Enrofloxacin (ENR) and atrazine (ATZ) are common co-contaminants in marine environments. Although the immunosuppressive effects of ENR and the endocrine-disrupting properties of ATZ are well established, the combined effects of these pollutants on hepatotoxicity, particularly concerning the regulation of the hypothalamic-pituitary-thyroid (HPT) and gut-liver axes, remain poorly understood. In this study, Larimichthys crocea was exposed to ENR and ATZ at environmentally relevant concentrations, individually and in combination, to investigate the hepatotoxicity. Liver cell swelling, necrosis, oxidative stress, and elevated liver injury markers were observed, indicating hepatic damage, with co-exposure exacerbating liver injury. Decreased levels of thyrotropin-releasing hormone and thyroid-stimulating hormone, increased triiodothyronine and thyroxine, and altered expression of HPT axis-related genes demonstrated enhanced disruption of the HPT axis under co-exposure, which was strongly associated with oxidative stress and liver dysfunction. Molecular docking confirmed that ENR and ATZ inhibited thyroid hormone binding to target proteins, likely provoking the enhanced hepatotoxicity. Additionally, ATZ significantly intensified the intestinal bacterial disturbances induced by ENR, further aggravating hepatotoxicity through the gut-liver axis. This study is the first to reveal the increased risk associated with ENR and ATZ co-exposure, highlighting the need for attention to such co-contaminants.

Chronic metabolic inflammation is a common mechanism linked to the development of metabolic disorders such as obesity, diabetes, and cardiovascular disease (CVD). Chronic metabolic inflammation often related to alterations in gut homeostasis, and pathological processes involve the activation of endotoxin receptors, metabolic reprogramming, mitochondrial dysfunction, and disruption of intestinal nuclear receptor activity. Recent investigations into homeostasis and chronic metabolic inflammation have revealed a novel mechanism which is characterized by a timing interaction involving multiple components and targets. This article explores the positive impact of tea consumption on metabolic health of populations, with a special focus on the improvement of inflammatory indicators and the regulation of gut microbiota. Studies showed that tea consumption is related to the enrichment of gut microbiota. The relative proportion of Firmicutes/Bacteroidetes (F/B) is altered, while the abundance of Lactobacillus, Bifidobacterium, and A. muciniphila increased significantly in most of the studies. Thus, tea consumption could provide potential protection from the development of chronic diseases by improving gut homeostasis and reducing chronic metabolic inflammation. The direct impact of tea on intestinal homeostasis primarily targets lipopolysaccharide (LPS)-related pathways. This includes reducing the synthesis of intestinal LPS, inhibiting LPS translocation, and preventing the binding of LPS to TLR4 receptors to block downstream inflammatory pathways. The TLR4/MyD88/NF-κB p65 pathway is crucial for anti-metaflammatory responses. The antioxidant properties of tea are linked to enhancing mitochondrial function and mitigating mitochondria-related inflammation by eliminating free radicals, inhibiting NLRP3 inflammasomes, and modulating Nrf2/ARE activity. Tea also contributes to safeguarding the intestinal barrier through various mechanisms, such as promoting the synthesis of short-chain fatty acids in the intestine, activating intestinal aryl hydrocarbon receptor (AhR) and farnesoid X receptor (FXR), and improving enteritis. Functional components that improve chronic metabolic inflammation include tea polyphenols, tea pigments, TPS, etc. Tea metabolites such as 4-Hydroxyphenylacetic acid and 3,4-Dihydroxyflavan derivatives, etc., also contribute to anti-chronic metabolic inflammation effects of tea consumption. The raw materials and processing technologies affect the functional component compositions of tea; therefore, consuming different types of tea may result in varying action characteristics and mechanisms. However, there is currently limited elaboration on this aspect. Future research should conduct in-depth studies on the mechanism of tea and its functional components in improving chronic metabolic inflammation. Researchers should pay attention to whether there are interactions between tea and other foods or drugs, explore safe and effective usage and dosage, and investigate whether there are individual differences in the tea-drinking population leading to different effects of tea intervention. Ultimately, the application of tea drinking could be a universal therapy for regulating intestinal homeostasis, anti-chronic metabolic inflammatory responses, and promoting metabolic health.

The aging population worldwide is on the rise, leading to a higher number of Parkinson's disease (PD) cases each year. PD is presently the second most prevalent neurodegenerative disease, affecting an estimated 7-10 million individuals globally. This research aimed to identify mobile genetic elements in human fecal samples using a shotgun metagenomics approach. We identified over 44,000 plasmid contigs and compared plasmid populations between PD patients (n = 68) and controls (n = 68). Significant associations emerged between groups (control vs PD) based on plasmid alpha and beta diversity. Moreover, the gene populations present on plasmids displayed marked differences in alpha and beta diversity between PD patients and controls. We identified a considerable number of phage contigs that were differentially abundant in the two groups. We also developed a predictive machine learning model based on phage abundance data, achieving a mean Area Under the Curve (AUC) of 0.74 with a standard deviation of 0.105 and a mean F1 score of 0.68 with a standard deviation of 0.14 across cross-validation folds, indicating moderate discriminatory power. Additionally, when tested on external data, the model yielded an AUC of 0.74 and an F1 score of 0.8, further demonstrating the predictive potential of phage populations in Parkinson's disease. Further, we improved the continuity and identification of the protein coding regions of the phage contigs by implementing alternative genetic codes.

Sexually transmitted infections are associated with gynaecological conditions, yet screening algorithms are lacking. The aim was determining the utility of endometrial specimens for chronic gynaecological diagnosis. In a retrospective cohort study of 91 patients (42.8 % CD138-positive), only 5.5 % tested were positive for Ureaplasma parvum. Endometrial STI screening was not useful in a population of low STI prevalence (<10 %), suggesting its value depends on STI prevalence.

This study investigated the effects of different non-starch polysaccharide (NSP) sources with NSP degrading enzymes (NSPases) and the influence on the mucosa-associated microbiota and intestinal immunity of nursery pigs, on growth performance and carcass traits at market weight.

One hundred and sixty newly weaned pigs at 7.0 ± 0.3 kg body weight (BW) were allotted in a 2 × 2 factorial with NSP sources and NSPases serving as factors. The 4 dietary treatments were: DDGS, corn distillers' dried grains with solubles as source of NSP; DDGS + NSPases (DDGS +), DDGS with xylanase at 0.01%, 3,000 U/kg of feed and β-mannanase at 0.05%, 400 U/kg of feed; SHWB, soybean hulls and wheat bran replacing corn DDGS as the source of NSP; SHWB with NSPases (SHWB +), SHWB with xylanase at 0.01%, 3,000 U/kg of feed and β-mannanase at 0.05%, 400 U/kg of feed. Pigs were fed for 37 d and housed in groups of 4 pigs per pen. At d 37, the median body weight pig in each pen was euthanized for sampling to analyze intestinal health parameters. Remaining pigs were fed a common diet for subsequent phases to evaluate the carryover effect on growth and carcass traits.

The SHWB decreased (P < 0.05) the relative abundance of Helicobacter, tended to increase (P = 0.074) the relative abundance of Lactobacillus, increased (P < 0.05) immunoglobulin G (IgG) in the jejunal mucosa, tended to increase (P = 0.096) the villus height (VH) in the jejunum, and tended to improve ADG (P = 0.099) and feed efficiency (P = 0.068) during phase 1 compared to DDGS treatment. Supplementation of NSPases increased (P < 0.05) Shannon index of diversity, increased the relative abundance of Streptococcus and Acinetobacter, and tended to increase (P = 0.082) dry matter digestibility. The BW of pigs fed SHWB was more uniform (P < 0.05) at the end of the 120 d study. Additionally, hot carcass weight of pigs fed SHWB tended to be more uniform (P = 0.089) than DDGS treatment.

Soybean hulls and wheat bran replacing DDGS in nursery diets improved uniformity of pigs at market weight, which might be attributed to beneficial modulation of the mucosa-associated microbiota and enhanced intestinal morphology during the nursery phase. Supplementation of NSPases had beneficial effects on the intestinal mucosa-associated microbiota, digestibility, and intestinal immunity in SHWB treatment, whereas no carryover effects were overserved at market weight.

Alzheimer's Disease (AD) is a debilitating neurocognitive disorder with an unclear underlying mechanism. Recent studies have implicated gut microbiota dysbiosis with the onset and progression of AD. The connection between gut microbiota and AD can significantly affect the prevention and treatment of AD patients. This systematic review summarizes primary outcomes of human and mouse AD models concerning gut microbiota alterations. A systematic literature search in February through March 2023 was conducted on PubMed, Embase, and Web of Science. We identified 711 as potential manuscripts of which 672 were excluded because of irrelevance to the identified search criteria. Primary outcomes include microbiota compositions of control and AD models in humans and mice. In total, 39 studies were included (19 mouse and 20 human studies), published between 2017 and 2023. We included studies involving well-established mice models of AD (5xFAD, 3xTg-AD, APP/PS1, Tg2576, and APPPS2) which harbor mutations and genes that drive the formation of Aß plaques. All human studies were included on those with AD or mild cognitive impairment. Among alterations in gut microbiota, most studies found a decreased abundance of the phyla Firmicutes and Bifidobacteria, a genus of the phylum Actinomycetota. An increased abundance of the phyla Bacteroidetes and Proteobacteria were identified in animal and human studies. Studies indicated that gut microbiota alter the pathogenesis of AD through its impact on neuroinflammation and permeability of the gastrointestinal tract. The ensuing increase in blood-brain barrier permeability may accelerate Aβ penetrance and formation of neuritic plaques that align with the amyloid hypothesis of AD pathogenesis. Further studies should assess the relationship between gut microbiota and AD progression and therapy preserving beneficial gut microbiota.

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.

Brain-machine interface performance can be affected by neuroinflammatory responses due to blood-brain barrier (BBB) damage following intracortical microelectrode implantation. Recent findings suggest that certain gut bacterial constituents might enter the brain through damaged BBB. Therefore, we hypothesized that damage to the BBB caused by microelectrode implantation could facilitate microbiome entry into the brain. In our study, we found bacterial sequences, including gut-related ones, in the brains of mice with implanted microelectrodes. These sequences changed over time. Mice treated with antibiotics showed a reduced presence of these bacteria and had a different inflammatory response, which temporarily improved microelectrode recording performance. However, long-term antibiotic use worsened performance and disrupted neurodegenerative pathways. Many bacterial sequences found were not present in the gut or in unimplanted brains. Together, the current study established a paradigm-shifting mechanism that may contribute to chronic intracortical microelectrode recording performance and affect overall brain health following intracortical microelectrode implantation.

Transplantation of beneficial bacteria to specific microbiota has been widely exploited to treat diseases by reshaping a healthy microbial structure. However, direct exposure of exogenous bacteria in vivo suffers from low bioavailability and infection risk. Here, we describe a noncontact microbiota transplantation system (NMTS) by core-shell microgel-enabled nonleakage envelopment. Bacteria are encapsulated into the core of core-shell microgels via two-step light-initiated emulsion polymerization of gelatin methacrylate. NMTS is versatile for biocontainment of diverse strains, showing near complete encapsulation and negligible influence on bacterial activity. As a proof-of-concept study on probiotic transplantation to the gut microbiota, NMTS demonstrates the shielding effect to protect sealed bacteria from intraluminal insults of low pH and bile acid, the toughness to prevent bacterial leakage during entire gastrointestinal passage and reduce infection risk, and the permeability to release beneficial metabolites and reconstruct a balanced intestinal microbial structure, proposing a contactless fashion for advanced microbiota transplantation.

Chronic restraint stress (CRS) is a tumour-promoting factor. However, the underlying mechanism is unknown.

We aimed to investigate whether CRS promotes head and neck squamous cell carcinoma (HNSCC) by altering the oral microbiota and related metabolites and whether kynurenine (Kyn) promotes HNSCC by modulating CD8+ T cells.

4-nitroquinoline-1-oxide (4NQO)-treated mice were exposed to CRS. Germ-free mice treated with 4NQO received oral microbiota transplants from either CRS or control mouse donors. 16S rRNA gene sequencing and liquid chromatography-mass spectrometry were performed on mouse saliva, faecal and plasma samples to investigate alterations in their microbiota and metabolites. The effects of Kyn on HNSCC were studied using the 4NQO-induced HNSCC mouse model.

Mice subjected to CRS demonstrated a higher incidence of HNSCC and oral microbial dysbiosis than CRS-free control mice. Pseudomonas and Veillonella species were enriched while certain oral bacteria, including Corynebacterium and Staphylococcus species, were depleted with CRS exposure. Furthermore, CRS-altered oral microbiota promoted HNSCC formation, caused oral and gut barrier dysfunction, and induced a host metabolome shift with increased plasma Kyn in germ-free mice exposed to 4NQO treatment. Under stress conditions, we also found that Kyn activated aryl hydrocarbon receptor (AhR) nuclear translocation and deubiquitination in tumour-reactive CD8+ T cells, thereby promoting HNSCC tumourigenesis.

CRS-induced oral microbiota dysbiosis plays a protumourigenic role in HNSCC and can influence host metabolism. Mechanistically, under stress conditions, Kyn promotes CD8+ T cell exhaustion and HNSCC tumourigenesis through stabilising AhR by its deubiquitination.

Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development1, metabolism2-4, immune responses5-7 and cognitive function8. However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear9,10. Here, using untargeted metabolomics of mouse tissues, we identified a family of BA-methylcysteamine (BA-MCY) conjugates that are abundant in the intestine and dependent on vanin 1 (VNN1), a pantetheinase highly expressed in intestinal tissues. This host-dependent MCY conjugation inverts BA function in the hepatobiliary system. Whereas microbiota-derived free BAs function as agonists of the farnesoid X receptor (FXR) and negatively regulate BA production, BA-MCYs act as potent antagonists of FXR and promote expression of BA biosynthesis genes in vivo. Supplementation with stable-isotope-labelled BA-MCY increased BA production in an FXR-dependent manner, and BA-MCY supplementation in a mouse model of hypercholesteraemia decreased lipid accumulation in the liver, consistent with BA-MCYs acting as intestinal FXR antagonists. The levels of BA-MCY were reduced in microbiota-deficient mice and restored by transplantation of human faecal microbiota. Dietary intervention with inulin fibre further increased levels of both free BAs and BA-MCY levels, indicating that BA-MCY production by the host is regulated by levels of microbiota-derived free BAs. We further show that diverse BA-MCYs are also present in human serum. Together, our results indicate that BA-MCY conjugation by the host balances host-dependent and microbiota-dependent metabolic pathways that regulate FXR-dependent physiology.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and progressive neuronal damage. Recent research has highlighted the significant roles of the gut microbiota and microRNAs (miRNAs) in the pathogenesis of AD. This review explores the intricate interaction between gut microbiota and miRNAs, emphasizing their combined impact on Alzheimer's progression. First, we discuss the bidirectional communication within the gut-brain axis and how gut dysbiosis contributes to neuroinflammation and neurodegeneration in AD. Changes in gut microbiota composition in Alzheimer's patients have been linked to inflammation, which exacerbates disease progression. Next, we delve into the biology of miRNAs, focusing on their roles in gene regulation, neurodevelopment, and neurodegeneration. Dysregulated miRNAs are implicated in AD pathogenesis, influencing key processes like inflammation, tau pathology, and amyloid deposition. We then examine how the gut microbiota modulates miRNA expression, particularly in the brain, potentially altering neuroinflammatory responses and synaptic plasticity. The interplay between gut microbiota and miRNAs also affects blood-brain barrier integrity, further contributing to Alzheimer's pathology. Lastly, we explore therapeutic strategies targeting this gut microbiota-miRNA axis, including probiotics, prebiotics, and dietary interventions, aiming to modulate miRNA expression and improve AD outcomes. While promising, challenges remain in fully elucidating these interactions and translating them into effective therapies. This review highlights the importance of understanding the gut microbiota-miRNA relationship in AD, offering potential pathways for novel therapeutic approaches aimed at mitigating the disease's progression.

Rising studies have consistently reported gut bacteriome alterations in schizophrenia (SCZ). However, little is known about the role of the gut virome on shaping the gut bacteriome in SCZ. Here in, we sequenced the fecal virome, bacteriome, and host peripheral metabolome in 49 SCZ patients and 49 health controls (HCs). We compared the gut bacterial community composition and specific abundant bacteria in SCZ patients and HCs. Specific gut viruses and host peripheral metabolites co-occurring with differential bacteria were identified using Multiple Co-inertia Analysis (MCIA). Additionally, we construct a latent serial mediation model (SMM) to investigate the effect of the gut virome on SCZ through the bacteriome and host metabolic profile. SCZ patients exhibited a decreased gut bacterial β-diversity compared to HCs, with seven differentially abundant bacteria, including Coprobacillaceae, Enterococcaceae etc. Gut viruses including Suoliviridae and Rountreeviridae, co-occur with these SCZ-related bacteria. We found that the viral-bacterial transkingdom correlations observed in HCs were dramatically lost in SCZ. The altered correlations profile observed in SCZ may impact microbiota-derived peripheral metabolites enriched in the bile acids pathway, eicosanoids pathway, and others, contributing to host immune dysfunction and inflammation. The SMM model suggested potential causal chains between gut viruses and SCZ, indicating that the effect of gut virome on SCZ is significantly mediated by bacteriome and metabolites. In conclusion, these findings provide a comprehensive perspective on the role of gut microbiota in the pathogenesis of SCZ. They reveal that patients with schizophrenia harbor an abnormal virome-bacteriome ecology, shedding light on the potential development of microbial therapeutics.

Despite gut microbiota-derived extracellular vesicles (EVs) serving as pivotal mediators in bacteria-host cell interactions, their potential role in modulating skin inflammation remains poorly understood. Here, we developed strategies for mass production of Parabacteroides goldsteinii-derived outer membrane vesicles (Pg OMVs), commonly known as EVs. We found that orally administered Pg OMVs can reach the colon, traverse the intestinal barrier, and circulate to the inflamed skin of psoriasis-like mice, resulting in reduced epidermal hyperplasia, suppressed infiltration of inflammatory cells in the skin lesions, and effective amelioration of both skin and systemic inflammation. Additionally, subcutaneous injection of thermosensitive PF-127 hydrogel loaded with Pg OMVs exerts similar immunomodulatory effects, allowing sustained release of Pg OMVs into skin cells, effectively suppressing skin inflammation and ameliorating symptoms of psoriasis. This study unveils the importance of gut microbiota-derived OMVs, which can target inflamed skin via both the gut-skin axis and local skin administration, providing a promising alternative to live bacteria therapy for the treatment of skin inflammatory diseases.

The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad of microbial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensive understanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points, thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remains incomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on the dynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures and functions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanisms involved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-related diseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immune responses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines and inhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention and treatment.

Microbiota composition regulates colitis severity, yet the innate immune mechanisms that control commensal communities and prevent disease remain unclear. We show that the innate immune receptor, Clec12a, impacts colitis severity by regulating microbiota composition. Transplantation of microbiota from a Clec12a-/- animal is sufficient to worsen colitis in wild-type mice. Clec12a-/- mice have expanded Faecalibaculum rodentium, and treatment with F. rodentium similarly exacerbates disease. However, Clec12a-/- animals are resistant to colitis development when rederived into an 11-member community, underscoring the role of specific species. Colitis in Clec12a-/- mice is dependent on monocytes, and cytokine and sequencing analysis in Clec12a-/- macrophages and serum shows enhanced inflammation with a reduction in phagocytic genes. F. rodentium specifically binds to Clec12a, and Clec12a-/--deficient macrophages are impaired in their ability to phagocytose F. rodentium. Thus, Clec12a contributes to an innate-immune-surveillance mechanism that controls the expansion of potentially harmful commensals while limiting inflammation.

The role of microbes and their metabolites in modulating tuft cell (TC) dynamics in the large intestine and the relevance of this pathway to infections is unknown. Here, we uncover that microbiome-driven colonic TC hyperplasia protects against Clostridioides difficile infection. Using selective antibiotics, we demonstrate increased type 2 cytokines and TC hyperplasia in the colon but not in the ileum. We demonstrate the causal role of the microbiome in modulating this phenotype using fecal matter transplantation and administration of consortia of succinate-producing bacteria. Administration of succinate production-deficient microbes shows a reduced response in a Pou2f3-dependent manner despite similar intestinal colonization. Finally, antibiotic-treated mice prophylactically administered with succinate-producing bacteria show increased protection against C. difficile-induced morbidity and mortality. This effect is nullified in Pou2f3-/- mice, confirming that the protection occurs via the TC pathway. We propose that activation of TCs by the microbiota in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by pathogens.

The gut microbiota, a dynamic ecosystem of trillions of microorganisms, produces secondary metabolites that profoundly influence host health. Recent research has highlighted the significant role of these metabolites, particularly short-chain fatty acids, indoles, and bile acids, in modulating immune responses, impacting epigenetic mechanisms, and contributing to disease processes. In gastrointestinal (GI) cancers such as colorectal, liver, and gastric cancer, microbial metabolites can drive tumorigenesis by promoting inflammation, DNA damage, and immune evasion. Conversely, these same metabolites hold therapeutic promise, potentially enhancing responses to chemotherapy and immunotherapy and even directly suppressing tumor growth. In addition, gut microbial metabolites play crucial roles in infectious disease susceptibility and resilience, mediating immune pathways that impact pathogen resistance. By consolidating recent insights into the gut microbiota's role in shaping disease and health, this review underscores the therapeutic potential of targeting microbiome-derived metabolites for treating GI cancers and infectious diseases and calls for further research into microbiome-based interventions.

Inflammatory bowel disease (IBD) is a spectrum of diseases characterized by the interplay of the aberrant immune system, genetic factors, environmental factors, and intestinal microbiota, resulting in relapsing inflammation of the gastrointestinal tract. Underlying pro-inflammatory state and immune dysregulation act as a catalyst for increasing the likelihood of developing extraintestinal manifestations, including cardiovascular diseases (CVD) like atherosclerosis, pericarditis, myocarditis, venous and arterial thromboembolism, arrhythmias, despite a lower prevalence of classic CVD risk factors, like high body mass index or dyslipidemia compared to the general population. Chronic inflammation damages endothelium resulting in the recruitment of inflammatory cells, which induce cytotoxicity, lipoprotein oxidation, and matrix degradation, which increases the risk of atherosclerosis. Additionally, intestinal dysbiosis disrupts the intestinal mucosal barrier, releasing endotoxins and lipopolysaccharides into circulation, further exaggerating the atherosclerotic process. Abnormal collagen metabolism and alteration of nitric oxide-mediated vasodilation lead to blood pressure dysregulation in patients with IBD. Therefore, it is essential to make lifestyle modifications like smoking cessation, dietary changes, and increasing physical activity with adherence to medication to mitigate the risk of developing CVD in patients with IBD. This article reviews the potential links between IBD and the increased risk of CVD in such individuals.

In inflammatory bowel diseases (IBD), the most promising therapies targeting cytokines or immune cell trafficking demonstrate around 40% efficacy. As IBD is a multifactorial inflammation of the intestinal tract, a single-target approach is unlikely to solve this problem, necessitating an alternative strategy that addresses its variability. One approach often overlooked by the pharmaceutically driven therapeutic options is to address the impact of environmental factors. This is somewhat surprising considering that IBD is increasingly viewed as a condition heavily influenced by such factors, including diet, stress, and environmental pollution-often referred to as the "Western lifestyle". In IBD, intestinal responses result from a complex interplay among the genetic background of the patient, molecules, cells, and the local inflammatory microenvironment where danger- and microbe-associated molecular patterns (D/MAMPs) provide an adjuvant-rich environment. Through activating DAMP receptors, this array of pro-inflammatory factors can stimulate, for example, the NLRP3 inflammasome-a major amplifier of the inflammatory response in IBD, and various immune cells via non-specific bystander activation of myeloid cells (e.g., macrophages) and lymphocytes (e.g., tissue-resident memory T cells). Current single-target biological treatment approaches can dampen the immune response, but without reducing exposure to environmental factors of IBD, e.g., by changing diet (reducing ultra-processed foods), the adjuvant-rich landscape is never resolved and continues to drive intestinal mucosal dysregulation. Thus, such treatment approaches are not enough to put out the inflammatory fire. The resultant smoldering, low-grade inflammation diminishes physiological resilience of the intestinal (micro)environment, perpetuating the state of chronic disease. Therefore, our hypothesis posits that successful interventions for IBD must address the complexity of the disease by simultaneously targeting all modifiable aspects: innate immunity cytokines and microbiota, adaptive immunity cells and cytokines, and factors that relate to the (micro)environment. Thus the disease can be comprehensively treated across the nano-, meso-, and microscales, rather than with a focus on single targets. A broader perspective on IBD treatment that also includes options to adapt the DAMPing (micro)environment is warranted.

Immunotherapy with immune checkpoint inhibitors represents a revolutionary approach to the treatment of solid tumors, including malignant melanoma, lung cancer, and gastrointestinal malignancies. Anti-CTLA-4 and anti-PD-1/PDL-1 therapies provide prolonged survival for cancer patients, but their efficacy and safety are highly variable. This review focuses on the crucial role of the gut microbiome in modulating the efficacy and toxicity of immune checkpoint blockade. Studies suggest that the composition of the gut microbiome may influence the response to immunotherapy, with specific bacterial strains able to promote an anti-tumor immune response. On the other hand, dysbiosis may increase the risk of adverse effects, such as immune-mediated colitis. Interventions aimed at modulating the microbiome, including the use of probiotics, prebiotics, fecal microbial transplantation, or dietary modifications, represent promising strategies to increase treatment efficacy and reduce toxicity. The combination of immunotherapy with the microbiome-based strategy opens up new possibilities for personalized treatment. In addition, factors such as physical activity and nutritional supplementation may indirectly influence the gut ecosystem and consequently improve treatment outcomes in refractory patients, leading to enhanced patient responses and prolonged survival.

Immunoglobulin (Ig) A supports mucosal immune homeostasis and host-microbiota interactions. While commensal bacteria are known for their ability to promote IgA, the role of non-bacterial commensal microbes in the induction of IgA remains elusive. Here, we demonstrate that permanent colonization with the protozoan commensal Tritrichomonas musculis (T.mu) promotes T cell-dependent, IgA class-switch recombination, and intestinal accumulation of IgA-secreting plasma cells (PC). T.mu colonization specifically drives the expansion of T follicular helper cells and a unique ICOS+ non-Tfh cell population, accompanied by an increase in germinal center B cells. Blockade of ICOS:ICOSL co-stimulation or MHCII-expression on B cells is central for the induction of IgA following colonization by T.mu, implicating a previously underappreciated mode of IgA induction following protozoan commensal colonization. Finally, T.mu further improves the induction of IgA-secreting PC specific to orally ingested antigens and their peripheral dissemination, identifying T.mu as a "natural adjuvant" for IgA. Collectively, these findings propose a protozoa-driven mode of IgA induction to support intestinal immune homeostasis.

Chronic kidney disease (CKD) can cause gut microbiota dysbiosis and decreasing production of short-chain fatty acids (SCFAs), which aggravate the injury of kidney. It has been found that a variety of Chinese medicine polysaccharides can regulate gut microbiota, especially probiotics, and have beneficial effects on human health. Astragalus polysaccharide (APS) is a major component of Astragalus aceus. The aim of this study was to investigate whether APS can regulate gut microbiota-SCFAs to slow the progression of CKD. Adenine-induced CKD mice (Ade) were established and APS was treated. The renal protection of APS on CKD mice was evaluated by renal function and pathological staining of renal tissues. Feces samples were collected for 16SrRNA sequence and LC-MS/MS analysis. Kidney G protein-coupled receptor (GPR) levels were also detected in renal tissue. APS supplementation can reduce serum creatinine and urea nitrogen levels in mice model (Ade) and attenuate renal tubular interstitial injury and renal fibrosis. Further application of 16SrRNA sequencing showed that the abundance of SCFA producing bacteria, such as Kineothrix, Faecalibaculum, Akkermansia, Lactobacillus, and Roseburia, was upregulated after APS treatment. Fecal LC-MS/MS detection showed that the levels of acetate, propionate and butyrate in Ade mice increased after APS supplementation. The detection of renal GPRs showed that APS supplementing could significantly increase the levels of renal GPR41 and GPR43, and also partially increase the levels of GPR109a in Ade mice. Our research confirms that APS supplementation can upregulate the abundance of SCFA producing bacteria and increase SCFA levels to attenuate renal tubular interstitial injury and fibrosis via GPRs.

Endometriosis, infertility, or recurrent pregnancy loss (RPL) are entities characterised by a decrease in Lactobacillus spp. and an increase in bacterial vaginosis-associated bacteria, (BVAV) according with 16S rRNA sequencing studies. However, the use of nucleic acid amplification tests (NAAT) as a tool for diagnosis algorithms is unknown. Seventy-four patients were included, with a median age of 36.5 years old (IQR: 34-39) including infertility (n=31), endometriosis (n=25), or RPL (n=18), for culturing and NAAT using the Allplex™ Bacterial Vaginosis Plus (ABVP) assay (SeegeneⓇ) with endometrial samples. The objective was determining the utility of ABVP assay for diagnosing the entities. Forty-six microorganisms were isolated from 31 out of 74 patients (41.9 %). Twenty-five endometrial samples (33.8 %) were positive for some targets included in the ABVP-assay, with median Ct value ∼37 (IQR: 31.3-37.1) and Qt value 1.43 Log10copies/reaction (IQR:1.1-2.6). For Lactobacillus species, sensitivity and specificity were 80 % and 84 %, respectively. Gardnerella vaginalis, 63.6 % and 95.7 %. No significant increase in BVAV was detected in any of the gynaecological entities. The ABVP and culture based algorithm did not show utility as a tool for endometriosis, infertility, or RPL diagnosis.

Gut microbiota is an intricate microbial community containing bacteria, fungi, viruses, archaea, and protozoa, and each of them contributes to diverse aspects of host health. Nevertheless, the influence of interaction among gut microbiota on host health remains uncovered. Here, we showed that the interaction between intestinal fungi and bacteria shaped lung inflammation during infection. Specifically, antifungal drug-induced dysbiosis of gut mycobiota enhanced lung inflammation during infection. Dysbiosis of gut mycobiota led to gut Escherichia coli (E. coli) overgrowth and translocation to the lung during infection, which induced lung accumulation of the CD45+F4/80+Ly6G-Ly6C-CD11b+CD11c+ macrophages. Clearance of macrophages or deletion of TLR4 (Toll-like receptor 4, recognition of LPS) rather than Dectin-1 (recognition of beta-1,3/1,6 glucans on fungi) blocked the antifungal drug-induced aggravation of lung inflammation during infection. These findings suggest that the interaction between intestinal mycobiota and commensal bacteria affects host health through the gut-lung axis, offering a potential therapeutic target for ameliorating lung inflammation during infection.

With the escalating prevalence of obesity, the association between obesity and cancer is a growing public health concern. Obesity will soon surpass tobacco smoking as the most important preventable cause of cancer. Obesity-driven mechanisms can alter cell functions to induce metabolic changes, chronic inflammation, and insulin resistance that are believed to contribute to cancer risk and development; yet the specific underlying biological mechanisms of obesity-related cancer development are largely unknown. The Metabolic Dysregulation and Cancer Risk Program: a transdisciplinary approach to obesity-associated cancers (MeDOC) is a trans-National Cancer Institute research initiative supported by the Division of Cancer Control and Population Sciences, the Division of Cancer Biology, the Division of Cancer Prevention, and the Center to Reduce Cancer Health Disparities. The overall purpose of the MeDOC Program is to advance our understanding of the underlying mechanisms that connect obesity, metabolic dysregulation, and increased obesity cancer risk as well as identify markers that will enhance cancer risk prediction, improve screening for high-risk individuals, and identify targets for preventive and therapeutic interventions for cancer interception or treatment. This report describes the funded research projects, the Coordinating Center, and the goals of the MeDOC program.

Alhagi-honey (AH) is a well-established traditional ethnic medicine with advantageous effects against diarrhea and headaches. We aimed to explore the preventive effect of AH on liver damage induced by heat stress (HS) and its underlying mechanism. HS models were established by thermostat, and mice were treated at 39 ℃ for 10 h, lasting for 7 days. Hematoxylin-eosin (H&E) staining and Periodic Acid-Schiff (PAS) staining were used for histological observation, and transmission electron microscopy (TEM) was used for ultrastructure examination of hepatocytes. Gut microbiota (GM) composition and liver metabolites were respectively analyzed by 16S rRNA sequencing and non-targeted metabolome sequencing. AH pretreatment alleviated liver damage caused by heat stress in mice. The main manifestation was that AH alleviated serum aspartate transferase (AST) and aspartate transaminase (ALT). It was found that AH improved symptoms of hepatocyte damage. In addition, the relative abundance of f_Rikenellaceae, g_Incertae_Sedis and s_Staphylococcus_Orisratti, g_Lachnoclostridium, g_GCA-900066575, and s_Alistipes_inops were modified by AH and these bacterial genera showed association with 6 metabolites (2- (3,4-dihydroxyphenyl) acetamide, 3-hydroxy-3-methylpentanedioic acid, PC (17:0/17:1), Y-L-Glutamy-L-glutamic acid, L-Isoleucine, 5-Methyluridine, 8,8-dimethyl-2-phenyl-4H,8H-pyrano [2, 3-h] chromen-4-one). The Pearson analysis also showed a strong correlation between these microbes and 2 risk indicators (AST and ALT) of liver damage. AH alleviated HS-induced liver damage by regulating liver metabolism and maintaining normal GM. It demonstrated that AH held potential as a prophylactic drug for the prevention of HS-induced liver damage.

Intestinal microbiota and selected strains of commensal bacteria influence regulatory T (Treg) cell functionality in the colon. Nevertheless, whether and how microbiota changes the transcriptome profile and TCR specificities of colonic Tregs remain to be precisely defined. In this study, we have employed single-cell RNA sequencing and comparatively analyzed colonic Tregs from specific pathogen-free and germ-free (GF) mice. We found that microbiota shifts the activation trajectory of colonic Tregs toward a distinct phenotypic subset enriched in specific pathogen-free but not in GF mice. Moreover, microbiota induced the expansion of specific Treg clonotypes with shared transcriptional specificities. The microbiota-induced subset of colonic Tregs, identified as PD-1- CXCR3+ Tregs, displayed enhanced suppressive capabilities compared with colonic Tregs derived from GF mice, enhanced production of IL-10, and were the primary regulators of enteric inflammation in dextran sodium sulfate-induced colitis. These findings identify a hitherto unknown gut microbiota and immune cell interaction module that could contribute to the development of a therapeutic modality for intestinal inflammatory diseases.

Previous studies have suggested that gut microbiota (GM) may be involved in the pathogenesis of epilepsy through the microbiota-gut-brain axis (MGBA). However, the causal relationship between GM and different epilepsy subtypes and whether circulating inflammatory proteins act as mediators to participate in epileptogenesis through the MGBA remain unclear. Therefore, it is necessary to identify specific GM associated with epilepsy and its subtypes and explore their underlying inflammatory mechanisms for risk prediction, personalized treatment, and prognostic monitoring of epilepsy.

We hypothesized the existence of a pathway GM-inflammatory proteins-epilepsy. We found genetic variants strongly associated with GM, circulating inflammatory proteins, epilepsy and its subtypes, including generalized and partial seizures, from large-scale genome-wide association studies (GWAS) summary data and used Multivariate Mendelian Randomization to explore the causal relationship between the three and whether circulating inflammatory proteins play a mediating role in the pathway from GM to epilepsy, with inverse variance weighted (IVW) method as the primary statistical method, supplemented by four methods: MR-Egger, weighted median estimator (WME), Weighted mode and Simple mode.

16 positive and three negative causal associations were found between the genetic liability of GM and epilepsy and its subtypes. There were nine positive and nine negative causal associations between inflammatory proteins and epilepsy and its subtypes. Furthermore, we found that C-X-C motif chemokine 11 (CXCL11) levels mediated the causal association between Genus Family XIII AD3011 group and epilepsy.

Our study highlights the possible causal role of specific GM and specific inflammatory proteins in the development of epilepsy and suggests that circulating inflammatory proteins may mediate epileptogenesis through the MGBA.

Our understanding of gut microbial populations and their immense influence on host immunity, health, and diseases has increased deeply in recent years. Numerous reports have identified the role of mosquito and mammalian gut microbiota in the modulation of host susceptibility to Plasmodium infection. Artemisinin resistance in malaria-endemic regions necessitates the development of new, safer, and more affordable treatments to supplement existing therapies. In this review, we compiled a colossal amount of data from numerous studies that have assessed the roles played by gut microbial communities in Plasmodium infection, progression, transmission, and severity. Most interestingly, our study points to the overwhelming evidence from experimental studies in mural malaria to human trials, suggesting that the presence of lactic acid bacteria in the gut microbiota of mammalian hosts provides a great degree of protection against malaria. Therefore, our study provides a compelling narrative for probiotic administration as an adjunct therapy for combatting malaria.

Gut microbiota contributes to the homeostasis of immune system and is related to various diseases such as tumorigenesis. Ferroptosis, a new type of cell death, is also involved in the disease pathogenesis. Recent studies have found the correlations of gut microbiota mediated ferroptosis and immune cell death. Gut microbiota derived immunosuppressive metabolites, which can promote differentiation and function of immune cells, tend to inhibit ferroptosis through their receptors, whereas inflammatory metabolites from gut microbiota also affect the differentiation and function of immune cells and their ferroptosis. Thus, it is possible for gut microbiota to regulate immune cell ferroptosis. Indeed, gut microbiota metabolite receptor aryl hydrocarbon receptor (AhR) can affect ferroptosis of intestinal intraepithelial lymphocytes, leading to disease pathogenesis. Since immune cell ferroptosis in tumor microenvironment (TME) affects the occurrence and development of tumor, the modulation of gut microbiota in these cell ferroptosis might influence on the tumorigenesis, and also immunotherapy against tumors. Here we will summarize the recent advance of ferroptosis mediated by gut microbiota metabolites, which potentially acts as regulator(s) on immune cells in TME for therapy against tumor.

Rosacea, a chronic inflammatory dermatological condition, is characterized by facial erythema and pustules. Recent investigations have delved into the interplay between the gut microbiota and rosacea pathogenesis, unveiling promising avenues for therapeutic intervention. In this study, we screened and isolated strains Ligilactobacillus salivarius 23-006 and Lacticaseibacillus paracasei 23-008 from the feces of healthy volunteers and evaluated the intervention effects of probiotics on rosacea by constructing an LL37 induced rosacea-like mouse model. Our results showed that both L. salivarius 23-006 and L. paracasei 23-008 were probiotic strains with favourable properties. In specific, we observed that both L. salivarius 23-006 and L. paracasei 23-008 alleviated skin lesions, reduced skin inflammatory infiltrates, and decreased the expression of inflammatory factors in mice, with the combination of L. salivarius 23-006 and L. paracasei 23-008 having the most significant effect. Moreover, the combination of strains reduced the expression of cathelicidin LL37 and rosacea-associated factors by inhibiting the TLR2/MyD88/NF-κB pathway. The 16S rRNA analysis showed that the combination enhanced the intestinal barrier, restored intestinal microbiota homeostasis, and up-regulated the abundance of Lactobacillus while down-regulating the abundance of Coprococcus and Oscillospira. We also explored the effects of postbiotics of L. salivarius 23-006 and L. paracasei 23-008 on rosacea. While postbiotics could also ameliorate the rosacea-like phenotype in mice via the TLR2/MyD88/NF-κB pathway, the effects were not as pronounced as those observed with probiotic treatment. However, the postbiotics still enhanced the intestinal barrier, up-regulated the Lactobacillus abundance, and modulated the intestinal microbiota. In conclusion, our study revealed that L. salivarius 23-006 and L. paracasei 23-008 improved rosacea by regulating the TLR2/MyD88/NF-κB pathway and intestinal microbiota, providing a theoretical basis for the treatment of rosacea.

The interaction of polyphenols-polysaccharides-gut microbiota to promote health benefits has become a hotspot and direction for precise dietary intervention strategies and foundational research in biomedicine. Both dietary polyphenols and polysaccharides possess biological activities that regulate body health. Single components, due to their inherent structure and physicochemical properties, have a low bioavailability, thus are unable to exert their optimal effects. The compound structure formed by the interaction of polyphenols and polysaccharides can enhance their functional properties, thereby more effectively promoting health benefits and preventing diseases. This review primarily focuses on the roles played by polyphenols and polysaccharides in regulating glucose and lipid metabolism, the improvement of glucose and lipid metabolism through the gut microbial pathway by polyphenols and polysaccharides, and the mechanisms by which polyphenols and polysaccharides interact to regulate glucose and lipid metabolism. A considerable amount of preliminary research has confirmed the regulatory effects of plant polyphenols and polysaccharides on glucose and lipid metabolism. However, studies on the combined effects and mechanisms of these two components are still very limited. This review aims to provide a reference for subsequent research on their interactions and changes in functional properties.

This study aimed to investigate the causal relationship between gut microbiota characteristics (207 taxa and 205 pathways) and Alzheimer's disease and determine and quantify the role of immune cells as potential mediators.

Gut microbiota characteristics (207 taxa and 205 pathways) were obtained from the NHGRI-EBI GWAS Catalog project, while Alzheimer's disease data and 731 immune cell characteristics were obtained from the IEU Open GWAS project. Two-sample Mendelian randomization (MR) was conducted to determine whether gut microbiota characteristics (207 taxa and 205 pathways) were causally related to Alzheimer's disease. Furthermore, two-step MR was employed to quantify the proportion of the effect of immune cell characteristics mediated by gut microbiota characteristics (207 taxa and 205 pathways) on Alzheimer's disease.

A total of 17 immune cell characteristics were identified as potential mediators for 13 gut microbiota influencing Alzheimer's disease, with Effector Memory CD4+ T-cell Absolute Count accounted for 8.99% of the causal relationship between genus Oscillibacter and Alzheimer's disease.

In summary, our research confirms a causal relationship between gut microbiota and Alzheimer's disease, with immune cells contributing to a significant portion of the effect. However, the full mediators of gut microbiota's impact on Alzheimer's disease remain unclear. Further investigation is warranted to explore additional potential risk factors acting as mediators.