions in gut microbiota composition have been implicated in various inflammatory diseases-including inflammatory bowel disease, Type 1 diabetes, and allergies. Furthermore, emerging evidence suggests a connection between gut dysbiosis and neurodegenerative disorders such as Alzheimer's disease. Understanding the role of the gut microbiota in disease pathogenesis across life stages provides insights into potential therapeutic interventions. Probiotics, prebiotics, and dietary modifications, as well as fecal microbiota transplantation, are being explored as promising strategies to promote a healthy gut microbiota and mitigate disease risks. This review focuses on the gut microbiota's role in infancy, adulthood, and aging, addressing its development, stability, and alterations linked to health and disease across these critical life stages. It outlines future research directions aimed at optimizing the gut microbiota composition to improve health.

Effective approaches to preventing and treating obesity are urgently needed. Although current strategies primarily focus on direct modulation of host metabolism, another promising approach may involve limiting nutrient availability through regulation of the gut microbiota, which links diet and host physiology. Here, we report that acetylated cellulose (AceCel), which markedly alters gut bacterial composition and function, reduces body mass gain in both wild-type and obese mice. AceCel limits carbohydrate oxidation and promotes fatty acid oxidation in the host liver in a microbiota-dependent manner. We further show that acetate enhances carbohydrate fermentation by the gut commensal Bacteroides thetaiotaomicron, depleting host-accessible simple sugars in the gut of AceCel-fed mice. These findings highlight the potential of AceCel as a prebiotic that regulates carbohydrate metabolism in both bacteria and host, offering promise as a therapeutic strategy for obesity.

Short-chain fatty acids (SCFAs) are a group of organic compounds produced by the fermentation of dietary fibre by the human gut microbiota. They play diverse roles in different physiological processes of the host with implications for human health and disease. This Review provides an overview of the complex microbial metabolism underlying SCFA formation, considering microbial interactions and modulating factors of the gut environment. We explore the multifaceted mechanistic interactions between SCFAs and the host, with a particular focus on the local actions of SCFAs in the gut and their complex interactions with the immune system. We also discuss how these actions influence intestinal and extraintestinal diseases and emerging therapeutic strategies using SCFAs.

The high prevalence and disability rate of type 2 diabetes (T2D) caused a huge social burden to the world. Currently, new mechanisms and therapeutic approaches that may affect this disease are being sought. With in-depth research on the pathogenesis of T2D and growing advances in microbiome sequencing technology, the association between T2D and gut microbiota has been confirmed. The gut microbiota participates in the regulation of inflammation, intestinal permeability, short-chain fatty acid metabolism, branched-chain amino acid metabolism and bile acid metabolism, thereby affecting host glucose and lipid metabolism. Interventions focusing on the gut microbiota are gaining traction as a promising approach to T2D management. For example, dietary intervention, prebiotics and probiotics, faecal microbiota transplant and phage therapy. Meticulous experimental design and choice of analytical methods are crucial for obtaining accurate and meaningful results from microbiome studies. How to design gut microbiome research in T2D and choose different machine learning methods for data analysis are extremely critical to achieve personalized precision medicine.

Non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and has become the greatest potential risk for cirrhosis and hepatocellular carcinoma. The metabolites produced by the gut microbiota act as signal molecules that mediate the interaction between microorganisms and the host and have biphasic effects on human health. The gut microbiota and its metabolites, short-chain fatty acids (SCFAs), have been discovered to ameliorate many prevalent liver diseases, including NAFLD. Currently, SCFAs have attracted widespread attention as potential therapeutic targets for NAFLD, but the mechanism of action has not been fully elucidated. This article summarizes the mechanisms of short-chain fatty acids of gut microbiota metabolites to regulate the metabolism of glucose and lipid, maintain the intestinal barrier, alleviate the inflammatory response, and improve the oxidative stress to improve NAFLD, in order to provide a reference for clinical application.

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

Polysaccharides, as complex carbohydrates, play a pivotal role in immune modulation and interactions with the gut microbiota. The diverse array of dietary polysaccharides influences gut microbial ecology, impacting immune responses, metabolism, and overall well-being. Despite their recognized benefits, there is limited understanding of the precise mechanisms by which polysaccharides modulate the immune system through the gut microbiota. A comprehensive search of Web of Science, PubMed, Google Scholar, and Embase up to May 2024 was conducted to identify relevant studies. This study employs a systematic approach to explore the interplay between polysaccharides and the gut microbiota, focusing on cytokine-mediated and short-chain fatty acid (SCFA)-mediated pathways. The findings underscore the significant role of polysaccharides in shaping the composition and function of the gut microbiota, thereby influencing immune regulation and metabolic processes. However, further research is necessary to elucidate the detailed molecular mechanisms and translate these findings into clinical applications.

Type 1 diabetes (T1D) is linked to an altered gut microbiota characterized by reduced short-chain fatty acid (SCFA) production. Oral delivery of a SCFA-yielding biotherapy in adults with T1D was followed by increased SCFAs, altered gut microbiota and immunoregulation, as well as delaying diabetes in preclinical models. Here, we show that SCFA-biotherapy in humans is accompanied by remodeling of the gut proteome and mucosal immune homeostasis. Metabolomics showed arginine, glutamate, nucleotide and tryptophan metabolism were enriched following the SCFA-biotherapy, and found metabolites that correlated with glycemic control. Fecal microbiota transfer demonstrated that the microbiota of SCFA-responders delayed diabetes progression in humanized gnotobiotic mice. The protected mice increased similar metabolite pathways to the humans including producing aryl-hydrocarbon receptor ligands and reducing inflammatory mucosal immunity and increasing IgA production in the gut. These data demonstrate that a potent SCFA immunomodulator promotes multiple beneficial pathways and supports targeting the microbiota as an approach against T1D. Trial registration: Australia New Zealand Clinical Trials Registry ACTRN12618001391268.

Colonic starch fermentation requires the assistance of gut microbial amylases (GMAs). However, it remains unknown whether chemically substituted butyryl groups induce a steric inhibitory effect on GMAs analogous to that observed with pancreatic amylase during the intestinal digestion of butyrylated starch. In this study, we investigated the in vitro fermentation and enzymatic hydrolysis performance of three types of butyrylated starch. The results showed that the esterolysis of butyryl groups was a rate-limiting process, and the fermentation of butyrylated starch was partially inhibited by steric inhibition of the butyryl groups on GMAs. X-ray photoelectron spectroscopy (XPS) results further confirmed the negative correlation between the fermentation rate of starch and the relative content of butyryl groups accessible to the gut microbiota. Moreover, analyses of the enzymatic characteristics and the resulting hydrolysate composition demonstrated that a relatively high multiple attack degree (MAD) made GMAs more susceptible to steric inhibition by butyryl groups, thus producing more malto-oligosaccharides, which are preferred by butyrate-producing bacteria. These findings provide important insights into the fermentation behavior of butyrylated starch from the perspective of interactions between microbial amylases and starch.

Lung pathogenic T helper type 2 (pTh2) cells are important in mediating allergic asthma, but fundamental questions remain regarding their heterogeneity and epigenetic regulation. Here we investigate immune regulation in allergic asthma by single-cell RNA sequencing in mice challenged with house dust mite, in the presence and absence of histone deacetylase 1 (HDAC1) function. Our analyses indicate two distinct highly proinflammatory subsets of lung pTh2 cells and pinpoint thymic stromal lymphopoietin (TSLP) and Tumour Necrosis Factor Receptor Superfamily (TNFRSF) members as important drivers to generate pTh2 cells in vitro. Using our in vitro model, we uncover how signalling via TSLP and a TNFRSF member shapes chromatin accessibility at the type 2 cytokine gene loci by modulating HDAC1 repressive function. In summary, we have generated insights into pTh2 cell biology and establish an in vitro model for investigating pTh2 cells that proves useful for discovering molecular mechanisms involved in pTh2-mediated allergic asthma.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated pancreatic β cell loss, resulting in lifelong absolute insulin deficiency and hyperglycaemia. Environmental factors are recognized as a key contributor to the development of T1D, with the gut serving as a primary interface for environmental stimuli. Recent studies have revealed that the alterations in the intestinal microenvironment profoundly affect host immune responses, contributing to the aetiology and pathogenesis of T1D. However, the dominant intestinal immune cells and the underlying mechanisms remain incompletely elucidated. In this review, we provide an overview of the possible mechanisms of the intestinal mucosal system that underpin the pathogenesis of T1D, shedding light on the roles of both non-classical and classical immune cells in T1D. Our goal is to gain insights into how modulating these immune components may hold potential implications for T1D prevention and provide novel perspectives for immune-mediated therapy.

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.

The intestinal microecology is comprises intestinal microorganisms and other components constituting the entire ecosystem, presenting characteristics of stability and dynamic balance. Current research reveals intestinal microecological imbalances are related to various diseases. However, fundamental research and clinical applications have not been effectively integrated. Considering the importance and complexity of regulating the intestinal microecological balance, this study provides an overview of the high-risk factors affecting intestinal microecology and detection methods. Moreover, it proposes the definition of intestinal microecological imbalance and the definition, formulation, and outcomes of gut microecological prescription to facilitate its application in clinical practice, thus promoting clinical research on intestinal microecology and improving the quality of life of the population.

Type 1 diabetes (T1D) is a complex disease triggered by a combination of genetic and environmental factors, where abnormal autoimmune responses lead to progressive damage of the pancreatic β cells and severe glucose metabolism disorder. Recent studies have increasingly highlighted the close link between gut microbiota dysbiosis and the development of T1D. This review delves into existing population studies to explore the intricate interactions between the gut microbiota and the immune and metabolic homeostasis in T1D. It summarizes how changes in the structure and function of the gut microbiota are closely associated with the onset and progression of T1D across its natural course and clinical stages. More importantly, based on evidence accumulated from clinical observations and trials, we pioneer the discussion on gut microbiota-based T1D prevention and treatment strategies, this not only enriches our understanding of the complex pathological mechanisms of T1D but also provides potential directions for developing novel prevention and treatment strategies.

Type 1 diabetes (T1D) is an autoimmune-mediated disorder caused by the destruction of pancreatic beta cells. Although there is an underlying genetic predisposition to developing T1D, the trigger is multifactorial and likely includes environmental factors. The intestinal microbiome has been identified as one such factor. Previous studies have illustrated differences in the microbiota of people with T1D compared with healthy controls. This study aims to describe the evolution of the microbiome and metabolome during the first year of clinical T1D, or stage 3 T1D diagnosis, and investigate whether there are differences in the microbiome and metabolome of children who present with and without diabetic ketoacidosis. The study will also explore possible associations between the microbiome, metabolome, glycaemic control and beta cell reserve.

This prospective cohort study will include children with newly diagnosed T1D and sibling controls (n=100, males and females) and their faecal microbiome will be characterised using shotgun metagenomic sequencing at multiple time points during the first year of diagnosis. We will develop a microbial culture biobank based on culturomic studies of stool samples from the healthy controls that will support future investigation. Metabolomic analysis will aim to identify additional biomarkers which may be involved in disease presentation and progression. Through this initial exploratory study, we aim to identify specific microbial biomarkers which may be used as future interventional targets throughout the various stages of T1D progression.

This study has been approved by the Clinical Research Ethics Committee of the Cork Teaching Hospitals. Study results will be available to patients with T1D and their families, carers, support networks and microbiome societies and other researchers.

The clinicaltrials.gov registration number for this trial is NCT06157736.

Human milk oligosaccharides (HMOs) are abundant, diverse and complex sugars present in human breast milk. HMOs are well-characterized barriers to microbial infection and by modulating the human microbiome they are also thought to be nutritionally beneficial to the infant. The structural variety of over 200 HMOs, including neutral, fucosylated and sialylated forms, allows them to interact with the immune system in various ways. Clinically, HMOs impact allergic diseases, reducing autoimmune and inflammatory responses, and offer beneficial support to the preterm infant immune health. This review examines the HMO composition and associated immunomodulatory effects, including interactions with immune cell receptors and gut-associated immune responses. These immunomodulatory properties highlight the potential for HMO use in early stage immune development and for use as novel immunotherapeutics. HMO research is rapidly evolving and promises innovative treatments for immune-related conditions and improved health outcomes.

Diabetes mellitus is a common chronic metabolic disease characterized by a high incidence and disability rate. Intestinal flora refers to the microbial community that lives in the intestines and plays a crucial role in maintaining intestinal health and the human immune system. In recent years, an increasing body of research has revealed a close relationship between intestinal flora and diabetes. The pathophysiological mechanisms between them have also been constantly uncovered, and the regulation of intestinal flora has shown promising efficacy in the adjuvant treatment of diabetes. This study mainly summarized the characteristics and mechanisms of intestinal flora in patients with diabetes in recent years, as well as the methods of regulating intestinal flora to prevent and treat diabetes, and prospected the future research direction. This will offer a theoretical basis for the clinical adjuvant treatment of diabetes with intestinal flora and the development of new drugs.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by multiple joints lesions. Tolerogenic dendritic cells (tolDCs) play crucial roles in maintaining immune homeostasis. The immunomodulatory activity of plant-derived arabinogalactan (AGs) has been well investigated, however, whether AGs could suppress autoimmune responses by inducing tolDCs is remain unclear.

Collagen-induced arthritis (CIA, a mouse model of RA) mice were utilized to ascertain the role of AGs (obtained from Cynanchum atratum) in autoimmune responses. An antibiotic cocktail was administered to eliminate gut microbiota. Germ-free (GF) and Toll-like receptor 2 (TLR2) knockout mice were used to determine the function of AGs in intestinal immune cells.

The oral administration of dietary AGs substantially reduced the severity of CIA and rebalanced the ratio of regulatory T cells (Tregs) to T helper 17 (Th17) cells. Although the antibiotic cocktail depleted the mice's gut microbiota, AGs had a therapeutic effect on their CIA. AGs restored Treg/Th17 homeostasis by inducing CD103+ tolDCs, regardless of the gut microbiota of the GF mice. Coculture experiments confirmed that AGs induced tolDCs and transforming growth factor β (TGF-β) secretion, leading to Treg amplification. RNA sequencing and TLR2 knockout experiments revealed that AGs induced tolDCs through a TLR2-mediated mechanism. Preventive interventions with AGs established a tolerogenic intestinal immune microenvironment, which delayed the onset and progression of CIA. AGs functioned synergistically with tofacitinib, a JAK inhibitor, to effectively restore Treg/Th17 balance and alleviate CIA.

This study introduces a novel microbiota-independent mechanism through which soluble dietary AGs inhibit systemic autoimmune responses. Our findings provide insights into the supplementation of dietary AGs in patients with preclinical or progressive RA.

The gut microbiota plays a crucial role in maintaining homeostasis and promoting health. A growing number of studies have indicated that gut microbiota can affect cancer development, prognosis, and treatment through their metabolites. By remodeling the tumor microenvironment and regulating tumor immunity, gut microbial metabolites significantly influence the efficacy of anticancer therapies, including chemo-, radio-, and immunotherapy. Several novel therapies that target gut microbial metabolites have shown great promise in cancer models. In this review, we summarize the current research status of gut microbial metabolites in cancer, aiming to provide new directions for future tumor therapy.

Gut microbiota regulates the immune system, the development and progression of autoimmune diseases (AIDs) and overall health. Recent studies have played a crucial part in understanding the specific role of different gut bacterial strains and their metabolites in different AIDs. Microbial signatures in AIDs are revealed by advanced sequencing and metabolomics studies. Microbes such as Faecalibacterium prausnitzii, Akkermansia muciniphila, Anaerostipes caccae, Bacteroides sp., Roseburia sp., Blautia sp., Blautia faecis, Clostridium lavalense, Christensenellaceae sp., Coprococcus sp., Firmicutes sp., Ruminococcaceae sp., Lachnospiraceae sp., Megamonas sp., Monoglobus sp., Streptococcus pneumoniae and Bifidobacterium sp. help maintain immune homeostasis; whereas, Prevotella copri, Ruminococcus gnavus, Lactobacillus salivarius, Enterococcus gallinarum, Elizabeth menigoseptica, Collinsella sp., Escherichia sp., Fusobacterium sp., Enterobacter ludwigii, Enterobacteriaceae sp., Proteobacteria, Porphyromonas gingivalis, Porphyromonas nigrescens, Dorea sp., and Clostridium sp. cause immuno-pathogenesis. A complex web of interactions is revealed by understanding the influence of gut microbiota on immune cells and various T cell subsets such as CD4+ T cells, CD8+ T cells, natural killer T cells, γδ T cells, etc. Certain AIDs, including rheumatoid arthritis, diabetes mellitus, atopic asthma, inflammatory bowel disease and non-alcoholic fatty liver disease exhibit a state of dysbiosis, characterized by alterations in microbial diversity and relative abundance of specific taxa. This review summarizes recent developments in understanding the role of certain microbiota composition in specific AIDs, and the factors affecting specific regulatory T cells through certain microbial metabolites and also focuses the potential application and therapeutic significance of gut microbiota-based interventions as novel adjunctive therapies for AIDs. Further research to determine the precise association of each gut bacterial strain in specific diseases is required.

Arginine vasopressin (AVP) has disparate impacts on immune responses by divergent receptors on cells including DCs. This study was conducted with the aim of investigating the impact of AVP on the maturation and expression of the inhibitory immune checkpoint molecules in tolerogenic monocyte-derived DCs. CD14 marker was used to separate monocytes from peripheral blood mononuclear cells (PBMCs) by MACS method. To differentiate monocytes from DCs, we utilized GM-CSF and IL-4 cytokines. Tolerogenic DCs were generated using vitamin D3 and dexamethasone. We added LPS and AVP to the culture medium on day 6 after incubation of DCs at 37 °C. Finally, we assessed the surface molecules by flow cytometry and used real-time PCR to evaluate the expression of genes related to the inhibitory immune checkpoints. Based on the obtained data, AVP increased the expression of CD11c (P ≤ 0.0001), HLA-DR (P ≤ 0.01), and CD86 (P ≤ 0.01) in AVP-mDCs. Also, the expression of all the immune checkpoint genes including CTLA-4 (P ≤ 0.001), BTLA (P ≤ 0.001), PDL-1 (P ≤ 0.05), B7H7 (P ≤ 0.001), LAG3 (P ≤ 0.01), and VISTA (P ≤ 0.001) in AVP-mDCs was increased in comparison to the control group. Vasopressin caused the generation of mature and tolerogenic DCs. Our data may help to consider AVP-mDCs to take part in autoimmune disease therapy, transplanted tissue rejection impedance, and allergies.

Gut microbiome is crucial for lipid metabolism in humans and animals. However, how specific gut microbiota and their associated metabolites impact fat deposition remains unclear. In this study, we demonstrated that the colonic microbiome of lean and obese pigs differentially contributes to fat deposition, as evidenced by colonic microbiota transplantation experiments. Notably, the higher abundance of Bifidobacterium pseudocatenulatum was significantly associated with lower backfat thickness in lean pigs. Microbial-derived lithocholic acid (LCA) species were also significantly enriched in lean pigs and positively correlated with the abundance of B. pseudocatenulatum. In a high-fat diet (HFD)-fed mice model, administration of live B. pseudocatenulatum decreased fat deposition and enhances colonic secondary bile acid biosynthesis. Importantly, pharmacological inhibition of the bile salt hydrolase (BSH), which mediates secondary bile acid biosynthesis, impaired the anti-fat deposition effect of B. pseudocatenulatum in antibiotic-pretreated, HFD-fed mice. Furthermore, dietary LCA also decreased fat deposition in HFD-fed rats and obese pig models. These findings provide mechanistic insights into the anti-fat deposition role of B. pseudocatenulatum and identify BSH as a potential target for preventing excessive fat deposition in humans and animals.

Type 1 diabetes (T1D) is characterized by immune cell infiltration in the islets of Langerhans, leading to the destruction of insulin-producing beta cells. This destruction is driven by secreted cytokines and cytotoxic T cells inducing apoptosis in beta cells. Butyrate, a metabolite produced by the gut microbiota, has been shown to have various health benefits, including anti-inflammatory and anti-diabetic effects. In this study, we investigated the potential protective effects of butyrate on cytokine-induced apoptosis in beta cells and explored the underlying mechanisms. Insulin-secreting INS-1E cells and isolated mouse islets were treated with interleukin-1beta (IL-1β) or a combination of IL-1β and interferon-gamma (IFN-γ) in the presence or absence of butyrate. We analyzed apoptosis, nitric oxide (NO) levels, expression of stress-related genes, and immune cell migration. Our results demonstrated that butyrate significantly attenuated cytokine-induced apoptosis in both INS-1E cells and mouse islets, accompanied by a reduction in NO levels. Butyrate also decreased the expression of endoplasmic reticulum (ER) stress markers such as Chop, phosphorylated eIF2α and Atf4, as well as some pro-apoptotic genes including Dp5 and Puma. Butyrate reduced the cytokine-induced expression of the chemokine genes Cxcl1 and Cxcl10 in mouse islets, as well as the chemotactic activity of THP-1 monocytes toward conditioned media from IL-1β-exposed islets. In conclusion, these findings indicate that butyrate protects beta cells from cytokine-induced apoptosis and ER stress, suggesting its potential as a therapeutic agent to prevent beta cell destruction in T1D.

Systemic lupus erythematosus (SLE) is linked to host gut dysbiosis. Here we performed faecal gut microbiome sequencing to investigate SLE-pathogenic gut microbes and their potential mechanisms.

There were 134 healthy controls (HCs) and 114 SLE cases for 16 S ribosomal RNA (rRNA) sequencing and 97 HCs and 124 SLE cases for shotgun metagenomics. Faecal microbial changes and associations with clinical phenotypes were evaluated, and SLE-associated microbial genera were identified in amplicon analysis. Next, metagenomic sequencing was applied for accurate identification of microbial species and discovery of their metabolic pathways and immunogenic peptides both relevant to SLE. Finally, contribution of specific taxa to disease development was confirmed by oral gavage into lupus-prone MRL/lpr mice.

SLE patients had gut microbiota richness reduction and composition alteration, particularly lupus nephritis and active patients. Proteobacteria/Bacteroidetes (P/B) ratio was remarkably up-regulated, and Escherichia was identified as the dominantly expanded genus in SLE, followed by metagenomics accurately located Escherichia coli and Escherichia unclassified species. Significant associations primarily appeared among Escherichia coli, metabolic pathways of purine nucleotide salvage or peptidoglycan maturation and SLE disease activity index (SLEDAI), and between multiple epitopes from Escherichia coli and disease activity or renal involvement phenotype. Finally, gavage with faecal Escherichia revealed that it upregulated lupus-associated serum traits and aggravated glomerular lesions in MRL/lpr mice.

We characterize a novel SLE exacerbating Escherichia outgrowth and suggest its contribution to SLE procession may be partially associated with metabolite changes and cross-reactivity of gut microbiota-associated epitopes and host autoantigens. The findings could provide a deeper insight into gut Escherichia in the procession of SLE.

The bidirectional interaction between the gut and the central nervous system (CNS), the so-called gut microbiota-brain axis, is reported to influence brain functions, thus having a potential impact on the development or the progression of several neurodegenerative disorders. Within this context, it has been documented that multiple sclerosis (MS), an autoimmune inflammatory, demyelinating, and neurodegenerative disease of the CNS, is associated with gastrointestinal symptoms, including constipation, dysphagia, and faecal incontinence. Moreover, some evidence suggests the existence of an altered gut microbiota (GM) composition in MS patients with respect to healthy individuals, as well as the potential influence of GM dysbiosis on typical MS features, including increased intestinal permeability, disruption of blood-brain barrier integrity, chronic inflammation, and altered T cells differentiation. Starting from these assumptions, the possible involvement of GM alteration in MS pathogenesis seems likely, and its restoration could represent a supplemental beneficial strategy against this disabling disease. In this regard, the present review will explore possible preventive approaches (including several dietary interventions, the administration of probiotics, prebiotics, synbiotics, and postbiotics, and the use of faecal microbiota transplantation) to be pursued as prophylaxis or in combination with pharmacological treatments with the aim of re-establishing a proper GM, thus helping to prevent the development of this disease or to manage it by alleviating symptoms or slowing down its progression.

Diabetes Mellitus (DM) is a substantial health concern worldwide, and its incidence is progressively escalating. Conventional pharmacological interventions frequently entail undesirable side effects, and while probiotics offer benefits, they are hindered by constraints such as diminished stability and effectiveness within the gastrointestinal milieu. Given these complications, the advent of bioengineered probiotics is a promising alternative for DM management.

The objective of this review is to provide an exhaustive synthesis of the most recent studies on the use of engineered probiotics in the management of DM. This study aimed to clarify the mechanisms through which these probiotics function, evaluate their clinical effectiveness, and enhance public awareness of their prospective advantages in the treatment of DM.

Scholarly critiques have explored diverse methodologies of probiotic engineering, including physical alteration, bioenrichment, and genetic manipulation. These techniques augment the therapeutic potency of probiotics by ameliorating gut microbiota, fortifying the intestinal barrier, modulating metabolic pathways, and regulating immune responses. Such advancements have established engineered probiotics as a credible therapeutic strategy for DM, potentially providing enhanced results compared to conventional treatments.

Nutrition is an essential part of therapy for type 1 diabetes and is constantly evolving, offering growing opportunities to prevent this disease, slow down its evolution, and mitigate it. An attempt was made to bring together the current state of knowledge. In the path from the preclinical phase of the disease to its clinical onset, there is a phase known as the "honeymoon period" or partial remission, where different possible dietary options for combatting this disease have been presented. The most commonly used dietary models were compared, and the most frequent co-existing pathologies, such as overweight, non-alcoholic fatty liver disease, dyslipidemia, celiac disease, and metabolic instability, were addressed from their nutritional and dietary perspectives to provide clinicians with an updated framework of knowledge and support researchers in further investigations into the topic. Finally, a glimpse into the possible interplay between nutrition and the gut microbiome, food security, and ultra-processed food is provided. It is hoped that clinicians treating people with type 1 diabetes will be provided with further opportunities for the daily management of their patients through personalized nutrition.

Latent Autoimmune Diabetes in Adults (LADA) is a type of diabetes mellitus often overlooked in clinical practice for its dual resemblance to Type 1 Diabetes Mellitus (T1DM) in pathogenesis and to Type 2 Diabetes Mellitus (T2DM) in clinical presentation. To better understand LADA's distinctiveness from T1DM and T2DM, we conducted a comprehensive review encompassing etiology, pathology, clinical features, treatment modalities, and prognostic outcomes. With this comparative lens, we propose that LADA defies simple classification as either T1DM or T2DM. The specific treatments for the disease are limited and should be based on the therapies of T1DM or T2DM that address specific clinical issues at different stages of the disease. It is crucial to identify LADA cases potentially misdiagnosed as T2DM, warranting prompt screening for poor blood sugar control, short-term blood sugar deterioration, and other conditions. If the prognosis for LADA is similar to T2DM, it can be managed as T2DM. However, if the prognosis fundamentally differs, early LADA screening is crucial to optimize patient outcomes and enhance research on tailored treatments. The pathogenesis of LADA is clear, so the prognosis may be the key to determining whether it can be classified as T2DM, which is also the direction of future research. On the one hand, this paper aims to provide suggestions for the clinical screening and treatment of LADA based on the latest progress and provide worthy directions for future research on LADA.

Autoimmune disorders are characterized by aberrant T cell and B cell reactivity to the body's own components, resulting in tissue destruction and organ dysfunction. Autoimmune diseases affect a wide range of people in many parts of the world and have become one of the major concerns in public health. In recent years, there have been substantial progress in our understanding of the epidemiology, risk factors, pathogenesis and mechanisms of autoimmune diseases. Current approved therapeutic interventions for autoimmune diseases are mainly non-specific immunomodulators and may cause broad immunosuppression that leads to serious adverse effects. To overcome the limitations of immunosuppressive drugs in treating autoimmune diseases, precise and target-specific strategies are urgently needed. To date, significant advances have been made in our understanding of the mechanisms of immune tolerance, offering a new avenue for developing antigen-specific immunotherapies for autoimmune diseases. These antigen-specific approaches have shown great potential in various preclinical animal models and recently been evaluated in clinical trials. This review describes the common epidemiology, clinical manifestation and mechanisms of autoimmune diseases, with a focus on typical autoimmune diseases including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and sjögren's syndrome. We discuss the current therapeutics developed in this field, highlight the recent advances in the use of nanomaterials and mRNA vaccine techniques to induce antigen-specific immune tolerance.

There is increased interest in utilizing dietary interventions to alter the progression of autoimmune diseases. These efforts are driven by associations of gut microbiota/metabolites with levels of short-chain fatty acids (SCFAs). Propionate is a key SCFA that is commonly used as a food preservative and is endogenously generated by bacterial fermentation of non-digestible carbohydrates in the gut. A thesis has suggested that a diet rich in propionate and other SCFAs can successfully modulate autoimmunity. Herein, we investigated the effect of long-term administration of propionylated high-amylose resistant starches (HAMSP) on the course of murine primary biliary cholangitis.

Groups of female ARE-Del mice were fed an HAMSP diet either before or after disease onset. A detailed immunobiological analysis was performed involving autoantibodies and rigorous T-cell phenotyping, including enumeration of T-cell subsets in the spleen, liver, intestinal intraepithelial lymphocytes and lamina propria by flow cytometry. Histopathological scores were used to assess the frequency and severity of liver inflammation and damage to hepatocytes and bile ducts.

Our results demonstrate that a long-term propionate-yielding diet re-populated the T-cell pool with decreased naïve and central memory T-cell subsets and an increase in the effector memory T cells in mice. Similarly, long-term HAMSP intake reduced CD4+CD8+ double-positive T cells in intraepithelial lymphocytes and the intestinal lamina propria. Critically, HAMSP consumption led to moderate-to-severe hepatocellular steatosis in ARE-Del mice, independent of the stage of autoimmune cholangitis.

Our data suggest that administration of HAMSP induces both regulatory and effector T cells. Furthermore, HAMSP administration resulted in hepatocellular steatosis. Given the interest in dietary modulation of autoimmunity and because propionate is widely used as a food preservative, these data have significant implications. This study also provides new insights into the immunological and pathological effects of chronic propionate exposure.

Short-chain fatty acids (SCFAs) are major metabolites produced by the gut microbiota through the fermentation of dietary fiber, and they have garnered significant attention due to their close association with host health. As important mediators between the gut microbiota and the host, SCFAs serve as energy substrates for intestinal epithelial cells and maintain homeostasis in host immune and energy metabolism by influencing host epigenetics, activating G protein-coupled receptors, and inhibiting pathogenic microbial infections. This review provides a comprehensive summary of SCFAs synthesis and metabolism and offering an overview of the latest research progress on their roles in protecting gut health, enhancing energy metabolism, mitigating diseases such as cancer, obesity, and diabetes, modulating the gut-brain axis and gut-lung axis, and promoting bone health.

The human gastrointestinal (GI) tract microbiome is a complex and all-encompassing ecological system of trillions of microorganisms. It plays a vital role in digestion, disease prevention, and overall health. When this delicate balance is disrupted, it can lead to various health issues. Fecal microbiota transplantation (FMT) is an emerging therapeutic intervention used as an adjuvant therapy for many diseases, particularly those with dysbiosis as their underlying cause. Its goal is to restore this balance by transferring fecal material from healthy donors to the recipients. FMT has an impressive reported cure rate between 80% and 90% and has become a favored treatment for many diseases. While FMT may have generally mild to moderate transient adverse effects, rare severe complications underscore the importance of rigorous donor screening and standardized administration. FMT has enormous potential as a practical therapeutic approach; however, additional research is required to further determine its potential for clinical utilization, as well as its safety and efficiency in different patient populations. This comprehensive literature review offers increased confidence in the safety and effectiveness of FMT for several diseases affecting the intestines and other systems, including diabetes, obesity, inflammatory and autoimmune illness, and other conditions.

Numerous studies have investigated a possible correlation between Epstein-Barr virus (EBV) and autoimmune rheumatic diseases (ARDs). However, establishing a cause-and-effect relationship remains a challenging endeavor. This study employs Mendelian randomization to examine the impact of EBV nuclear antigen-1 antibody (EBNA-1) antibody levels on the susceptibility to nine distinct ARDs, including rheumatoid arthritis (RA), primary Sjogren's syndrome (PSS), systemic lupus erythematosus (SLE), undifferentiated reactive arthritis (UA), systemic sclerosis (SSc), adult-onset Still's disease (AOSD), psoriatic arthritis (PsA), dermatomyositis (DM), and ankylosing spondylitis (AS).

The researchers applied a two-sample Mendelian randomization approach, utilizing online data from separate cohorts of European descent. We drew upon data from GWAS related to EBNA-1 antibody levels and the nine autoimmune-related disorders. Our primary analyses predominantly relied on the Inverse Variance Weighted methodology, complemented by a range of sensitivity assessments.

Our analysis revealed significant direct associations between EBNA-1 antibody levels and the risk of developing PSS (95 % CI: 0.44 to 0.85, p = 0.003), PsA (95 % CI: 0.36 to 0.99, p = 0.044), AS (95 % CI: 0.07 to 0.88, p = 0.031), and UA (95 % CI: 0.56 to 0.96, p = 0.025). These results remained consistent through comprehensive sensitivity analyses. However, no clear associations were found for the other specified conditions.

Our findings provide compelling evidence that EBNA-1 antibody levels play a role in developing ARDs. These findings enhance our understanding of ARD pathogenesis and hold substantial promise for developing potential treatment strategies.

Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC.

We measured fecal short-chain fatty acids levels using targeted gas chromatography-mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and chromatin immunoprecipitation-quantitative polymerase chain reaction), and metabolic (untargeted liquid chromatography-mass spectrometry, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in a 2-octynoic acid-bovine serum albumin-induced cholangitis murine model.

Decreased butyrate levels and defective MDSC function were found in patients with incomplete response to ursodeoxycholic acid, compared with those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid β-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced acetylation of lysine 27 on histone H3 at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from ursodeoxycholic acid nonresponders, and their impaired suppressive function was restored by butyrate.

We identify a critical role for butyrate in modulation of MDSC homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC.