The gut-brain axis is a bidirectional communication system linking the gastrointestinal tract and the central nervous system (CNS). Short-chain fatty acids (SCFAs) are microbial metabolites produced through the anaerobic fermentation of dietary fiber. Growing evidence positions SCFAs as critical signaling molecules within this axis, capable of modulating key neurobiological processes relevant to neurodegenerative diseases (NDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). SCFAs exert neuroprotective effects by mitigating neuroinflammation, promoting neurogenesis, enhancing synaptic plasticity, and preserving blood-brain barrier integrity. These actions are largely mediated through epigenetic mechanisms. Butyrate functions as a histone deacetylase inhibitor to alter gene expression related to neuronal survival, inflammation, and metabolism. SCFAs also influence DNA methylation dynamics via modulation of DNA methyltransferases and ten-eleven translocation (TET) enzymes. Emerging findings suggest their involvement in novel histone modifications, such as lactylation. This review synthesizes current understanding of SCFA production, metabolic fate, and their multifaceted epigenetic actions in the brain, while evaluating their translational and therapeutic potential. Gut-derived SCFAs represent promising modulators of the brain's epigenetic landscape. Elucidating their mechanisms offers a foundation for developing novel interventions, including dietary, probiotic, and epigenetics-based strategies, for the prevention and treatment of NDs.

IntroductionGut microbial dysbiosis has been linked to both high blood pressure and neurodegeneration, but its involvement in hypertensive patients with amnestic mild cognitive impairment (aMCI) has not been well characterized in this specific population.MethodsIn this cross-sectional investigation, we enrolled 205 older Chinese adults: 52 healthy controls, 83 hypertensive individuals with normal cognition (HTN-CN), and 70 hypertensive subjects with aMCI (HTN-aMCI). Gut microbiota composition was profiled by 16S rRNA sequencing, and serum levels of 27 inflammatory mediators were quantified by multiplex immunoassay.ResultsCompared to the HTN-CN and control groups, the HTN-aMCI group showed not only a greater richness of gut microbes but also a markedly segregated microbial community structure. The HTN-aMCI microbiota was characterized by significant depletion of short-chain fatty acid (SCFA)-producing genera (Roseburia, Blautia, Faecalibacterium) and enrichment of opportunistic pathogens (Streptococcus, Clostridium_sensu_stricto_1, Enterococcus). Co-occurrence network analysis revealed disrupted microbial interactions in HTN-aMCI, and functional prediction showed enhanced lipopolysaccharide biosynthesis and reduced SCFA metabolism. HTN-aMCI patients had elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-17, IP-10, RANTES). Notably, after FDR correction, Blautia abundance correlated negatively with inflammatory markers and positively with cognitive scores, whereas pathobionts showed opposite patterns (all q < 0.05).DiscussionThese findings indicate that hypertensive individuals with aMCI harbor a specific gut microbial dysbiosis marked by loss of SCFA producers, expansion of pathobionts, and disrupted microbial networks, which together associate with systemic inflammation and cognitive decline. Our results support the notion that targeting gut microbiota might represent a potential therapeutic avenue for hypertension-related cognitive impairment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with rising global prevalence, yet the peripheral mechanisms linking gut dysbiosis, systemic redox imbalance, and immune activation remain poorly understood. Here, we performed integrated multi-omics profiling of fecal microbiome, serum metabolome, and circulating cytokines in 40 patients with AD and 40 cognitively normal controls, with a specific focus on oxidative stress and antioxidant signatures. Compared with controls, AD patients exhibited marked gut microbial dysbiosis characterized by depletion of butyrate-producing genera (including Faecalibacterium and Roseburia) and enrichment of pro-inflammatory taxa (including Escherichia/Shigella). Serum metabolomics identified a distinct oxidative stress phenotype: AD samples showed significantly elevated levels of xanthosine, (±)-3-hydroxynonanoic acid, and several acyl-carnitines, alongside a marked reduction in the antioxidant carotenoid capsorubin (AUC = 0.98) and other protective compounds. Lipid peroxidation products, including 15,16-epoxy-9,12-octadecadienoic acid and (Z)-5,8,11-trihydroxyoctadec-9-enoic acid, inversely correlated with cognitive scores (MMSE, Barthel Index, WAIS-IV). Concurrently, circulating pro-inflammatory cytokines (IL-8, MCP-1, IP-10, TNF-α) were elevated and correlated positively with both AD-enriched bacteria and oxidative metabolites, while showing negative correlations with antioxidant-related compounds. Integrated network analysis linked loss of butyrate-producing microbes to accumulation of oxidative stress biomarkers and heightened chemokine signaling, which together associated with worse cognitive performance. Selected microbial and redox-related metabolic features achieved excellent diagnostic accuracy (AUC > 0.95). Collectively, these findings define a convergent gut-metabolic-immune axis in AD where systemic oxidative stress serves as a central hub, providing specific, measurable redox biomarkers and mechanistic insights for noninvasive biomarker candidate development and therapeutic target exploration.

Human microbiome research has become pivotal in advancing our understanding of complex diseases such as diabetes, inflammatory bowel disease, and cancer. Much of this work relies on comparing microbial communities across health and disease states, or case-control cohorts, using high-throughput metagenomic sequencing. Yet the very nature of sequencing-derived microbiome data makes robust cohort design and power-based sample-size estimation unusually difficult. Unlike other omics, microbiome profiles are compositional, sparse, and often zero inflated, properties that complicate statistical modeling and inflate sample-size requirements. These challenges are further compounded by the diversity of analytical frameworks-ranging from diversity indices to causal inference-each built on different statistical assumptions and optimized for a distinct research hypothesis. This review synthesizes current approaches around the study design and sample-size estimation in microbiome research, aiming to provide clinicians and researchers with practical guidance for navigating the statistical complexities unique to this field.

While bacterial dysbiosis has been extensively studied in schizophrenia with metabolic syndrome (SZ-MetS), the role of gut mycobiota in this comorbidity remains unclear. This study represents the first comprehensive investigation of fungal communities in SZ-MetS patients (n=109) versus healthy controls (HCs, n=101) using ITS1 sequencing and multi-parameter immune profiling. Although global mycobiota structure showed no significant differences, compositional analyses revealed profound taxonomic shifts: pathobionts (Trichosporon asahii, Candida albicans, Lodderomyces elongisporus) were enriched, while putative beneficial species (Saccharomyces cerevisiae, Pleurotus ostreatus) were reduced in patients. Enterotyping identified two mycobiota clusters (Candida-dominant vs Aspergillus-dominant), though their distribution was similar between groups. Notably, machine learning revealed a six-species fungal signature with strong diagnostic potential (AUC = 0.86). Species-specific immune correlations were also observed: inflammatory cytokines such as IL-6 and MIP-1α were positively associated with Ustilago esculenta and Trichosporon asahii, but negatively correlated with Saccharomyces cerevisiae. Furthermore, fungal abundances were differentially correlated with metabolic and psychiatric parameters, with Lodderomyces linked to elevated triglycerides and S. cerevisiae associated with reduced symptom severity. These findings reveal that while overall fungal community structure is preserved, SZ-MetS exhibits distinct mycobiota alterations that interact with host immunity and clinical manifestations, suggesting fungi may contribute to the SZ-MetS vicious cycle through taxon-specific mechanisms.

ABSTRACT Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a critical global health threat with limited treatment options. While the gut microbiota is a reservoir for opportunistic pathogens and a regulator of host immunity, the reciprocal impact of systemic CRKP infection on gut microbial ecology and immune responses remains poorly defined. In a prospective case-control study, 38 patients with confirmed CRKP infection and 38 matched hospitalized controls without CRKP were enrolled. Fecal samples underwent 16S rRNA gene sequencing to characterize microbial profiles, and serum cytokine levels were quantified using multiplex immunoassays. CRKP infection was associated with significantly reduced microbial diversity and a distinct shift in community structure, characterized by depletion of beneficial commensals (Bacteroides, Faecalibacterium, Roseburia) and enrichment of pathobionts (Klebsiella, Enterococcus). Enterotype analysis revealed a predominance of a Klebsiella/Enterococcus-dominated enterotype in CRKP patients. Functional predictions indicated impaired carbohydrate and butyrate metabolism alongside increased virulence- and resistance-associated pathways. Systemically, patients exhibited elevated pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) and chemokines (IP-10, MCP-1, RANTES). Correlation analyses linked opportunistic taxa with heightened inflammatory markers, while beneficial short-chain fatty acid producers showed inverse associations. Systemic CRKP infection is associated with profound gut dysbiosis and a hyper-inflammatory immune response. The strong microbiota–immune correlations suggest that the gut microbiota may serve as a biomarker and a potential therapeutic target for mitigating CRKP-associated immune dysfunction, though the directional relationship (cause vs. consequence) between dysbiosis and CRKP infection remains to be elucidated.IMPORTANCECarbapenem-resistant Klebsiella pneumoniae (CRKP) is a critical global threat with limited therapeutic options. This study reveals that systemic CRKP infection is associated with profound gut dysbiosis—characterized by loss of beneficial commensals (e.g., Faecalibacterium) and expansion of pathobionts (e.g., Klebsiella, Enterococcus)—as well as a hyperinflammatory immune response. We demonstrate strong correlations between specific microbial taxa and host cytokines, suggesting that the gut microbiome may hold potential as a biomarker and therapeutic target. These findings enhance our understanding of host-microbe interactions in CRKP infection and support the exploration of microbiota-based therapies. However, further studies, including longitudinal and animal models, are needed to clarify whether gut dysbiosis directly influences CRKP outcomes or is a secondary consequence.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, tau hyperphosphorylation, and chronic neuroinflammation. While neuroinflammation-mediated by microglial and astrocyte activation-has long been considered a secondary response to Aβ pathology, emerging evidence positions it as a primary driver of cognitive decline. Notably, the gut microbiota, through the microbiota-gut-brain axis (MGBA), is crucial in modulating neuroinflammation. Dysbiosis disrupts gut barrier integrity, promotes systemic inflammation, and exacerbates neuroinflammatory responses, thereby accelerating AD progression. Recent advances reveal that gut microbiota-derived metabolites (e.g., short-chain fatty acids, lipopolysaccharides) directly influence microglial activation and Aβ aggregation. These findings have opened new therapeutic possibilities, with microbiota-targeted approaches such as probiotics, prebiotics, and fecal microbiota transplantation demonstrating promising neuroprotective effects in preclinical studies by reducing neuroinflammation and preserving cognitive function. However, translating these findings into clinical applications requires further validation through randomized controlled trials. This review summarizes the current understanding of gut microbiota-driven neuroinflammation in AD, from molecular mechanisms to potential therapeutic strategies. Targeting the MGBA represents a paradigm shift in AD management, emphasizing the modulation of neuroinflammation and pathological progression through gut microbiota interventions. The discussion also addresses existing research challenges and outlines future directions to advance this promising field.

Vaccination is an essential strategy against COVID-19 in the current era of emerging variants. This study evaluates the immunogenicity of the recombinant subunit COVID-19 vaccine (Zifivax) in Alzheimer’s disease (AD) patients. A total of 249 patients with Alzheimer’s disease (AD) were enrolled in an eight-month, prospective study conducted across three medical centers in Hangzhou, Zhejiang Province, from May 2022 to January 2023, Zhe Jiang province, and were categorized into unvaccinated (AD-UV) and vaccinated groups (AD-V). Levels of RBD-IgG, neutralization antibody activity, and cytokines were identified to evaluate the immune responses. Clinical outcomes were assessed within one month following breakthrough infection (BTI) with the Omicron variant. Following three doses, the vaccine induced a robust immune response, elevating neutralizing antibodies and activating T-cells in AD-V cohort. AD-V patients exhibited significantly higher humoral immune responses compared to AD-UV counterparts. The anti-RBD antibodies level and pseudoviral neutralizing activity demonstrated an increase concurrent with the onset of immunity and infection, and the seroresponse rate exhibited a similar trend in AD-V cohort. RBD-IgG antibody levels against WT, DELTA, and BA.5 variants in AD-V cohort showed significantly higher compared to AD-UV cohort. Following Omicron infection, unvaccinated patients experienced higher levels of Th1/Th2-type cytokines than vaccinated individuals. Vaccination correlated with reduced severe illness, increased survival rates and extended survival times after Omicron BTI. The findings highlight the immunogenicity and suggest a certain degree of protective effectiveness of the recombinant subunit COVID-19 vaccine (Zifivax) in AD patients.

Antimicrobial resistance (AMR) has become a major and escalating global health threat, undermining the effectiveness of current antibiotic and antimicrobial therapies. The rise of multidrug-resistant bacteria has led to increasingly difficult-to-treat infections, resulting in higher morbidity, mortality, and healthcare costs. Tackling this crisis requires the development of novel antimicrobial agents, optimization of current therapeutic strategies, and global initiatives in infection surveillance and control. Recent studies highlight the crucial role of the human gut microbiota in defending against AMR pathogens. A balanced microbiota protects the body through mechanisms such as colonization resistance, positioning it as a key ally in the fight against AMR. In contrast, gut dysbiosis disrupts this defense, thereby facilitating the persistence, colonization, and dissemination of resistant pathogens. This review will explore how gut microbiota influence drug-resistant bacterial infections, its involvement in various types of AMR-related infections, and the potential for novel microbiota-targeted therapies, such as fecal microbiota transplantation, prebiotics, probiotics, phage therapy. Elucidating the interactions between gut microbiota and AMR pathogens will provide critical insights for developing novel therapeutic strategies to prevent and treat AMR infections. While previous reviews have focused on the general impact of the microbiota on human health, this review will specifically look at the latest research on the interactions between the gut microbiota and the evolution and spread of AMR, highlighting potential therapeutic strategies.

Emerging evidence has highlighted that altered gut microbiota are associated with the onset and progression of depression via regulating the gut-brain axis. However, existing research has predominantly focused on children and adults, frequently neglecting adolescent depression. Given the rising prevalence and substantial impact of adolescent depression on functional impairment and suicidality, it is essential to focus more on this age group. In this study, we examined the fecal microbiota and inflammatory profiles of 99 depressed adolescents and 106 age-matched healthy controls using Illumina NovaSeq sequencing and multiplex immunoassays, respectively. Our findings revealed lower bacterial α-diversity and richness, alongside altered β-diversity in adolescents with depression. Gut dysbiosis associated with adolescent depression was characterized by increased pro-inflammatory genera such as Streptococcus and decreased anti-inflammatory genera like Faecalibacterium. These differential genera may serve as potential non-invasive biomarkers for adolescent depression, either individually or in combination. We also observed disruptions in the inferred microbiota functions in adolescent depression-associated microbiota, particularly in glycolysis and gluconeogenesis. Additionally, depressed adolescents exhibited systemic immune dysfunction, with elevated levels of pro-inflammatory cytokines and chemokines, which showed significant correlations with the differential genera. Our study bridges the gap between children and adults by providing new insights into the fecal microbiota characteristics and their links to immune system disruptions in depressed adolescents, which offer new targets for the diagnosis and treatment of depression in this age group.

Depression, a highly prevalent and relapsing mental disorder, exacts profound personal and socioeconomic tolls globally, warranting urgent scientific and clinical attention. Emerging evidence from both preclinical models and human clinical investigations has established the microbiota-gut-brain axis (MGBA) as a critical determinant in depression pathogenesis. This intricate bidirectional network integrates gut microbiota with central nervous system function, influencing mental health through mechanisms previously underrecognized. This review systematically synthesizes gut microbiota alterations associated with depression and their impacts on neuroendocrine, neuroimmune, and metabolic pathways. Advanced therapeutic strategies targeting the MGBA are discussed, including probiotics, fecal microbiota transplantation, and artificial intelligence-enabled microbiome interventions for depression management. While challenges in standardization, mechanistic understanding, efficacy and safety remain, MGBA-centered approaches offer a promising shift toward microbiota-based diagnostics and personalized treatments for depression.

Antimicrobial resistance (AMR) poses a global health threat, particularly in critically ill patients with multidrug-resistant organism (MDRO) colonization or infection. While evidence suggests the gut microbiota plays a critical role in MDRO colonization and infection, its specific characteristics and the host immune response remain poorly understood. This case–control study compared 88 MDRO-infected patients, 100 MDRO-colonized patients, and 86 healthy controls, using 16S rRNA sequencing and cytokine profiling. MDRO cohorts exhibited profound gut dysbiosis, including reduced gut microbial diversity and distinct community structures, reduced beneficial bacteria (e.g., Bacteroides, Faecalibacterium, Roseburia, Prevotella), and expansion of pathobionts—resident microbes with pathogenic potential (e.g., Enterococcus, Klebsiella, Escherichia-Shigella). Enterotype analysis revealed a shift from a Bacteroides-dominated to one Enterococcus-dominated microbiota in both colonized and infected patients compared to controls. Serum cytokine profiling indicated immune dysfunction in MDRO-associated patients. Correlation analysis showed that beneficial genera were negatively correlated with pro-inflammatory cytokines (IL-1ra, IL-2, IL-7, TNF-α, and IFN-γ) and positively associated with anti-inflammatory markers, while pathobionts exhibited the opposite trend. Several key differential genera, such as Enterococcus and Klebsiella, either individually or in combination, have been identified as key discriminators of MDRO status. Functional predictions through PiCRUSt observed disruptions in carbohydrate and lipid metabolism in the MDRO cohorts. Overall, MDRO colonization and infection lead to gut dysbiosis and immune dysfunction, with microbiota-immune interactions playing a crucial role in disease progression, suggesting the gut microbiota as a potential diagnostic and therapeutic target for AMR.

Hypertension (HTN) remains the leading modifiable risk factor for global mortality and morbidity. The number of adults aged 30–79 with HTN has doubled worldwide, reaching approximately 1.3 billion, with nearly half unaware of their condition. Despite available therapies, the global control rate remains unacceptably low at around 20%, particularly in low- and middle-income countries. This substantial treatment gap contributes to a high burden of preventable cardiovascular events and strains healthcare systems globally, underscoring the urgent need for more effective, accessible, and personalized management strategies. Growing evidence suggests that gut microbiota dysbiosis plays a role in HTN pathogenesis, though its mechanistic basis remains incompletely understood. In this case-control study, we investigated the gut microbiota composition of 205 elderly Chinese individuals (153 HTN patients, 52 controls) using NovaSeq sequencing and assessed systemic inflammation using multiplex immunoassays. Enterotype analysis and receiver operating characteristic (ROC) modeling were employed to identify microbial signatures. HTN patients demonstrated significant β-diversity alterations and distinct taxonomic changes, characterized by enriched Escherichia_Shigella, Prevotella_9, and Enterococcus, and depletion of Blautia and butyrate-producing genera. The Escherichia_Shigella-dominated enterotype (E2) was significantly more prevalent in HTN. ROC-based biomarker analysis identified Blautia, Butyricicoccus, Lachnoclostridium, Prevotella_9, and Enterococcus as potential diagnostic biomarkers. HTN patients also exhibited elevated pro-inflammatory cytokines such as IL-1ra and TNF-α, indicative of chronic low-grade inflammation. Correlation analysis revealed strong associations between pathobionts (e.g., Escherichia_Shigella) and pro-inflammatory cytokines, and between butyrate producers (Blautia) and anti-inflammatory mediators. These findings underscore gut dysbiosis and systemic inflammation as key pathophysiological features in elderly hypertension and provide a foundation for developing microbiota-based diagnostic and therapeutic approaches for this population.

Schizophrenia (SZ) is a severe psychiatric disorder with a complex etiology involving both genetic and environmental factors. Emerging evidence highlights the role of gut microbiome dysbiosis in SZ, yet the fungal component (mycobiota) remains largely unexplored. This study aimed to evaluate the gut mycobiota using internal transcribed spacer 1 (ITS1) amplicon sequencing and assess host immune responses via multiplex immunoassays in 87 elderly SZ patients and 64 age- and gender-matched healthy controls (HCs). We observed significant increases in fungal α-diversity and richness, along with altered β-diversity in SZ patients. Specifically, there was an elevated Basidiomycota/Ascomycota ratio, with enrichment of Candida, Aspergillus, and Saccharomyces, coupled with a depletion of Purpureocillium. Enterotype analysis revealed a shift from Purpureocillium-dominant (E1) to Candida-dominant (E2) communities in SZ. Notably, key fungal species, such as S. cerevisiae and P. lilacinum, were correlated with systemic immune dysfunction. Our receiver operating characteristic (ROC) analysis indicated that these fungal species could effectively distinguish SZ patients from HCs, suggesting their potential as non-invasive biomarkers for SZ diagnosis. In conclusion, this study demonstrates significant alterations in the gut mycobiota and immune dysfunction in elderly SZ patients, suggesting that mycobiota dysbiosis may contribute to SZ pathogenesis through immune modulation, offering new avenues for potential biomarkers and therapeutic interventions.

Copper dysmetabolism is associated with various neurodegenerative disorders, making high-spatiotemporal-resolution imaging of Cu 2+ in the brain essential for understanding the underlying pathophysiological processes. Nevertheless, the current probes encounter obstacles in crossing the blood–brain barrier (BBB) and providing high-spatial-resolution in deep tissues. Herein, we present a photoacoustic probe capable of imaging Cu 2+ dynamics in the mouse brain with high-spatiotemporal-resolution. The probe demonstrates selective ratiometric and reversible responses to Cu 2+ , while also efficiently crossing the BBB. Using the probe as the imaging agent, we successfully visualized Cu 2+ in the brain of Parkinson's disease (PD) model mouse with a remarkable micron-level resolution. The imaging results revealed a significant increase in Cu 2+ levels in the cerebral cortex as PD progresses, highlighting the close association between Cu 2+ alternations in the region and the disease. We also demonstrated that the probe can be used to monitor changes in Cu 2+ distribution in the PD model mouse brain during L-dopa intervention. Mechanism studies suggest that the copper dyshomeostasis in the PD mouse brain was dominated by the expression levels of divalent metal transporter 1. The application of our probe in imaging Cu 2+ dynamics in the mouse brain offers valuable insights into the copper-related molecular mechanisms underlying neurodegenerative diseases.

Multiple sclerosis (MS) is an autoimmune disorder caused by chronic inflammatory reactions in the central nervous system. Currently, little is known about the changes of plasma proteomic profiles in Chinese patients with MS (CpwMS) and its relationship with the altered profiles of multi-omics such as metabolomics and gut microbiome, as well as potential molecular networks that underlie the etiology of MS. To uncover the characteristics of proteomics landscape and potential multi-omics interaction networks in CpwMS, Plasma samples were collected from 22 CpwMS and 22 healthy controls (HCs) and analyzed using a Tandem Mass Tag (TMT)-based quantitative proteomics approach. Our results showed that the plasma proteomics pattern was significantly different in CpwMS compared to HCs. A total of 90 differentially expressed proteins (DEPs), such as LAMP1 and FCG2A, were identified in CpwMS plasma comparing to HCs. Furthermore, we also observed extensive and significant correlations between the altered proteomic profiles and the changes of metabolome, gut microbiome, as well as altered immunoinflammatory responses in MS-affected patients. For instance, the level of LAMP1 and ERN1 were significantly and positively correlated with the concentrations of metabolite L-glutamic acid and pro-inflammatory factor IL-17 (Padj < 0.05). However, they were negatively correlated with the amounts of other metabolites such as L-tyrosine and sphingosine 1-phosphate, as well as the concentrations of IL-8 and MIP-1α. This study outlined the underlying multi-omics integrated mechanisms that might regulate peripheral immunoinflammatory responses and MS progression. These findings are potentially helpful for developing new assisting diagnostic biomarker and therapeutic strategies for MS.

Autism spectrum disorder (ASD) is a persistent neurodevelopmental disorder affecting brains of children. Mounting evidences support the associations between gut microbial dysbiosis and ASD, whereas detailed mechanisms are still obscure. Here we probed the potential roles of gut microbiome in ASD using fecal metagenomics and metabolomics. Children with ASD were found to be associated with augmented serum cytokines milieu, especially TNFα. Metagenomic analysis generated 29 differential species and 18 dysregulated functional pathways such as Bifidobacterium bifidum, Segatella copri, and upregulated ‘Sphingolipid metabolism’ in children with ASD. Metabolomics revealed steroid hormone dysgenesis in children with ASD with lower abundances of metabolites such as estriol, estradiol and deoxycorticosterone. A three-way association analysis showed positive correlations between TNFα and microbial function potentials such as ‘Bacterial toxins’ and ‘Lysosome’, indicating the contribution of microbial dysbiosis to neuroinflammation. TNFα also correlated positively with ‘Sphingolipid metabolism’, which further showed negative correlations with metabolites estriol and deoxycorticosterone. Such results, in consistent with current findings, revealed the contribution of increased TNFα to upregulated sphingolipid metabolism, which further impaired steroid hormone biosynthesis. Our study proposed the gut microbial ‘TNFα-sphingolipids-steroid hormones’ axis in children with ASD, which may provide new perspectives for developing gut microbiome-based treatments in the future.

High SARS-CoV-2-specific antibody levels can protect against SARS-CoV-2 reinfection. The gut microbiome can affect a host’s immune response. However, its role in the antibody response to SARS-CoV-2 in people living with HIV (PLWH) remains poorly understood. Here, we categorised PLWH and healthy individuals into high- and low-antibody-response groups. Shotgun metagenomic sequencing and targeted metabolomic assays were used to investigate the differences in the gut microbiome and metabolic functions between the high- and low-antibody-response groups. PLWH demonstrated a higher abundance of short-chain fatty acid (SCFA)-producing species, accompanied by high serum levels of several SCFAs, in the high-antibody-response group than in the low-antibody-response group. In contrast, healthy individuals demonstrated higher enrichment of pilus-bearing bacterial species, with flagella-expressing genes, in the high-antibody-response group than in the low-antibody-response group. Therefore, gut-microbiota-derived SCFAs play a key role in antibody responses in PLWH but not in healthy individuals. Our results afford a novel understanding of how the gut microbiome and its metabolites are associated with host immunity. Moreover, they may facilitate the exploration of modalities to prevent SARS-CoV-2 reinfection through various gut-microbiota-targeted interventions tailored to different populations.

Metabolic syndrome (MetS) is highly prevalent in individuals with schizophrenia (SZ), leading to negative consequences like premature mortality. Gut dysbiosis, which refers to an imbalance of the microbiota, and chronic inflammation are associated with both SZ and MetS. However, the relationship between gut dysbiosis, host immunological dysfunction, and SZ comorbid with MetS (SZ-MetS) remains unclear. This study aims to explore alterations in gut microbiota and their correlation with immune dysfunction in SZ-MetS, offering new insights into its pathogenesis. We enrolled 114 Chinese patients with SZ-MetS and 111 age-matched healthy controls from Zhejiang, China, to investigate fecal microbiota using Illumina MiSeq sequencing targeting 16 S rRNA gene V3-V4 hypervariable regions. Host immune responses were assessed using the Bio-Plex Pro Human Cytokine 27-Plex Assay to examine cytokine profiles. In SZ-MetS, we observed decreased bacterial α-diversity and significant differences in β-diversity. LEfSe analysis identified enriched acetate-producing genera (Megamonas and Lactobacillus), and decreased butyrate-producing bacteria (Subdoligranulum, and Faecalibacterium) in SZ-MetS. These altered genera correlated with body mass index, the severity of symptoms (as measured by the Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms), and triglyceride levels. Altered bacterial metabolic pathways related to lipopolysaccharide biosynthesis, lipid metabolism, and various amino acid metabolism were also found. Additionally, SZ-MetS exhibited immunological dysfunction with increased pro-inflammatory cytokines, which correlated with the differential genera. These findings suggested that gut microbiota dysbiosis and immune dysfunction play a vital role in SZ-MetS development, highlighting potential therapeutic approaches targeting the gut microbiota. While these therapies show promise, further mechanistic studies are needed to fully understand their efficacy and safety before clinical implementation.

Oral microbial dysbiosis contributes to the development of schizophrenia (SZ). While numerous studies have investigated alterations in the oral bacterial microbiota among SZ patients, investigations into the fungal microbiota, another integral component of the oral microbiota, are scarce. In this cross-sectional study, we enrolled 118 Chinese patients with SZ and 97 age-matched healthy controls (HCs) to evaluate the oral fungal microbiota from tongue coating samples using internal transcribed spacer 1 amplicon sequencing and assess host immunity via multiplex immunoassays. Our findings revealed that SZ patients exhibited reduced fungal richness and significant differences in β-diversity compared to HCs. Within the oral fungal communities, we identified two distinct fungal clusters (mycotypes): Candida and Malassezia, with SZ patients showing increased Malassezia and decreased Candida levels. These key functional oral fungi may serve as potential diagnostic biomarkers for SZ. Furthermore, SZ patients displayed signs of immunological dysfunction, characterized by elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α, and chemokines including MIP-1α and MCP-1. Importantly, Malassezia mycotype correlated positively with peripheral pro-inflammatory cytokines, while Candida mycotype exhibited a negative correlation with these cytokines. In conclusion, we have demonstrated, for the first time, the presence of altered oral fungal communities and systemic immune dysfunction in Chinese SZ patients compared to HCs, providing novel insights into the potential role of oral fungi as biomarkers and the broader implications for understanding SZ pathogenesis.