The most common extra-intestinal manifestation (EIM) of inflammatory bowel disease (IBD), IBD-associated arthritis (IAA), occurs in 25-40% of patients and can be debilitating. In IBD, mucosal and stool microbiota richness is decreased, and compositional changes can precede or accompany disease onset. Likewise, spondyloarthritides are associated with altered gut microbiota, with overlapping bacterial signatures observed in IBD, suggesting key shared microbial factors are involved in both conditions. Much has been learned about the role of the intestinal microbiome in IBD, but less is known regarding its role in IAA. To address this knowledge gap, we analyzed the mucosa-associated intestinal microbiota of participants enrolled in the LOCATION-IBD cohort. Microbiota composition was established using 16S rRNA gene amplicon sequencing of intestinal biopsy samples taken from participants with IBD, with or without arthropathy. Microbiota samples clustered predominantly by participant, and similar taxa were present across the colon. The mucosal intestinal microbiota of females with IAA displayed a lower relative abundance of R. intestinalis, while males with IAA had a higher relative abundance of Corynebacterium, even when controlling for IBD-type, whether samples were taken from a site of inflammation and intestinal location. These findings indicate the mucosa-associated intestinal microbiota is associated with IAA in a sex-specific manner.

Diet has a profound impact in human health, which is partly driven by changes in the intestinal microbiota. Several associations between dietary intake and the intestinal microbiota composition and function have been described. Namely, the Mediterranean diet is associated with beneficial bacteria, while the intake of ultraprocessed foods is linked to dysbiosis. It is, therefore, very tempting to tailor dietary approaches to the individual needs of the microbiota; however, high-quality prospective data are lacking. Provisionally, a diet rich in fruits and vegetables and low in ultraprocessed foods is recommended to improve the intestinal microbiota composition and function.

Chronic inflammation creates an oxidative environment, altering the gut microbiota. However, the mechanisms underlying oxidative stress-induced community changes remain poorly understood, owing to the complexity of the host environment, high inter-individual variability, and a lack of comparative data on stress tolerance across intestinal taxa. To address this, we developed an in vitro cultivation approach to assess the effects of oxidative stress, induced by 12 concentrations each of hydrogen peroxide (H₂O₂) and oxygen (O₂), on 41 intestinal strains and seven adults' fecal microbiota. Fusicatenibacter saccharivorans and Lachnospira eligens emerged as particularly sensitive taxa in both pure cultures and complex communities. Oxidative stress also reduced butyrate-producing taxa, like Agathobacter and Anaerostipes, along with total butyrate levels. In contrast, facultative anaerobes, like Escherichia-Shigella and Enterococcus, were largely unaffected, and Bacteroides showed high resilience. Notably, the impact of oxidative stress varied among individuals, with numerous genera showing taxon-specific changes depending on the host microbiota composition. These findings underscore the importance of considering individual microbiota backgrounds when assessing oxidative stress effects on microbial communities. Our study provides a tolerance profile of gut microbes to oxidative stress, reveals overlooked taxa involved in community restructuring, and introduces a screening tool to characterize individual microbial and metabolic responses.

A wide variety of human diseases are associated with loss of microbial diversity in the human gut, inspiring a great interest in the diagnostic or therapeutic potential of the microbiota. However, the ecological forces that drive diversity reduction in disease states remain unclear, rendering it difficult to ascertain the role of the microbiota in disease emergence or severity. One hypothesis to explain this phenomenon is that microbial diversity is diminished as disease states select for microbial populations that are more fit to survive environmental stress caused by inflammation or other host factors. Here, we tested this hypothesis on a large scale, by developing a software framework to quantify the enrichment of microbial metabolisms in complex metagenomes as a function of microbial diversity. We applied this framework to over 400 gut metagenomes from individuals who are healthy or diagnosed with inflammatory bowel disease (IBD). We found that high metabolic independence (HMI) is a distinguishing characteristic of microbial communities associated with individuals diagnosed with IBD. A classifier we trained using the normalized copy numbers of 33 HMI-associated metabolic modules not only distinguished states of health vs IBD, but also tracked the recovery of the gut microbiome following antibiotic treatment, suggesting that HMI is a hallmark of microbial communities in stressed gut environments.

Crohn's disease (CD) and ulcerative colitis (UC) are the two major entities of inflammatory bowel disease (IBD). These disorders are known for their relapsing disease course and severe gastrointestinal symptoms including pain, diarrhoea and bloody stool. Accumulating evidence suggests that IBD is not only restricted to the gastrointestinal tract and that disease processes are able to reach distant organs including the brain. In fact, up to 35 % of IBD patients also suffer from neuropsychiatric disorders such as generalized anxiety disorder and major depressive disorder. Emerging research in this area indicates that in many cases these neuropsychiatric disorders are a secondary condition as a consequence of the disturbed communication between the gut and the brain via the microbiota-gut-brain axis. In this review, we summarise the current knowledge on IBD-associated neuropsychiatric disorders. We examine the role of different pathways of the microbiota-gut-brain axis in the development of CNS disorders highlighting altered neural, immunological, humoral and microbial communication. Finally, we discuss emerging therapies targeting the microbiota-gut-brain axis to alleviate IBD and neuropsychiatric symptoms including faecal microbiota transplantation, psychobiotics, microbial metabolites and vagus nerve stimulation.

The global incidence of colorectal cancer (CRC) is increasing. In the majority of CRC cases, colon cancer develops from alterations in the adenoma-carcinoma sequence pathway. Currently, there are few studies regarding the effects of enteric viruses on the adenoma-carcinoma sequence pathway, and subsequently, the progression and development of the CRC. Here, fecal and tissue samples from a normal control group, an adenomatous polyp group, and a colorectal adenocarcinoma group were collected to gain a deeper understanding of the variations in enteric viruses in CRC patients and to analyze their significance. With the progression of CRC from adenoma to adenocarcinoma, the number of DNA viruses in the virus-like particles (VLPs) of fecal and tissue samples gradually increased, and there were distinct differences in the composition of enteric viruses among the different groups. Multiple species correlation analysis revealed extensive interactions among viruses, bacteria, and fungi in fecal and tissue samples. Functional analysis also revealed that the functional pathways in fecal and tissue samples also underwent significant changes. In conclusion, the changes in the composition and function of enteric viruses in the progression of CRC via adenoma-carcinoma sequence pathway were analyzed in this study, and these changes hold certain importance for exploring the role of enteric viruses in the occurrence of this disease; however, their mode of action and specific mechanisms require further investigation.

This review summarizes and discusses key recent findings suggesting that microbiomes can play a role in the development and progression of osteoarthritis. Evidence supporting a gut microbiome-joint connection derived from human and animal studies is enumerated and discussed, with particular attention on the microbial and molecular basis for the development of therapeutic interventions that involve targeting the gut. Additionally, clinical data supporting the concept of a living microbiome within a diarthrodial joint are summarized. A discussion of key limitations in the current data and important technical considerations for firmly establishing the existence of a synovial joint microbial community is included.

Sarcopenia, an age-related disorder marked by decreased skeletal muscle mass, strength, and function, is associated with negative health impacts in individuals and financial burdens on families and society. Studies have suggested that age-related alterations in gut microbiota may contribute to the development of sarcopenia in older people through the gut-muscle axis, thus modulation of gut microbiota may be a promising approach for sarcopenia treatment. However, the characteristic gut microbiota for sarcopenia has not been consistent across studies. Therefore, the aim of this study was to compare the diversity and compositional differences in the gut microbiota of older people with and without sarcopenia, and to identify gut microbiota biomarkers with therapeutic potential for sarcopenia.

The PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Database were searched studies about the gut microbiota characteristics in older people with sarcopenia. The quality of included articles was assessed by the Newcastle-Ottawa Scale (NOS). Weighted standardized mean differences (SMDs) and 95% confidence intervals (CIs) for α-diversity index were estimated using a random effects model. Qualitative synthesis was conducted for β-diversity and the correlation between gut microbiota and muscle parameters. The relative abundance of the gut microbiota was analyzed quantitatively and qualitatively, respectively.

Pooled estimates showed that α-diversity was significantly lower in older people with sarcopenia (SMD: -0.41, 95% CI: -0.57 to -0.26, I²: 71%, P < 0.00001). The findings of β-diversity varied across included studies. In addition, our study identified gut microbiota showing a potential and negative correlation with sarcopenia, such as Prevotella, Slackia, Agathobacter, Alloprevotella, Prevotella copri, Prevotellaceae sp., Bacteroides coprophilus, Mitsuokella multacida, Bacteroides massiliensis, Bacteroides coprocola Conversely, a potential and positive correlation was observed with opportunistic pathogens like Escherichia-Shigella, Eggerthella, Eggerthella lenta and Collinsella aerofaciens.

This study showed that α-diversity is decreased in sarcopenia, probably predominantly due to diminished richness rather than evenness. In addition, although findings of β-diversity varied across included studies, the overall trend toward a decrease in SCFAs-producing bacteria and an increase in conditionally pathogenic bacteria. This study provides new ideas for targeting the gut microbiota for the prevention and treatment of sarcopenia.

https://www.crd.york.ac.uk/PROSPERO/view/CRD42024573090, identifier CRD42024573090.

Crohn's disease (CD) is a chronic inflammatory bowel disorder frequently associated with significant nutritional deficiencies. Enteral nutrition (EN), particularly exclusive enteral nutrition (EEN), has gained recognition not only for its nutritional support but also for its therapeutic potential in reducing intestinal inflammation. While EEN is well established in pediatric populations, its application in adults remains limited due to lower adherence and palatability challenges. Nonetheless, emerging evidence supports its efficacy in various clinical settings, including as an adjunct to pharmacologic therapies and in mitigating pre- and postoperative disease burden. The heterogeneity of study designs, formula compositions, and clinical protocols underscores the need for standardized guidelines and personalized approaches. This narrative review synthesizes the current evidence on the role of EN in adult patients with CD, with a focus on its use for induction and maintenance of remission, as well as perioperative optimization.

The association of obesity with inflammatory bowel disease (IBD) can be understood by the intricate role of pro- and anti-inflammatory cytokines, especially adipokines, which are secreted by adipose tissue and are responsible for IBD because of their structural similarity with tumor necrosis factor-alpha (TNF-α), an important cytokine involved in IBD pathogenesis. The current study was carried out to evaluate the therapeutic potential of Benincasa hispida in obesity-associated IBD. Approximately 18 compounds sourced from Benincasa hispida (Thunb.) were comprehensively analyzed, among which 11 presented favorable drug-likeness scores and adherence to Lipinski's Rule of Five. Various methodologies, including compound-gene set pathway enrichment analysis, network pharmacology, docking studies, and molecular dynamics simulations, have been employed. Safety assessments via Protox confirmed the nontoxic nature of these compounds, which is crucial for their therapeutic potential. Through Venn diagram analysis of the Gene Card and OMIM databases, proteins associated with obesity and IBD management were pinpointed. Pathway enrichment analysis revealed 810 targets across 192 distinct pathways, with 8 directly related to the pathogenesis of obesity and IBD. Notable therapeutic targets, such as MTOR, were identified through STRING and KEGG pathway database analyses, shedding light on the molecular pathways modulated by these protein targets. Interactions among compounds, proteins, and pathways were visualized via Cytoscape 3.6.1. Furthermore, the compounds were docked with the protein target via AutoDock 4.2, and the compound ajmalin exhibited the highest binding affinity with the MTOR protein, with a binding energy of -7.8 kcal/mol; later, a dynamic study was performed for the ajmaline and protein complex. These findings shed light on the potential efficacy of Benincasa hispida in targeting crucial pathways for managing obesity and IBD. Hence, in vivo studies involving Wistar rats exposed to microplastics and monosodium glutamate (MSG) were carried out to evaluate the potential of Benincasa hispida extracts in mitigating obesity-related IBD. Fecal lipid analysis revealed alterations associated with these conditions, whereas histopathological examinations of the liver and intestine revealed the inflammatory changes induced by MSG and microplastics. The protective effects of this extract on liver and intestinal histology suggest promising avenues for further investigations, emphasizing its potential as a therapeutic intervention for IBD and obesity.

The increasing global prevalence of inflammatory diseases, such as ulcerative colitis and irritable bowel syndrome, represents a challenging task for healthcare systems. Several approaches to disease management target the intestinal microbiome, which plays a key role in health and disease. One promising approach is modulating the microbiome using human milk oligosaccharides (HMOs). Originating from human milk, HMOs are indigestible carbohydrates that act in a host-optimized prebiotic fashion by providing an energy source for health-promoting intestinal bacteria and exhibiting systemic effects. Commercial products supporting infant health and development have been the primary fields of HMO application. Advancements in the large-scale production of HMOs through bioengineering and precision fermentation have led to evaluation of their potential for managing inflammatory diseases. Several in vitro studies and observations on model systems have been clinically validated in infants, resulting in a large body of evidence supporting the safety and efficacy of HMOs in inflammatory disorders. Although novel approaches seek to explore interventions in adults, the primary goal for the future is to provide cost-efficient, safe, and reliable healthcare compounds across all age groups.

The development and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in children are closely related to alterations of gut microbiota. This study aims to investigate changes in the gut microbiota signature and microbial metabolites in children with MASLD. We collected fecal samples from children and adolescents aged 6-16 years, and the presence of MASLD was diagnosed by ultrasound. We performed 16S ribosomal DNA sequencing and targeted metabolomics in 36 and 25 subjects, consisting of healthy controls, children with obesity, and children with MASLD. The α-diversity was significantly lower in children with obesity and MASLD compared with healthy controls. Linear discriminant analysis of effect size analysis identified Anaerostipes and A. hadrus as the top biomarkers differentiating the obesity group from the MASLD group. In MASLD patients with high alanine aminotransferase values (≥50 U/L for boys and 44 U/L for girls), we observed a decrease in the gut microbiota health index. MASLD patients with high shear wave elastography (E) values (≥6.2 kPa) showed an increased abundance of Ruminococcus torques, which was positively correlated with the levels of deoxycholic acid (DCA) and E values. Importantly, the mediation analysis identified positive associations between R. torques and clinical indicators of MASLD that were mediated by DCA. Overall, our study suggests that gut microbiota and metabolites are significantly altered in children with MASLD, and targeting R. torques may offer potential benefits for disease management.IMPORTANCEThis study investigated alterations in the gut microbiota signature and microbial metabolites in children with metabolic dysfunction-associated steatotic liver disease (MASLD). We found that an increased abundance of Ruminococcus torques was associated with increased levels of deoxycholic acid and the progression of MASLD, suggesting that R. torques may serve as a novel clinical target in pediatric MASLD.

Inflammatory bowel disease (IBD) refers to a group of chronic inflammatory disorders impacting the gastrointestinal (GI) tract. It represents a significant public health challenge due to its rising global incidence and substantial impact on patients' quality of life. Emerging research suggests a pivotal role of the human microbiome in IBD pathogenesis. Bacteriophages, integral components of the human microbiome, are indicated to influence the disease onset, progression, and therapeutic strategies. Here, we review the effect of bacteriophages on the pathogenesis of IBD and, more specifically, on the gut bacteria, the systemic immunity, and the susceptibility genes. Additionally, we explore the potential therapeutic use of the bacteriophages to modify gut microbiota and improve the health outcomes of IBD patients. This review highlights the potential of therapeutic bacteriophages in regulating gut microbiota and modulating the immune response to improve health outcomes in IBD patients. Future studies on personalized bacteriophage therapy and its integration into clinical practice could advance treatment strategies for IBD.

This study aims to investigate whether human milk exosomes from gestational diabetes mellitus (GDM-EXO) and healthy (HEA-EXO) parturients differ in regulating intestinal development in offspring. The differential miRNAs associated with intestinal development in GDM-EXO and HEA-EXO were verified by using qPCR and their relationships with gut microbiota (GM) in infants were analyzed. C57BL/6J mice were gavaged with 50 mg/kg·BW HEA-EXO or GDM-EXO. The intestinal morphology, gut barriers, ZO-1 and Occludin, and GM were determined by histological staining, Western blotting, and 16S rDNA amplicon sequencing, respectively. Hsa-miR-19b-3p, hsa-miR-148a-3p, and hsa-miR-320a-3p were upregulated, and hsa-miR-429 was decreased in GDM-EXO compared to HEA-EXO. The GDM parturients' infants had increased intestinal Coriobacteriaceae, Clostridiaceae, Erysipelotrichaceae, Erysipelatoclostridiaceae, and fewer Lactobacillaceae than the healthy parturient's infants. The four differential miRNAs in GDM-EXO all correlated with the infants' GM. GDM-EXO- and HEA-EXO-fed mice had greater villus lengths, villus length-to-crypt depth ratios, goblet cell numbers, elevated ZO-1 and Occludin, and lower crypt depths than control mice. HEA-EXO-fed mice had better intestinal morphology and gut barrier integrity than GDM-EXO-fed mice. GDM-EXO-fed mice had significantly decreased Lachnospiraceae and Oscillospiraceae than HEA-EXO-fed mice. GDM-EXO demonstrate weaker ability to promote intestinal development in offspring than HEA-EXO.

Inflammatory bowel disease (IBD) includes chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis, characterized by impaired function of the intestinal mucosal epithelial barrier. In recent years, ferroptosis, a novel form of cell death, has been confirmed to be involved in the pathological process of IBD and is related to various pathological changes, such as oxidative stress and inflammation. Recent studies have further revealed the complex interactions between the microbiome and ferroptosis, indicating that ferroptosis is an important target for the regulation of IBD by the gut microbiota and its metabolites. This article reviews the significant roles of gut microbial metabolites, such as short-chain fatty acids, tryptophan, and bile acids, in ferroptosis in IBD. These metabolites participate in the regulation of ferroptosis by influencing the intestinal microenvironment, modulating immune responses, and altering oxidative stress levels, thereby exerting an impact on the pathological development of IBD. Treatments based on the gut microbiota for IBD are gradually becoming a research hotspot. Finally, we discuss the potential of current therapeutic approaches, including antibiotics, probiotics, prebiotics, and fecal microbiota transplantation, in modulating the gut microbiota, affecting ferroptosis, and improving IBD symptoms. With a deeper understanding of the interaction mechanisms between the gut microbiota and ferroptosis, it is expected that more precise and effective treatment strategies for IBD will be developed in the future.

Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.

Chronic inflammation in the gut might be linked to microbiota dysbiosis.

This study aimed to investigate alterations in the gut microbiota composition of adult IBD patients compared to healthy controls.

This case-control study investigated the relationship between faecal microbiota composition and IBD in adults. Real-time qPCR analysis using bacterial 16S rRNA gene quantified the abundance of six key bacterial groups (Firmicutes, Lactobacillus spp., Bifidobacterium spp., Fusobacterium spp., Bacteroides fragilis, and Faecalibacterium prausnitzii) in faecal samples from 30 IBD patients (13 Crohn's disease, 17 ulcerative colitis) and 30 healthy controls. A correlation matrix was employed to assess relationships between these bacteria.

Real-time qPCR revealed significant differences (p-value <0.05) in the abundance of several bacterial groups between IBD patients and healthy controls. Firmicutes, Fusobacterium spp., and B. fragilis were significantly more abundant (p-value <0.05) in IBD patients compared to controls. Conversely, Lactobacillus spp. and F. prausnitzii were both significantly less abundant (p-value <0.05) in IBD patients. While some bacterial groups exhibited trends toward higher abundance in either CD or UC patients, these differences were not statistically significant (p-value >0.111). The correlation matrix analysis revealed specific co-occurrence patterns: Bacteroides showed a strong negative correlation with Prevotella, more abundant in healthy controls, suggesting a shift in dominance in IBD patients. Lactobacillus spp. and F. prausnitzii exhibited a positive correlation in healthy individuals, indicating their potential cooperative role in maintaining gut homeostasis.

This study identified significant alterations in gut microbiota composition in adult IBD patients compared to healthy controls, with notable differences in the abundance of specific bacterial groups. These findings suggest that gut microbiota dysbiosis may play a critical role in IBD pathogenesis. The identification of specific bacterial imbalances provides a foundation for developing microbiota-based therapies, such as probiotics, prebiotics, and fecal microbiota transplantation, as potential interventions for restoring microbial balance and mitigating disease progression. Further research is needed to translate these insights into targeted therapeutic strategies and to explore their effectiveness in clinical settings.

Given the heightened focus on high-risk populations, this study aimed to provide insights into early susceptibility and preventive strategies for colorectal cancer (CRC) by focusing on high-risk populations. In this research, fecal samples from 1,647 individuals across three discovery cohorts and nine external validation cohorts were sequenced using whole-genome metagenomic sequencing. A prediction model based on random forest was constructed using the nine external cohorts and independently validated with the three discovery cohorts. A disease probability (POD) model based on microbial biomarkers was developed to assess CRC risk. We found that the gut microbiome composition of CRC relatives differed from that of controls, with enrichment of species such as Fusobacterium and Bacteroides and a reduction in beneficial genera like Coprococcus and Roseburia. Additionally, dietary red meat intake emerged as a risk factor. The POD model indicated an elevated risk of CRC in unaffected relatives. The findings suggest that the POD for CRC may be increased in unaffected relatives or individuals living in shared environments, although this difference did not reach statistical significance. Our study introduces a novel framework for assessing the risk of colorectal cancer in ostensibly healthy individuals.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis, is characterised by chronic and relapsing inflammation of the gastrointestinal tract, leading to significant morbidity and reduced quality of life. The global rise in IBD incidence is driven by a complex interplay of genetic, environmental, dietary and microbiome-related factors. Despite advancements in treatment, such as biologics, response rates remain variable, highlighting the need for personalised approaches. Recent research suggests that specific microbiome signatures may serve as biomarkers for predicting therapeutic efficacy, offering a potential tool for optimising treatment strategies in CD. The aim of the Optimising IBD Patient Treatment with Integrated Microbiome Investigation for Specialised Therapeutics (OPTIMIST) study is to evaluate microbiome profiles across various sample types in a Canadian CD cohort starting or already on advanced therapy, with the goal of developing predictive models for personalised therapeutics.

This study is a two-phase, longitudinal, prospective observational pilot study conducted in British Columbia, Canada, involving both CD patients and non-IBD controls. Phase 1 focuses on baseline microbiome differences across participant cohorts through cross-sectional analysis. Phase 2 follows participants over 12 months to assess microbiome changes and their association with treatment response. Stool samples, intestinal biopsies from the left colon, right colon and ileum, as well as mucosal wash samples from the proximal part of the distal colon, will undergo metagenomics, metaproteomics and metabolomics analyses to explore compositional and functional differences. Data will be analysed using alpha and beta diversity metrics, differential abundance analyses and multivariate analyses to identify microbiome-based predictors of therapeutic response.

Ethical approval was received by the Research Ethics Board (REB) of University of British Columbia-Providence Healthcare (UBC-PHC) with a REB number H23-02927. All amendments to the protocol are reported and adapted based on the requirements of the REB. The results of this study will be submitted to peer-reviewed journals and will be communicated in editorials/articles by the IBD Centre of BC and BC Children's Hospital Research Institute.

NCT06453720.

2024-06-21, version 3.0.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD), ulcerative colitis (UC), and IBD unclassified (IBD-U), is a complex intestinal disorder influenced by genetic, environmental, and microbial factors. Recent evidence highlights the gut microbiota as a pivotal biomarker and modulator in IBD pathogenesis. Dysbiosis, characterized by reduced microbial diversity and altered composition, is a hallmark of IBD. A consistent decrease in anti-inflammatory bacteria, such as Faecalibacterium prausnitzii, and an increase in pro-inflammatory species, including Escherichia coli, have been observed. Metabolomic studies reveal decreased short-chain fatty acids (SCFAs) and secondary bile acids, critical for gut homeostasis, alongside elevated pro-inflammatory metabolites. The gut microbiota interacts with host immune pathways, influencing morphogens, glycosylation, and podoplanin (PDPN) expression. The disruption of glycosylation impairs mucosal barriers, while aberrant PDPN activity exacerbates inflammation. Additionally, microbial alterations contribute to oxidative stress, further destabilizing intestinal barriers. These molecular and cellular disruptions underscore the role of the microbiome in IBD pathophysiology. Emerging therapeutic strategies, including probiotics, prebiotics, and dietary interventions, aim to restore microbial balance and mitigate inflammation. Advanced studies on microbiota-targeted therapies reveal their potential to reduce disease severity and improve patient outcomes. Nevertheless, further research is needed to elucidate the bidirectional interactions between the gut microbiome and host immune responses and to translate these insights into clinical applications. This review consolidates current findings on the gut microbiota's role in IBD, emphasizing its diagnostic and therapeutic implications, and advocates for the continued exploration of microbiome-based interventions to combat this debilitating disease.

Inflammatory Bowel Disease (IBD) is an autoimmune disease characterized by chronic relapsing inflammation of the intestinal tract. Gut microbiota (GM) and CD4+T cells are important in the development of IBD. A lot of studies have shown that GM and their metabolites like short-chain fatty acids, bile acids and tryptophan can be involved in the differentiation of CD4+T cells through various mechanisms, which in turn regulate the immune homeostasis of the IBD patients. Therefore, regulating CD4+T cells through GM may be a potential therapeutic direction for the treatment of IBD. Many studies have shown that Traditional Chinese Medicine (TCM) formulas and some herbal extracts can affect CD4+T cell differentiation by regulating GM and its metabolites. In this review, we mainly focus on the role of GM and their metabolites in regulating the differentiation of CD4+T cells and their correlation with IBD. We also summarize the current research progress on the regulation of this process by TCM.

The human gut microbiome plays a crucial role in regulating intestinal and systemic health, impacting host immune response and metabolic function. Dysbiosis of the gut microbiome is linked to various diseases, including steatotic liver diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic liver disease characterized by excess hepatic lipid content and impaired metabolism, is the leading cause of liver disease worldwide. Among the gut microbes, Ruminococcus gnavus (R. gnavus) has garnered attention for its association with inflammatory and metabolic diseases. While R. gnavus abundance correlates to liver fat accumulation, further research is needed to identify a causal role or therapeutic intervention in steatotic liver disease. This review surveys our current understanding of R. gnavus in the development and progression of steatotic liver diseases, highlighting its potential mechanisms through metabolite secretion, and emphasizes the need for comprehensive microbiome analyses and longitudinal studies to better understand R. gnavus' impact on liver health. This knowledge could pave the way for targeted interventions aimed at modulating gut microbiota to treat and prevent MASLD and its comorbidities.

Vitamin D was discovered as the cure for nutritional rickets, a disease of bone growth arising from inadequate intestinal calcium absorption, and for much of the 20th century, it was studied for its critical role in calcium homeostasis. However, we now recognize that the vitamin D receptor and vitamin D metabolic enzymes are expressed in numerous tissues unrelated to calcium homeostasis. Notably, vitamin D signaling can induce cellular differentiation and cell cycle arrest. Moreover, the vitamin D receptor and the enzyme CYP27B1, which produces the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), are expressed throughout the immune system. In addition, CYP27B1 expression in immune cells is regulated by physiological inputs independent of those controlling its expression in calcium homeostatic tissues. These observations have driven the development of 1,25D-like secosteroidal analogs and nonsecosteroidal analogs to separate the effects of vitamin D on cell differentiation and function from its calcemic activities. Notably, some of these analogs have had considerable success in the clinic in the treatment of inflammatory and immune-related disorders. In this review, we described in detail the mechanisms of vitamin D signaling and the physiological signals controlling 1,25D synthesis and catabolism, with a focus on the immune system. We also surveyed the effects of 1,25D and its analogs on the regulation of immune system function and their implications for human immune-related disorders. Finally, we described the potential of vitamin D analogs as anticancer therapeutics, in particular, their use as adjuncts to cancer immunotherapy. SIGNIFICANCE STATEMENT: Vitamin D signaling is active in both the innate and adaptive arms of the immune system. Numerous vitamin D analogs, developed primarily to minimize the dose-limiting hypercalcemia of the active form of vitamin D, have been used widely in preclinical and clinical studies of immune system regulation. This review presents a description of the mechanisms of action of vitamin D signaling, an overview of analog development, and an in-depth discussion of the immunoregulatory roles of vitamin D analogs.

Inflammatory bowel disease (IBD) is characterized by disruptions in the gut microbiome. While most studies on gut dysbiosis in IBD rely on sequencing-based methods, we employed a streamlined culturomics approach to obtain a more comprehensive understanding of gut microbiota imbalance in patients with IBD that may not be captured by sequencing alone. A total of 367 bacteria were identified at the species level, including 211 species from ulcerative colitis patients, 164 species from Crohn's disease (CD) patients, and 263 species from healthy individuals. Consistent with our 16S rRNA gene amplicon sequencing results, a significant decrease in microbial diversity and a severe imbalance, especially in CD patients, were also observed in the culture-based analysis. Our culturomics approach provided additional insights, highlighting dysbiosis in unique anaerobic and Gram-negative species in CD patients. Moreover, species-level findings for Bifidobacterium and Enterobacterales emphasized specific species expansions in IBD patients. Notably, Mediterraneibacter gnavus, Thomasclavelia ramosa, Parabacteroides merdae, and Collinsella aerofaciens are of particular clinical interest due to their correlation with inflammatory biomarkers. This comprehensive analysis underscores the value of integrating a culture-based approach with a genome-based approach to provide complementary insights and therapeutic targets in IBD.

Cancer has the highest death rates due to increased immuno-oncological (IO) challenges and chemoresistance caused by gut dysbiosis, whereas administration of probiotics may reverse these responses against anticancer therapies. Recently, immunotherapeutics have extensively been focused for significant advancements in pharmacological drug discovery and clinical outcomes. Mammals have intestinal epithelial cells, mucosal immune cells, and indigenous gut microbiota which may reshape immunotherapeutics efficacy. These include use of T-cell immune checkpoint inhibitors (ICPI), genetically engineered T-cells, tumor vaccines, monoclonal antibodies (mAbs), and anti-B- and T-cell antibodies. Immunotherapeutics for cancer treatment became popular in both veterinary and human health care systems due to their strong inhibitory actions against PD-1 and CTLA-4 to check tumorigenesis. IO issues in animals also need special attention, where caninized mAbs targeting CD-20 and CD-52 have been clinically used in treating canine B-cell and T-cell lymphomas, respectively. Probiotics appeared as strong immunotherapeutics that might be shaping the epigenetics of the organisms specifically in animal breeding practices for desired features, but limited literature regarding the immunomodulatory effects in humans and animals is available. In addition, considering the important role of probiotics in humans and veterinary medicine, a new perspective on the probiotic-mediated modulation of ncRNAs (miRNAs, lncRNAs, circRNAs) is also highlighted and would be a new therapeutic tool. This review provides insight into the cellular processes and pharmacological activities for treating veterinary infectious diseases and covers small drug molecules as ncRNA-modulators in veterinary medicine.

Crohn's disease (CD) results from alterations in the gut microbiota and the immune system. However, the exact metabolic dysfunctions of the gut microbiota during CD are still unclear. Here, we investigated metagenomic functions using PICRUSt2 during the course of CD to better understand microbiota-related disease mechanisms and provide new insights for novel therapeutic strategies.

We performed 16S rRNA-based microbial profiling of 567 faecal samples collected from a cohort of 383 CD patients, including 291 remissions (CR), 177 mild-moderate (CM) and 99 severe (CS) disease states. Gene and pathway composition was assessed using PICRUSt2 analyses of 16S data.

As expected, changes in alpha and beta diversity, in interaction networks and increases in Proteobacteria abundance were associated with disease severity. However, microbial function was more consistently disrupted than composition from CR, to CM and then to CS. Major shifts in oxidative stress pathways and reduced carbohydrate and amino acid metabolism in favour of nutrient transport were identified in CS compared to CR. Virulence factors involved in host invasion, host evasion and inflammation were also increased in CS.

This functional metagenomic information provides new insights into community-wide microbial processes and pathways associated with CD pathogenesis. This study paves the way for new advanced strategies to rebalance gut microbiota and/or eliminate oxidative stress, and biofilm to downregulate gut inflammation.

Microbiota dysfunction induces intestinal disorders and neurological diseases. Mannuronate oligosaccharides (MAOS), a kind of alginate oligosaccharide (AOS), specifically exert efficacy in shaping gut microbiota and relieving cognitive impairment. However, the key regulatory factors involved, such as the specific strains and metabolites as well as their regulatory mechanisms, remain unclear at present. This research investigates how MAOS specifically impact the gut-brain axis in vivo and in vitro. The results showed that pretreatment with MAOS significantly ameliorated dextran sodium sulfate (DSS)-induced colitis and secondary nerve injury. This preventive mechanism operates through the regulation of serum DOPC abundance and the gut-brain axis, achieved by inhibiting the TLR4/MyD88/NF-κB pathway. These findings underscore the crucial role of dietary MAOS in the prevention of colitis and neurological disorders, providing a rationale for the application of MAOS in disease prevention and functional food ingredients.

Inflammatory bowel disease is a chronic inflammatory condition predominantly affecting the intestines, encompassing both ulcerative colitis and Crohn disease (CD). As one of the most common gastrointestinal disorders, CD's pathogenesis is closely linked with the intestinal microbiota. Recently, fecal microbiota transplantation (FMT) has gained attention as a potential treatment for CD, with the effective reestablishment of intestinal microecology considered a crucial mechanism of FMT therapy. This article synthesizes the findings of population-based cohort studies to enhance our understanding of gut microbial characteristics in patients with CD. It delves into the roles of "beneficial" and "pathogenic" bacteria in CD's development. This article systematically reviews and compares data on clinical response rates, remission rates, adverse events, and shifts in bacterial microbiota. Among these studies, gut microbiome analysis was conducted in only 7, and a single study examined the metabolome. Overall, FMT has demonstrated a partial restoration of typical CD-associated microbiological alterations, leading to increased α-diversity in responders and a moderate shift in patient microbiota toward the donor profile. Several factors, including donor selection, delivery route, microbial state (fresh or frozen), and recipient condition, are identified as pivotal in influencing FMT's effectiveness. Future prospective clinical studies with larger patient cohorts and improved methodologies are imperative. In addition, standardization of FMT procedures, coupled with advanced genomic techniques such as macroproteomics and culture genomics, is necessary. These advancements will further clarify the bacterial microbiota alterations that significantly contribute to FMT's therapeutic effects in CD treatment, as well as elucidate the underlying mechanisms of action.

Crohn's disease (CD) is a multifactorial inflammatory bowel disease whose pathogenetic mechanisms are a field of ongoing study. Changes in the intestinal microbiome in CD may influence metabolite production and reflect the disease's severity. We investigate the relationship between trimethylamine N-oxide (TMAO) and lipopolysaccharide-binding protein (LPS) levels and changes in the gut microbiome in patients with CD of various degrees of activity.

In total, 29 CD patients and 15 healthy individuals were investigated for their levels of TMAO by HPLC-MS, and LPS protein by ELISA and metagenomic 16 s-sequencing of feces was performed.

We found significant differences in TMAO levels in patients in the remission/mild and moderate/severe groups compared to the control group (p = 0.02 and p = 0.014), changes in alpha diversity with the Shannon index (p = 0. 0151 and p = 0.0018) and in beta diversity (ANOSIM p = 0.009 and PERMANOVA p = 0.005) in both groups compared to controls. Strongly positive correlations in TMAO levels and mixed correlations of LPS with alpha diversity metrics were found, as well as significant correlations with microbiota species.

Changes in the level of metabolites may reflect specific disturbances in the composition of the intestinal microbiome at different degrees of severity of CD.

Paratuberculosis (PTB), primarily caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic infection that affects ruminants and is difficult to prevent, diagnose, and treat. Investigating how MAP infections affect the gut microbiota in sheep can aid in the prevention and treatment of ovine PTB. This study examined fecal samples from eight small-tail Han sheep (STHS) at various stages of infection and from three different field areas. All samples underwent DNA extraction and 16S rRNA sequencing. Among all samples, the phyla p. Firmicutes and p. Bacteroidota exhibited the highest relative abundance. The dominant genera in groups M1-M6 were UCG-005, Christensenellaceae_R-7_group, Rikenellaceae_RC9_gut_group, Akkermansia, UCG-005, and Bacteroides, whereas those in groups A-C were Christensenellaceae_R-7_group, Escherichia-Shigella, and Acinetobacter, respectively. The microbial community structure varied significantly among groups M1-M6. Specifically, 56 microbiota consortia with different taxonomic levels, including the order Clostridiales, were significantly enriched in groups M1-M6, whereas 96 microbiota consortia at different taxonomic levels, including the family Oscillospiraceae, were significantly enriched in groups A-C. To the best of our knowledge, this is the first study to report that MAP infection alters the intestinal microbiota of STHS. Changes in p. Firmicutes abundance can serve as a potential biomarker to distinguish MAP infection and determine the infection stage for its early diagnosis. Our study provides a theoretical basis for the treatment of PTB by regulating the intestinal microbiota, including p. Firmicutes.

Numerous studies have revealed a correlation between the risk of developing diabetic nephropathy (DN) and the gut microbiota (GM) composition. However, it remains uncertain whether the GM composition causes DN. We aimed to explore any potential causal links between the GM composition and the risk of developing DN. A meta-analysis conducted by the MiBioGen consortium of the largest genome-wide association study (GWAS) provided aggregated data on the GM. DN data were obtained from the IEU database. The inverse-variance weighting (IVW) method was employed as the primary analytical approach. The IVW analysis indicated that genus Dialister (OR = 0.51, 95% CI: 0.34-0.77, p = 0.00118) was protective against DN. In addition, class Gammaproteobacteria (OR = 0.47, 95% CI: 0.27-0.83, p = 0.0096), class Lentisphaeria (OR =0.76, 95% CI: 0.68-0.99, p = 0.04), order Victivallales (OR = 0.76, 95% CI: 0.58-0.99, p = 0.04), and phylum Proteobacteria (OR = 0.53, 95% CI: 0.33-0.85, p = 0.00872) were negatively associated with the risk of developing DN. Genus LachnospiraceaeUCG008 (OR =1.45, 95% CI: 1.08-1.95, p = 0.01), order Bacteroidales (OR = 1.59, 95% CI: 1.02-2.49, p = 0.04), and genus Terrisporobacter (OR = 1.98, 95% CI: 1.14-3.45, p = 0.015) were positively associated with the risk of developing DN. In this study, we established a causal relationship between the genus Dialister and the risk of developing DN. Further trials are required to confirm the protective effects of probiotics on DN and to elucidate the precise protective mechanisms involving genus Dialister and DN.

Observational studies have established a connection between gut microbiota and ankylosing spondylitis (AS) risk; however, whether the observed associations are causal remains unclear. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to assess the potential causal associations of gut microbiota with AS risk.

Instrumental variants of gut microbiota were obtained from the MiBioGen consortium (n = 18,340) and the Dutch Microbiome Project (n = 7738). The FinnGen consortium provided genetic association summary statistics for AS, encompassing 2860 cases and 270,964 controls. We used the inverse-variance weighted (IVW) method as the primary analysis, supplemented with the weighted median method, maximum likelihood-based method, MR pleiotropy residual sum and outlier test, and MR-Egger regression. In addition, we conducted a reverse MR analysis to assess the likelihood of reverse causality.

After the Bonferroni correction, species Bacteroides vulgatus remained statistically significantly associated with AS risk (odds ratio (OR) 1.55, 95% confidence interval (CI) 1.22-1.95, P = 2.55 × 10-4). Suggestive evidence of associations of eleven bacterial traits with AS risk was also observed (P < 0.05 by IVW). Among them, eight were associated with an elevated AS risk (OR 1.37, 95% CI 1.07-1.74, P = 0.011 for phylum Verrucomicrobia; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for class Verrucomicrobiae; OR 1.17, 95% CI 1.01-1.36, P = 0.035 for order Bacillales; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for order Verrucomicrobiales; OR 1.43, 95% CI 1.13-1.82, P = 0.003 for family Alcaligenaceae; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for family Verrucomicrobiaceae; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for genus Akkermansia; OR 1.55, 95% CI 1.19-2.02, P = 0.001 for species Sutterella wadsworthensis). Three traits exhibited a negative association with AS risk (OR 0.68, 95% CI 0.53-0.88, P = 0.003 for genus Dialister; OR 0.84, 95% CI 0.72-0.97, P = 0.020 for genus Howardella; OR 0.75, 95% CI 0.59-0.97, P = 0.026 for genus Oscillospira). Consistent associations were observed when employing alternate MR methods. In the reverse MR, no statistically significant correlations were detected between AS and these bacterial traits.

Our results revealed the associations of several gut bacterial traits with AS risk, suggesting a potential causal role of gut microbiota in AS development. Nevertheless, additional research is required to clarify the mechanisms by which these bacteria influence AS risk. Key Points • The association of gut microbiota with AS risk in observational studies is unclear. • This MR analysis revealed associations of 12 gut bacterial traits with AS risk.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that persists into adulthood in the majority of individuals. While the gut-microbiome seems to be relevant for ADHD, the few publications on gut-microbial alterations in ADHD are inconsistent, in the investigated phenotypes, sequencing method/region, preprocessing, statistical approaches, and findings. To identify gut-microbiome alterations in adult ADHD, robust across studies and statistical approaches, we harmonized bioinformatic pipelines and analyses of raw 16S rRNA sequencing data from four adult ADHD case-control studies (NADHD=312, NNoADHD=305). We investigated diversity and differential abundance of selected genera (logistic regression and ANOVA-like Differential Expression tool), corrected for age and sex, and meta-analyzed the study results. Converging results were investigated for association with hyperactive/impulsive and inattentive symptoms across all participants. Beta diversity was associated with ADHD diagnosis but showed significant heterogeneity between cohorts, despite harmonized analyses. Several genera were robustly associated with adult ADHD; e.g., Ruminococcus_torques_group (LogOdds=0.17, pfdr=4.42 × 10-2), which was more abundant in adults with ADHD, and Eubacterium_xylanophilum_group (LogOdds= -0.12, pfdr=6.9 × 10-3), which was less abundant in ADHD. Ruminococcus_torques_group was further associated with hyperactivity/impulsivity symptoms and Eisenbergiella with inattention and hyperactivity/impulsivity (pfdr<0.05). The literature points towards a role of these genera in inflammatory processes. Irreproducible results in the field of gut-microbiota research, due to between study heterogeneity and small sample sizes, stress the need for meta-analytic approaches and large sample sizes. While we robustly identified genera associated with adult ADHD, that might overall be considered beneficial or risk-conferring, functional studies are needed to shed light on these properties.