Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with limited treatment options at advanced stages. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, plays a pivotal role in regulating immune responses through the gut-liver axis. Emerging evidence underscores its impact on HCC progression and the efficacy of immunotherapy. This review explores the intricate interactions between gut microbiota and the immune system in HCC, with a focus on key immune cells and pathways involved in tumor immunity. Additionally, it highlights strategies for modulating the gut microbiota - such as fecal microbiota transplantation, dietary interventions, and probiotics - as potential approaches to enhancing immunotherapy outcomes. A deeper understanding of these mechanisms could pave the way for novel therapeutic strategies aimed at improving patient prognosis.

Microbiota encompasses a diverse array of microorganisms inhabiting specific ecological niches. Gut microbiota significantly influences physiological processes, including gastrointestinal motor function, neuroendocrine signalling, and immune regulation. They play a crucial role in modulating the central nervous system and bolstering body defence mechanisms by influencing the proliferation and differentiation of innate and adaptive immune cells. Given the potential consequences of antibiotic therapy on gut microbiota equilibrium, there is a need for prudent antibiotic use to mitigate associated risks. Observational studies have linked increased antibiotic usage to various pathogenic conditions, including obesity, inflammatory bowel disease, anxiety-like effects, asthma, and pulmonary carcinogenesis. Addressing dysbiosis incidence requires proactive measures, including prophylactic use of β-lactamase drugs (SYN-004, SYN-006, and SYN-007), hydrolysing the β-lactam in the proximal GIT for maintaining intestinal flora homeostasis. Prebiotic and probiotic supplementations are crucial in restoring intestinal flora equilibrium by competing with pathogenic bacteria for nutritional resources and adhesion sites, reducing luminal pH, neutralising toxins, and producing antimicrobial agents. Faecal microbiota transplantation (FMT) shows promise in restoring gut microbiota composition. Rational antibiotic use is essential to preserve microflora and improve patient compliance with antibiotic regimens by mitigating associated side effects. Given the significant implications on gut microbiota composition, concerted intervention strategies must be pursued to rectify and reverse the occurrence of antibiotic-induced dysbiosis. Here, antibiotics-induced microbiota dysbiosis mechanisms and their systemic implications are reviewed. Moreover, proposed interventions to mitigate the impact on gut microflora are also discussed herein.

Ulcerative colitis (UC) is an incurable autoimmune disease. Patients with UC endure the burden of recurrent flare-ups and face a substantial economic burden due to long-term medication. The complex etiology and unclear pathogenesis pose a significant challenge to the development of effective and curative treatments. Recent research indicates that local memory at the site of inflammatory intestinal mucosa in UC is closely associated with the persistent presence of tissue-resident memory T (TRM) cells. TRM cells, a subset of memory T cells, exhibit long-lived, low-migration characteristics. These cells reside in tissues, where they provide immediate immune protection while also contributing to chronic, localized inflammation. The presence of TRM cells in the inflamed intestinal mucosa of UC patients is a crucial factor in the recurrence of the disease. However, the process involved in the formation and differentiation of TRM cells within the intestinal mucosa remains poorly understood. Various surface markers, transcriptional networks, and signaling pathways regulate the formation and maintenance of TRM cells in the intestine. To further understand the role of TRM cells in UC pathogenesis, we have summarized the latest findings to pave the way for the development of future targeted therapies.

Anti-citrullinated protein antibodies (ACPA) have been detected in sputum and saliva, indicating that anti-modified protein antibodies (AMPA) can be produced at mucosal sites in patients with rheumatoid arthritis (RA). However, the body's largest mucosal compartment, the gut, has not yet been examined. We therefore investigated the presence of several AMPA (ACPA, anti-carbamylated protein antibodies [anti-CarP], and anti-acetylated protein antibodies [AAPA]) at different mucosal sites, including the intestinal tract.

Paired fecal/ileal wash, saliva, and serum samples of patients with RA and healthy volunteers were collected in two independent cohorts. Data involving feces were replicated in a third cohort. In these secretions, AMPA were analyzed using in-house enzyme-linked immunosorbent assay with unmodified peptides as control. In fecal samples, total IgA and anti-Escherichia coli IgA were measured.

ACPA, anti-CarP, and AAPA IgA were measurable in saliva of seropositive patients with RA (prevalence 9%-40%). No AMPA could be detected in feces. IgA was present because total IgA and anti-E. coli IgA were detectable in feces of ACPA-positive patients with RA and healthy donors. Results were confirmed in another cohort using colonoscopically collected ileal wash samples.

Our study shows the presence of ACPA, anti-CarP, and AAPA IgA in saliva of ACPA-seropositive patients with RA. However, no AMPA could be detected in feces/ileal wash samples of these patients, although our assays were able to measure other antigen-specific antibodies. These data suggest that mucosal autoantibody secretion may occur in the oral mucosa of patients with RA, whereas no evidence could be found for this process in the lower gastrointestinal tract.

Antigen-specific B and T cell responses play a critical role in vaccine-mediated protection against infectious diseases, but these responses are highly variable between individuals and vaccine immunogenicity is frequently sub-optimal in infants, the elderly and in people living in low- and middle-income countries. Although many factors such as nutrition, age, sex, genetics, environmental exposures, and infections may all contribute to variable vaccine immunogenicity, mounting evidence indicates that the gut microbiota is an important and targetable factor shaping optimal immune responses to vaccination. In this review, we discuss evidence from human, preclinical and experimental studies supporting a role for a healthy gut microbiota in mediating optimal vaccine immunogenicity, including the immunogenicity of COVID-19 vaccines. Furthermore, we provide an overview of the potential mechanisms through which this could occur and discuss strategies that could be used to target the microbiota to boost vaccine immunogenicity where it is currently sub-optimal.

Porphyromonas gingivalis (P. gingivalis) is a gram-negative bacterium and the main causative agent of periodontitis, a disease closely associated with the development of periodontal disease. The progression of periodontitis, a chronic infectious disease, is intricately linked to the inflammatory immune response. Inflammatory cytokines act on periodontal tissues via immunomodulation, resulting in the destruction of the periodontal tissue. Recent studies have established connections between periodontitis and various systemic diseases, including cardiovascular diseases, tumors, and neurodegenerative diseases. Neurodegenerative diseases are neurological disorders caused by immune system dysfunction, including Alzheimer's and Parkinson's diseases. One of the main characteristics of neurodegenerative diseases is an impaired inflammatory response, which mediates neuroinflammation through microglial activation. Some studies have shown an association between periodontitis and neurodegenerative diseases, with P. gingivalis as the primary culprit. P. gingivalis can cross the blood-brain barrier (BBB) or mediate neuroinflammation and injury through a variety of pathways, including the gut-brain axis, thereby affecting neuronal growth and survival and participating in the onset and progression of neurodegenerative diseases. However, comprehensive and systematic summaries of studies on the infectious origin of neurodegenerative diseases are lacking. This article reviews and summarizes the relationship between P. gingivalis and neurodegenerative diseases and its possible regulatory mechanisms. This review offers new perspectives into the understanding of neurodegenerative disease development and highlights innovative approaches for investigating and developing tailored medications for treating neurodegenerative conditions, particularly from the viewpoint of their association with P. gingivalis.

Chronic autoimmune diseases often lead to long-term sequelae and require lifelong immunosuppression because of an incomplete understanding of the triggers and drivers in genetically predisposed patients. Gut bacteria that escape the gut barrier, known as translocating gut pathobionts, have been implicated as instigators and perpetuators of extraintestinal autoimmune diseases in mice. The gut microbial contributions to autoimmunity in humans remain largely unclear, including whether specific pathological human adaptive immune responses are triggered by such pathobionts. Here, we show that the translocating pathobiont Enterococcus gallinarum can induce both human and mouse interferon-γ+ T helper 17 (TH17) differentiation and immunoglobulin G3 (IgG3) subclass switch of anti-E. gallinarum RNA antibodies, which correlated with anti-human RNA autoantibody responses in patients with systemic lupus erythematosus (SLE) and autoimmune hepatitis, two extraintestinal autoimmune diseases. E. gallinarum RNA, but not human RNA, triggered Toll-like receptor 8 (TLR8), and TLR8-mediated human monocyte activation promoted human TH17 induction by E. gallinarum. Translocation of the pathobiont triggered increased anti-RNA autoantibody titers that correlated with renal autoimmune pathophysiology in murine gnotobiotic lupus models and with disease activity in patients with SLE. These studies elucidate cellular mechanisms of how a translocating gut pathobiont induces systemic human T cell- and B cell-dependent autoimmune responses and provide a framework for developing host- and microbiota-derived biomarkers and targeted therapies in autoimmune diseases.

Despite the success of biological therapies in treating inflammatory bowel disease, managing patients remains challenging due to the absence of reliable predictors of therapy response.

In this study, we prospectively sampled 2 cohorts of patients with inflammatory bowel disease receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry; single-cell RNA sequencing; single-cell B and T cell receptor sequencing (BCR/TCR-seq); serum proteomics; and multiparametric flow cytometry to comprehensively assess vedolizumab-induced immunologic changes in the peripheral blood and their potential associations with treatment response.

Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T-cell receptor diversity of gut-homing CD4+ memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4+ memory T cells among nonresponders before treatment compared with responders. This predictive T-cell signature demonstrated an activated T-helper 1/T-helper 17 cell phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab.

These findings provide a reliable predictive classifier with significant implications for personalized inflammatory bowel disease management.

Nutrition, the gut microbiota and immunity are all important factors in the maintenance of health. However, there is a growing realization of the complex interplay between these elements coalescing in a nutrition-gut microbiota-immunity axis. This regulatory axis is critical for health with disruption being implicated in a broad range of diseases, including autoimmune disorders, allergies and mental health disorders. This new perspective continues to underpin a growing number of innovative therapeutic strategies targeting different elements of this axis to treat relevant diseases. This review describes the inter-relationships between nutrition, the gut microbiota and immunity. It then details several human diseases where disruption of the nutrition-gut microbiota-immunity axis has been identified and presents examples of how the various elements may be targeted therapeutically as alternate treatment strategies for these diseases.

Background: Tissue-resident memory T (TRM) cells possess unique abilities to migrate, establish themselves in tissues, and monitor peripheral tissues without circulating. They are crucial in providing long-lasting and local immune protection against surface infections. TRMs demonstrate distinct phenotypic and functional characteristics compared to central memory T (Tcm) cells and effector memory T (Tem) cells.Methods: We reviewed a large number of literature to explore the physiological and functional roles of tissue-resident memory T cells, as well as the link between TRM cells and the development and prognosis of digestive tract tumors. We also investigated the association between TRM cells, intestinal flora, and metabolites.Results: Recent studies have implicated TRMs in the immune response against tumors, making them a potential target for cancer therapy. However, research specifically focused on gastrointestinal tumors is limited.Conclusion: This review aims to compile and assess the most recent data on the role of TRM cells in gastrointestinal tumor immunity. Additionally, it explores recent advancements in immunotherapy and investigates how TRMs may influence intestinal flora and metabolites.

Ulcerative colitis (UC) is characterized by complex immunological interactions involving CD4 T cell subsets and the NLRP3 inflammasome, which influence inflammatory responses. This investigation focused on delineating the activation profiles of these components and their correlation with disease severity and activity, assessing their diagnostic implications in UC.

We conducted immunohistochemistry and ELISA assays to measure markers expression of CD4 T cell subsets and the NLRP3 inflammasome in UC patients versus controls. Findings were validated using correlation analysis, molecular docking and ROC curves.

UC patients displayed increased Th1 (T-bet, TNF-α), Th2 (GATA3, IL-6), and Th17 (RORγt, IL-17, IL-22, IL-23) markers versus controls. Additionally, Th1 and Th2 cytokines (IL-2 and IL-4) were significantly elevated in severe UC, while Treg markers (FOXP3, IL-10, TGF-β1) were elevated only in mild-to-moderate UC. Enhanced NLRP3 inflammasome activation, indicated by elevated NLRP3, Caspase-1, and IL-1β levels. These molecular patterns, confirmed through correlation analysis and molecular docking, underscored strong correlations among NLRP3, T-bet, and GATA3, supporting the proposed NLRP3/T-bet/GATA3 axis. This axis, along with other biomarkers, showed strong associations with UC severity, Mayo score, UCEIS, demonstrated relatively high diagnostic value.

The NLRP3/T-bet/GATA3 axis provides a referable strategy for multi-targeted combined treatment of UC and may serve as potential biomarkers for enhancing diagnostic accuracy and guiding therapy.

Crohn's disease (CD) significantly affects patients' well-being and is influenced by stress and lifestyle factors, highlighting the importance of improving quality of life in CD management. An imbalance between pro- and anti-inflammatory CD4+ T cell responses is a key factor in CD, and stress has been shown to alter the function of CD4+ T cells. Therefore, this study aimed to evaluate the effect of a mind-body medicine stress management and lifestyle modification (MBM) program on the CD4+ T cell profile in CD patients.

Circulating CD4+ T cells from CD patients were analyzed by flow cytometry following the MBM program. Patients were randomly assigned to either a guided intervention group (IG) or a self-guided waitlist control group (CG) over a 9-month trial and compared with healthy blood donors.

Lifestyle intervention reduced regulatory T cell (Treg) frequencies in the blood of CD patients. Notably, we observed a significant correlation between the quality of life improvement and Treg frequencies in the IG but not in the CG. Furthermore, differential activation and expression of the gut-homing molecules G protein-coupled receptor 15 and CCR9 on circulating Tregs and CD4+ effector T cells were detected in both the IG and CG.

The MBM program, whether guided or self-directed, has the potential to restore the CD4+ T cell profile of CD patients to levels comparable to healthy blood donors. Lifestyle interventions may benefit CD progression, symptoms, and immunological status, but further analysis is needed to substantiate these findings and to fully understand their clinical implications. (ClinicalTrials.gov: NCT05182645).

Exercise can effectively prevent and treat depression and anxiety, with gut microbiota playing a crucial role in this process. Studies have shown that exercise can influence the diversity and composition of gut microbiota, which in turn affects depression through immune, endocrine, and neural pathways in the gut-brain axis. The effectiveness of exercise varies based on its type, intensity, and duration, largely due to the different changes in gut microbiota. This article summarizes the possible mechanisms by which exercise affects gut microbiota and how gut microbiota influences depression. Additionally, we reviewed literature on the effects of exercise on depression at different intensities, types, and durations to provide a reference for future exercise-based therapies for depression.

The intestinal microbiota plays a critical role in host immunity and might contribute to the significant variation between individuals' vaccine responses. A systematic search was done using MEDLINE and Embase to identify original human studies investigating the association between intestinal microbiota composition and humoral and cellular vaccine responses. In total, 30 publications (26 studies, 14 in infants, 12 in adults), were included. Of these, 26 publications found an association between intestinal microbiota composition and vaccine responses. A beneficial effect of Actynomycetota (particularly Bifidobacterium) and a detrimental effect of Pseudomonadota (particularly Gammaproteobacteria) were observed across studies. Study designs were highly heterogenous, with variation in vaccine type, outcome measure, timing of stool analysis and analysis methods. Overall, studies support the concept that the composition of the intestinal microbiota influences vaccine responses. Further adequately powered studies are needed to confirm this association and inform potential microbiota-targeted interventions to optimise vaccine responses.

Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis are influenced by environmental and immunological factors and may differ according to the patient's sex.

The objective was to study the differences in the clinical profile of a Brazilian sample of inflammatory bowel disease patients according to sex.

Retrospective study with chart review of 158 inflammatory bowel disease patients (43 with Crohn's disease and 115 with ulcerative colitis) from a single university hospital in southern Brazil.

The Crohn's disease sample showed a female/male ratio of 2.1, and the sample of ulcerative colitis showed a ratio of 1.5. The only significant difference found in the clinical profile was an increased constipation rate in female patients with ulcerative colitis. No other differences in epidemiological, symptom profile, or treatment could be detected.

More females with inflammatory bowel diseases sought healthcare facilities compared to males. The only notable difference was a higher incidence of constipation symptoms among females; all other aspects were similar between the sexes.

Ulcerative colitis (UC) is a long-term bowel inflammation of unknown cause. Recent research points to gut microbiota, especially Enterotoxigenic Bacteroides fragilis (ETBF), in UC's development. This study examined the presence of Bacteroides fragilis (B. fragilis) and ETBF in the saliva of UC patients and Healthy Controls (HCs) in Iran.

A total of 40 UC patients and 40 healthy controls were included in the study. Saliva samples were collected and analyzed for the presence of B. fragilis and ETBF using real-time polymerase chain reaction (PCR).

B. fragilis was more prevalent in HCs (70%) than UC patients (67.5%), but not significantly (p = 0.809). ETBF was significantly more prevalent in UC patients (50%) than HCs (10%) (p < 0.0001). The mean count of B. fragilis was higher in UC patients, but not significantly (p = 0.47). However, the mean count of ETBF was significantly higher in UC patients (p = 0.000089). In terms of gender, the number of B. fragilis in women was not significant (p = 0.16), but the number of ETBF was significantly higher in women with UC (p = 0.000458). For men, no significant differences were observed.

The present study suggest a higher prevalence of B. fragilis observed in UC patients compared to HCs. Further research is needed to confirm these findings and explore potential mechanisms underlying this association.

Antiretroviral therapy (ART) controls HIV-1 replication in people with HIV-1 (PWH), but immunological restauration at mucosal barrier surfaces is not achieved. This fuels microbial translocation, chronic immune activation, and increased comorbidities, including cardiovascular disease (CVD). Here, we sought to identify novel markers of mucosal barrier impairment in the blood to predict the HIV and/or CVD status. Flow cytometry was used to characterize CD326/EpCAM + intestinal epithelial cells (IEC); CD4 + T-cells; CD8 + and CD4 + intraepithelial lymphocytes (IELs); and subsets of CD4 + T-cells expressing Th17 (CCR6) and gut-homing (Itgβ7) markers. To this aim, we collected peripheral blood mononuclear cells (PBMCs) from 42 ART-treated PWH (HIV + ) and 40 uninfected participants (HIV - ) from the Canadian HIV and Aging Cohort Study (CHACS). Both groups were categorized based on the presence of coronary atherosclerotic plaques measured by CT scan angiography as total plaque volume (TPV, mm 3 ). Our findings associate the HIV-1 status with increased frequencies of circulating CD326 + IEC; CD326 + CD4 + T-cells with activated (CD69 + HLA-DR + ) and gut-homing (ItgαE + CCR6 + CCR9 + ) phenotypes, CCR6 + Itgβ7 - CD4 + T-cells; and decreased frequencies of CD8 + IELs. Logistic regression analyses confirmed the predictive capacity of the above cellular markers regarding HIV status. Spearman correlation revealed a positive correlation between TPV and CCR6 + Itgβ7 - and CCR6 + Itgβ7 + CD4 + T-cell frequencies.Together, these results highlighted significant immune dysregulation and persistent mucosal barrier alterations despite effective viral suppression by ART and linked the abundance of CCR6 + Itgβ7 + and CCR6 + Itgβ7 - CD4 + T-cells to increased atherosclerotic plaque burden. Thus, strategies targeting the gut-immune axis restoration may reduce CVD onset and improve long-term health outcomes in PWH.

CD4+ memory T cell (TM) reactivation drives chronicity in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis. Defects driving loss of TM regulation likely differ between patients but remain undefined. In health, approximately 40 % of circulating gut-homing CD38+TM express co-inhibitory receptor T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). TIGIT+CD38+TM have regulatory function while TIGITnegCD38+TM are enriched in IFN-γ-producing cells. We hypothesized TIGITnegCD38+TM are inflammatory and drive disease in a subgroup of IBD patients. We characterized TIGIT+CD38+TM in a uniquely large cohort of pediatric IBD patients from time of diagnosis into adulthood. Circulating TIGITnegCD38+TM frequencies were higher in a subgroup of therapy-naïve CD patients with high plasma IFN-γ and a more severe disease course. TIGITnegCD38+TM were highly enriched in HLA-DR+ and ex-Th17/Th1-like cells, high producers of IFN-γ. Cultures of healthy-adult-stimulated TM identified IL-12 as the only IBD-related inflammatory cytokine to drive the pathogenic ex-Th17-TIGITnegCD38+ phenotype. Moreover, IL12RB2 mRNA expression was higher in TIGITnegCD38+TM than TIGIT+CD38+TM, elevated in CD biopsies compared to controls, and correlated with severity of intestinal inflammation. Overall, we argue that in a subgroup of pediatric CD, increased IL-12 signaling drives reprogramming of Th17 to inflammatory Th1-like TIGITnegCD38+TM and causes more severe disease.

The human gut microbiome dysbiosis plays an important role in the pathogenesis of Parkinson's disease (PD). The bidirectional relationship between the enteric nervous system (ENS) and central nervous system (CNS) under the mediation of the gut-brain axis control the gastrointestinal functioning. This review article discusses key mechanisms by which modifications in the composition and function of the gut microbiota (GM) influence PD progression and motor control loss. Increased intestinal permeability, chronic inflammation, oxidative stress, α-synuclein aggregation, and neurotransmitter imbalances are some key factors that govern gastrointestinal pathology and PD progression. The bacterial taxa of the gut associated with PD development are discussed with emphasis on the enteric nervous system (ENS), as well as the impact of gut bacteria on dopamine production and levodopa metabolism. The pathophysiology and course of the disease are associated with several inflammatory markers, including TNF-α, IL-1β, and IL-6. Emerging therapeutic strategies targeting the gut microbiome include probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT). The article explored how dietary changes may affect the gut microbiota (GM) and the ways that can affect Parkinson's disease (PD), with a focus on nutrition-based, Mediterranean, and ketogenic diets. This comprehensive review synthesizes current evidence on the role of the gut microbiome in PD pathogenesis and explores its potential as a therapeutic target. Understanding these complex interactions may assist in the development of novel diagnostic tools and treatment options for this neurodegenerative disorder.

Despite the efficacy of antiretroviral therapy (ART) in reducing the global incidence of vertical HIV transmissions, more than 120,000 children are still infected with the virus each year. Since ART cannot clear the HIV reservoir that is established soon after infection, children living with HIV (CLWH) are forced to rely on therapy for their lives and suffer from long-term drug-related complications. Pediatric HIV infection, like adult infection, is associated with gut microbial dysbiosis, loss of gut epithelial integrity, bacterial translocation, CD4 + T cell depletion, systemic immune activation, and viral reservoir establishment. However, unlike in adults, HIV that is vertically acquired by infants interacts with a gut microbiome that is continuously evolving while concomitantly shaping the infant's immune ontogeny. Therefore, to determine whether there may be interventions that target the HIV reservoir through microbiome-directed approaches, understanding the complex tripartite interactions between the transmitted HIV, the maturing gut microbiome, and the developing immune system during early life is crucial. Importantly, early life is the time when the gut microbiome of an individual is highly dynamic, and this temporal development of the gut microbiome plays a crucial role in educating the maturing immune system of a child. Therefore, manipulation of the gut microbiome of CLWH to a phenotype that can reduce HIV persistence by fostering an antiviral immune system might be an opportune strategy to achieve ART-free viral suppression in CLWH. This review summarizes the current state of knowledge on the vertical transmission of HIV, the developing gut microbiome of CLWH, and the immune landscape of pediatric elite controllers, and explores the prospect of employing microbial modulation as a potential therapeutic approach to achieve ART-free viral suppression in the pediatric population.

Constitution is a valuable part of traditional Chinese medicine theory; it is defined as the internal foundation for the occurrence, development, transformation and outcome of diseases, and has its characteristic gut microbiota. Previous study showed that deficiency constitution was related to lower Hb counts. However, no research has examined how alterations in the gut microbiome induced by deficiency constitution may increase the tendency for anemia.

We used a multiomics strategy to identify and quantify taxonomies and compounds found under deficient constitution individuals and further explore the possible pathological factors that affect red blood cell indices.

① People with deficient constitution showed lower hemoglobin (Hb), more Firmicutes, less Bacteroidetes, and higher α diversity. ② We identified Escherichia coli, Clostridium bolteae, Ruminococcus gnavus, Streptococcus parasanguinis and Flavonifractor plautii as potential biomarkers of deficient constitution. ③ Slackia piriformis, Clostridium_sp_L2_50 and Bacteroides plebeius were enriched in balanced-constitution individuals, and Parabacteroides goldsteinii was the key bacterial marker of balanced constitution. ④ Flavonifractor plautii may be a protective factor against the tendency for anemia among deficient individuals. ⑤ Ruminococcus gnavus may be the shared microbe base of deficiency constitution-related the tendency for anemia. ⑥ The microorganism abundance of the anaerobic phenotype was lower in deficient constitution group. ⑦ Alterations in the microbiome of deficient-constitution individuals were associated with worse health status and a greater risk of anemia, involving intestinal barrier function, metabolism and immune responses, regulated by short-chain fatty acids and bile acid production.

The composition of the gut microbiome was altered in people with deficient constitution, which may explain their poor health status and tendency toward anemia.

Epithelial barriers, such as the lungs and skin, face the challenge of providing the tissues' physiological function and maintaining tolerance to the commensal microbiome and innocuous environmental factors while defending the host against infectious microbes. Asthma and allergic diseases can result from maladaptive immune responses, resulting in exaggerated and persistent type 2 immunity and tissue inflammation.

Among the diverse populations of tissue immune cells, CD4+ regulatory T cells (Treg cells) are central to controlling immune responses and inflammation and restoring tissue homeostasis. Humans and mice that are deficient in Treg cells experience extensive inflammation in their mucosal organs and skin. During past decades, major progress has been made toward understanding the immunobiology of Treg cells and the molecular and cellular mechanisms that control their differentiation and function. It is now clear that Treg cells are not a single cell type and that they demonstrate diversity and plasticity depending on their differentiation stages and tissue environment. They could also take on a proinflammatory phenotype in certain conditions.

Treg cells perform distinct functions, including the induction of immune tolerance, suppression of inflammation, and promotion of tissue repair. Subsets of Treg cells in mucosal tissues are regulated by their differentiation stage and tissue inflammatory milieu. Treg cell dysfunction likely plays roles in persistent immune responses and tissue inflammation in asthma and allergic diseases.

Gut-residing bacteria, such as Escherichia coli, can acetylate their proteome under conditions of amine starvation. It is postulated that the (gut) microbiome is involved in the breach of immune tolerance to modified self-proteins leading to the anti-modified protein antibodies (AMPAs), hallmarking seropositive rheumatoid arthritis (RA). Our aim was to determine whether acetylated bacterial proteins can induce AMPA responses cross-reactive to modified self-proteins and be recognised by human AMPA (hAMPA).

E. coli bacteria were grown under amine starvation to generate endogenously acetylated bacterial proteins. Furthermore, E. coli proteins were acetylated chemically. Recognition of these proteins by hAMPA was analysed by western blotting and ELISA; recognition by B cells carrying a modified protein-reactive B cell receptor (BCR) was analysed by pSyk (Syk phosphorylation) activation assay. C57BL/6 mice were immunised with (modified) bacterial protein fractions, and sera were analysed by ELISA.

Chemically modified bacterial protein fractions contained high levels of acetylated proteins and were readily recognised by hAMPA and able to activate B cells carrying modified protein-reactive BCRs. Likely due to substantially lower levels of acetylation, endogenously acetylated protein fractions were not recognised by hAMPA or hAMPA-expressing B cells. Immunising mice with chemically modified protein fractions induced a strong cross-reactive AMPA response, targeting various modified antigens including citrullinated proteins.

Acetylated bacterial proteins are recognisable by hAMPA and are capable of inducing cross-reactive AMPA in mice. These observations provide the first conceptual evidence for a novel mechanism involving the (endogenous) acetylation of the bacterial proteome, allowing a breach of tolerance to modified proteins and the formation of cross-reactive AMPA.

Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4+ T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.

In two previous studies, we showed that supplementing a high-fat (HF) diet with 9% w/w U. dioica protects against fat accumulation, insulin resistance, and dysbiosis. This follow-up study in C57BL6/J mice aimed at testing: (i) the efficacy of the vegetable at lower doses: 9%, 4%, and 2%, (ii) the impact on intestinal T and B cell phenotype and secretions, (iii) impact on fat and glucose absorption during excess nutrient provision. At all doses, the vegetable attenuated HF diet induced fat accumulation in the mesenteric, perirenal, retroperitoneal fat pads, and liver but not the epididymal fat pad. The 2% dose protected against insulin resistance, prevented HF diet-induced decreases in intestinal T cells, and IgA+ B cells and activated T regulatory cells (Tregs) when included both in the LF and HF diets. Increased Tregs correlated with reduced inflammation; prevented increases in IL6, IFNγ, and TNFα in intestine but not expression of TNFα in epididymal fat pad. Testing of nutrient absorption was performed in enteroids. Enteroids derived from mice fed the HF diet supplemented with U. dioica had reduced absorption of free fatty acids and glucose compared to enteroids from mice fed the HF diet only. In enteroids, the ethanolic extract of U. dioica attenuated fat absorption and downregulated the expression of the receptor CD36 which facilitates uptake of fatty acids. In conclusion, including U. dioica in a HF diet, attenuates fat accumulation, insulin resistance, and inflammation. This is achieved by preventing dysregulation of immune homeostasis and in the presence of excess fat, reducing fat and glucose absorption.

Chinese herbal medicine Gegen Qinlian Decoction (GQD) has been clinically shown to be an effective treatment of ulcerative colitis (UC) in China. However, the underlying mechanism of GQD's anti-ulcerative colitis properties and its effect on gut microbiota still deserve further exploration.

This study observed the regulatory effects of GQD on Th2/Th1 and Tregs/Th17 cells balance, the NOD-like receptor family pyrin domain containing 3 (NLRP3) infammasome and gut microbiota in TNBS-induced UC in BALB/c mice.

61 main chemical compounds in the GQD were determined by UPLC-Q-TOF/MS. The UC BALB/c model was established by intrarectal administration of trinitrobenzene sulfonic acid (TNBS), and GQD was orally administered at low and high dosages of 2.96 and 11.83 g/kg/day, respectively. The anti-inflammatory effects of GQD for ulcerative colitis were evaluated by survival rate, body weight, disease activity index (DAI) score, colonic weight and index, spleen index, hematoxylin-eosin (HE) staining and histopathological scores. Flow cytometry was used to detect the percentage of CD4, Th1, Th2, Th17 and Tregs cells. The levels of Th1-/Th2-/Th17-/Tregs-related inflammatory cytokines and additional proinflammatory cytokines (IL-1β, IL-18) were detected by CBA, ELISA, and RT-PCR. The expressions of GATA3, T-bet, NLRP3, Caspase-1, IL-Iβ, Occludin and Zonula occludens-1 (ZO-1) on colon tissues were detected by Western blot and RT-PCR. Transcriptome sequencing was performed using colon tissue and 16S rRNA gene sequencing was performed on intestinal contents. Fecal microbiota transplantation (FMT) was employed to assess the contribution of intestinal microbiota and its correlation with CD4 T cells and the NLRP3 inflammasome.

GQD increased the survival rate of TNBS-induced UC in BALB/c mice, and significantly improved their body weight, DAI score, colonic weight and index, spleen index, and histological characteristics. The intestinal barrier dysfunction was repaired after GQD administration through promoting the expression of tight junction proteins (Occludin and ZO-1). GQD restored the balance of Th2/Th1 and Tregs/Th17 cells immune response of colitis mice, primarily inhibiting the increase in Th2/Th1 ratio and their transcription factor production (GATA3 and T-bet). Morever, GQD changed the secretion of Th1-/Th2-/Th17-/Tregs-related cytokines (IL-2, IL-12, IL-5, IL-13, IL-6, IL-10, and IL-17A) and reduced the expressions of IL-1β, IL-18. Transcriptome results suggested that GQD could also remodel the immune inflammatory response of colitis by inhibiting NOD-like receptor signaling pathway, and Western blot, immunohistochemistry and RT-PCR further revealed that GQD exerted anti-inflammatory effects by inhibiting the NLRP3 inflammasome, such as down-regulating the expression of NLRP3, Caspase-1 and IL-1β. More interestingly, GQD regulated gut microbiota dysbiosis, suppressed the overgrowth of conditional pathogenic gut bacteria like Helicobacter, Proteobacteria, and Mucispirillum, while the probiotic gut microbiota, such as Lactobacillus, Muribaculaceae, Ruminiclostridium_6, Akkermansia, and Ruminococcaceae_unclassified were increased. We further confirmed that GQD-treated gut microbiota was sufficient to relieve TNBS-induced colitis by FMT, involving the modulation of Th2/Th1 and Tregs/Th17 balance, inhibition of NLRP3 inflammasome activation, and enhancement of colonic barrier function.

GQD might alleviate TNBS-induced UC via regulating Th2/Th1 and Tregs/Th17 cells Balance, inhibiting NLRP3 inflammasome and reshaping gut microbiota, which may provide a novel strategy for patients with colitis.

In inflammatory bowel diseases (IBDs), such as Crohn's disease (CD) and ulcerative colitis (UC), the immune system relentlessly attacks intestinal cells, causing recurrent tissue damage over the lifetime of patients. The etiology of IBD is complex and multifactorial, involving environmental, microbiota, genetic, and immunological factors that alter the molecular basis of the organism. Among these, the microbiota and immune cells play pivotal roles; the microbiota generates antigens recognized by immune cells and antibodies, while autoantibodies target and attack the intestinal membrane, exacerbating inflammation and tissue damage. Given the altered molecular framework, the analysis of multiple molecular biomarkers in patients proves exceedingly valuable for diagnosing and prognosing IBD, including markers like C reactive protein and fecal calprotectin. Upon detection and classification of patients, specific treatments are administered, ranging from conventional drugs to new biological therapies, such as antibodies to neutralize inflammatory molecules like tumor necrosis factor (TNF) and integrin. This review delves into the molecular basis and targets, biomarkers, treatment options, monitoring techniques, and, ultimately, current challenges in IBD management.

IgA nephropathy, presently recognized as the foremost primary glomerular disorder, emerges as a principal contributor to renal failure globally, with its pathogenesis yet to be fully elucidated. Extensive research has highlighted the critical role of gut microbiome in the onset and progression of IgA nephropathy, underscoring its importance in accurately delineating the disease's etiology. For example, gut microbiome dysbacteriosis can lead to the production of nephritogenic IgA1 antibodies, which form immune complexes that deposit in the kidneys, causing inflammation and damage. The gut microbiome, a source of numerous bioactive compounds, interacts with the host and plays a regulatory role in gut-immune axis modulation, earning it the moniker of the "second brain." Recent investigations have particularly emphasized a significant correlation between IgA nephropathy and gut microbiome dysbacteriosis. This article offers a detailed overview of the pathogenic mechanisms of IgA nephropathy, specifically focusing on elucidating how alterations in the gut microbiome are associated with anomalies in the intestinal mucosal system in IgA nephropathy. Additionally, it describes the possible influence of gut microbiome on recurrent IgA nephropathy following kidney transplantation. Furthermore, it compiles potential therapeutic interventions, offering both theoretical and practical foundations for the management of IgA nephropathy. Lastly, the challenges currently faced in the therapeutic approaches to IgA nephropathy are discussed.

Though the microbiome's impact on immune system homeostasis is well documented, the effect of circulating T cells on the gut microbiome remains unexamined. We analyzed data from 50 healthy volunteers in a pilot trial of aspirin, using immunophenotyping and 16S rRNA sequencing to evaluate the effect of baseline T cells on microbiome changes over 6 weeks. We employed an unsupervised sparse canonical correlation analysis (sCCA) and used multivariable linear regression models to evaluate the association between selected T cell subsets and selected bacterial genera after adjusting for covariates. In the cross-sectional analysis, percentages of naïve CD4+ T cells were positively associated with a relative abundance of Intestinimonas, and the percentage of activated CD8+ T cells was inversely associated with Cellulosibacter. In the longitudinal analysis, the baseline percentages of naïve CD4+ T cells and activated CD4+ T cells were inversely associated with a 6-week change in the relative abundance of Clostridium_XlVb and Anaerovorax, respectively. The baseline percentage of terminal effector CD4+ T cells was positively associated with the change in Flavonifractor. Notably, the microbiome taxa associated with T cell subsets exclusively belonged to the Bacillota phylum. These findings can guide future experimental studies focusing on the role of T cells in impacting gut microbiome homeostasis.

Tissue-resident memory T cells (TRM) are long-lived memory lymphocytes that persist in non-lymphoid tissues and provide the first line of defence against invading pathogens. They adapt to their environment in a tissue-specific manner, exerting effective pathogen control through a diverse T cell receptor (TCR) repertoire and the expression of proinflammatory cytokines and cytolytic proteins. More recently, several studies have indicated that TRM can egress from the tissue into the blood as so-called "ex-TRM", or "circulating cells with a TRM phenotype". The numerically small ex-TRM population can re-differentiate in the circulation, giving rise to new memory and effector T cells. Following their egress, ex-TRM in the blood and secondary lymphoid organs can be identified based on their continued expression of the residency marker CD103, alongside other TRM-like features. Currently, it is unclear whether exit is a stochastic process, or is actively triggered in response to unknown factors. Also, it is not known whether a subset or all TRM are able to egress. Ex-TRM may be beneficial in health, as mobilisation of specialised TRM and their recruitment to both their site of origin as well as distant tissues results in an efficient distribution of the immune response. However, there is emerging evidence of a pathogenic role for ex-TRM, with a suggestion that they may perpetuate both local and distant tissue inflammation. Here, we review the evidence for the existence of ex-TRM and examine their potential involvement in disease pathogenesis.

The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.

Tissue-resident memory T cells (TRM) serve as the frontline of host defense, playing a critical role in protection against invading pathogens. This emphasizes their role in providing rapid on-site immune responses across various organs. The physiological significance of TRM is not just confined to infection control; accumulating evidence has revealed that TRM also determine the pathology of diseases such as autoimmune disorders, inflammatory bowel disease, and cancer. Intensive studies on the origin, mechanisms of formation and maintenance, and physiological significance of TRM have elucidated the transcriptional and functional diversity of these cells, which are often affected by local cues associated with their presence. These were further confirmed by the recent remarkable advancements of next-generation sequencing and single-cell technologies, which allow the transcriptional and phenotypic characterization of each TRM subset induced in different microenvironments. This review first overviews the current knowledge of the cell fate, molecular features, transcriptional and metabolic regulation, and biological importance of TRM in health and disease. Finally, this article presents a variety of recent studies on disease-associated TRM, particularly focusing and elaborating on the TRM in the gut, which constitute the largest and most intricate immune network in the body, and their pathological relevance to gut inflammation in humans.

The gut microbiota, often called the "forgotten organ," plays a crucial role in bidirectional communication with the host for optimal physiological function. This communication helps regulate the host's immunity and metabolism positively and negatively. Many factors influence microbiota homeostasis and subsequently lead to an immune system imbalance. The correlation between an unbalanced immune system and acute diseases such as acute kidney injury is not fully understood, and the role of gut microbiota in disease pathogenesis is still yet uncovered. This review summarizes our understanding of gut microbiota, focusing on the interactions between the host's immune system and the microbiome and their impact on acute kidney injury.

Metabolic-associated liver diseases have emerged pandemically across the globe and are clinically related to metabolic disorders such as obesity and type 2 diabetes. The new nomenclature and definition (i.e. metabolic dysfunction-associated steatotic liver disease - MASLD; metabolic dysfunction-associated steatohepatitis - MASH) reflect the nature of these complex systemic disorders, which are characterized by inflammation, gut dysbiosis and metabolic dysregulation. In this review, we summarize recent advantages in understanding the pathophysiology of MASLD, which we parallel to emerging therapeutic concepts.

We summarize the pathophysiologic concepts of MASLD and its transition to MASH and subsequent advanced sequelae of diseases. Furthermore, we highlight how dietary constituents, microbes and associated metabolites, metabolic perturbations, and immune dysregulation fuel lipotoxicity, hepatic inflammation, liver injury, insulin resistance, and systemic inflammation. Deciphering the intricate pathophysiologic processes that contribute to the development and progression of MASLD is essential to develop targeted therapeutic approaches to combat this escalating burden for health-care systems.

The rapidly increasing prevalence of metabolic dysfunction-associated steatotic liver disease challenges health-care systems worldwide. Understanding pathophysiologic traits is crucial to improve the prevention and treatment of this disorder and to slow progression into advanced sequelae such as cirrhosis and hepatocellular carcinoma.

Neutralizing antibody level wanes with time after COVID-19 vaccination. We aimed to study the relationship between baseline gut microbiota and immunogenicity after three doses of CoronaVac.

This was a prospective cohort study recruiting three-dose CoronaVac recipients from two centers in Hong Kong. Blood samples were collected at baseline and one year post-first dose for virus microneutralization (vMN) assays to determine neutralization titers. The primary outcome was high immune response (defined as with vMN titer ≥ 40). Shotgun DNA metagenomic sequencing of baseline fecal samples identified potential bacterial species and metabolic pathways using Linear Discriminant Analysis Effect Size (LEfSe) analysis. Univariate and multivariable logistic regression models were used to identify high response predictors.

In total, 36 subjects were recruited (median age: 52.7 years [IQR: 47.9-56.4]; male: 14 [38.9%]), and 18 had low immune response at one year post-first dose vaccination. Eubacterium rectale (log10LDA score = 4.15, p = 0.001; relative abundance of 1.4% vs. 0, p = 0.002), Collinsella aerofaciens (log10LDA score = 3.31, p = 0.037; 0.39% vs. 0.18%, p = 0.038), and Streptococcus salivarius (log10LDA score = 2.79, p = 0.021; 0.05% vs. 0.02%, p = 0.022) were enriched in low responders. The aOR of high immune response with E. rectale, C. aerofaciens, and S. salivarius was 0.03 (95% CI: 9.56 × 10-4-0.32), 0.03 (95% CI: 4.47 × 10-4-0.59), and 10.19 (95% CI: 0.81-323.88), respectively. S. salivarius had a positive correlation with pathways enriched in high responders like incomplete reductive TCA cycle (log10LDA score = 2.23). C. aerofaciens similarly correlated with amino acid biosynthesis-related pathways. These pathways all showed anti-inflammation functions.

E. rectale,C. aerofaciens, and S. salivarius correlated with poorer long-term immunogenicity following three doses of CoronaVac.

Periodontitis is closely related to inflammatory bowel disease (IBD). An excessive and non-self-limiting immune response to the dysbiotic microbiome characterizes the two. However, the underlying mechanisms that overlap still need to be clarified. We demonstrate that the critical periodontal pathogen Porphyromonas gingivalis (Pg) aggravates intestinal inflammation and Th17/Treg cell imbalance in a gut microbiota-dependent manner. Specifically, metagenomic and metabolomic analyses shows that oral administration of Pg increases levels of the Bacteroides phylum but decreases levels of the Firmicutes, Verrucomicrobia, and Actinobacteria phyla. Nevertheless, it suppresses the linoleic acid (LA) pathway in the gut microbiota, which was the target metabolite that determines the degree of inflammation and functions as an aryl hydrocarbon receptor (AHR) ligand to suppress Th17 differentiation while promoting Treg cell differentiation via the phosphorylation of Stat1 at Ser727. Therapeutically restoring LA levels in colitis mice challenged with Pg exerts anti-colitis effects by decreasing the Th17/Treg cell ratio in an AHR-dependent manner. Our study suggests that Pg aggravates colitis via a gut microbiota-LA metabolism-Th17/Treg cell balance axis, providing a potential therapeutically modifiable target for IBD patients with periodontitis.

Despite promising preclinical and earlier clinical data, a recent phase III trial on the anti-β7 integrin antibody etrolizumab in Crohn's disease (CD) did not reach its primary endpoint. The mechanisms leading to this outcome are not well understood. Here we characterize the β7+ T cell compartment from patients with CD in comparison to cells from individuals without inflammatory bowel disease. By flow cytometric, transcriptomic and functional profiling of circulating T cells, we find that triple-integrin-expressing (α4+β7+β1hi) T cells have the potential to home to the gut despite α4β7 blockade and have a specific cytotoxic signature. A subset of triple-integrin-expressing cells readily acquires αE expression and could be co-stimulated via E-Cadherin-αEβ7 interactions in vitro. Etrolizumab-s fails to block such αEβ7 signalling at high levels of T cell stimulation. Consistently, in CD patients treated with etrolizumab, T cell activation correlates with cytotoxic signatures. Collectively, our findings might add one important piece to the puzzle to explain phase III trial results with etrolizumab, while they also highlight that αEβ7 remains an interesting target for future therapeutic approaches in inflammatory bowel disease.