Food hydrogels targeting respiration of microorganisms via changing the micro-ecological environment in gut were prepared through the self-assembly of polyphenols extracted from tea leaves harvested in summer and autumn and the protein fibrils originating from egg white lysozyme. Oral administration with the hydrogels effectively inhibited the over-expansion of the facultative anaerobic bacterium indicated by E. coli Nissle 1917 (EcN) and alleviated the clinic symptoms of chronic intestinal inflammation in mice. Importantly, the hypoxia of epithelial cells was elevated significantly and the overexpression of the inducible NO synthase (INOs)-related NOS2 gene was inhibited substantially in colons of the colitis mice, which accounted for prevention of the abnormal expansion of E. coli via blocking respiration. The treatment with the hydrogels preserved normal mitochondrial function in colonic epithelial cells under oxidative stress, which could serve as the mechanism to maintain the capability to consume oxygen.

Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C+ monocytes. Mechanistically, LGG induced IL-10 production via the stimulator of IFN genes (STING)/TBK1/NF-κB (RELA) signaling pathway in intestinal Ly6C+ monocytes, enhancing their immune-suppressive function. Elevated IL-10 subsequently activated IL-10 signaling in Ly6C+ monocytes, resulting in an IL-10-based autocrine regulatory loop and inhibition of proinflammatory cytokine production. Furthermore, LGG shifted the gut microbial community and its metabolic functions, leading to intestinal immune responses against colitis. Fecal microbiota transplantation from LGG-colonized mice alleviated immune checkpoint blockade-associated colitis. Our findings highlight the importance of STING signaling in IL-10-dependent antiinflammatory immunity and establish an empirical basis for developing oral administration of live LGG as an efficient and safe therapeutic strategy against inflammatory colitis.

Genetics is central to the susceptibility or resistance to autoimmunity, and mounting evidence indicates that the intestinal microbiota also plays an essential role. In murine arthritis models, short-chain fat acid supplementation reduces disease severity by modulating tryptophan-metabolizing bacteria. Common microbiota transfer methods modulate arthritis severity, however, they are not practical for chronic models such as pristane-induced arthritis (PIA). PIA-resistant (HIII) and PIA-susceptible (LIII) mice harbor diverse intestinal microbiomes, which might be implicated in their divergent susceptibility. To investigate this hypothesis, we used cross-fostering to stably transfer the microbiota. In this study, we show that extreme susceptibility to arthritis can be modulated by early microbiota transfer, with long-lasting effects. HIII and LIII pups were cross-fostered and injected with pristane after weaning. PIA severity in cross-fostered LIII mice was significantly reduced in the chronic phase. Metagenomic analyses showed that HIII and LIII microbiomes were partly shifted by cross-fostering. Microbial groups whose abundance was associated with either HIII or LIII mice presented similar composition in cross-fostered mice of the opposite strains, suggesting a role in PIA susceptibility. Identification of bacterial groups that modulate chronic arthritis will contribute novel insights on the pathogenesis of human rheumatoid arthritis and targets for replication and functional studies.

Background/Objectives: Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), is characterized by colorectal immune infiltration and significant microbiota compositional changes. Gut microbiota homeostasis is necessary to maintain the healthy state of humans. MR2938, a quinazolin-4(3H)-one derivative derived from the marine natural product penipanoid C, alleviated DSS-induced colitis in a dose-dependent manner. Herein, we aimed to investigate the impact of MR2938 on the gut microbiota in dextran sodium sulfate (DSS)-induced colitis in mice and to elucidate the role of the gut microbiota in the therapeutic mechanism of MR2938 for alleviating colitis. Methods: Acute colitis was induced with DSS in mice. Mice were administered with 100 mg/kg or 50 mg/kg of MR2938. Cecal content was also preserved in liquid nitrogen and subsequently analyzed following 16S RNA sequencing. Antibiotic cocktail-induced microbiome depletion was performed to further investigate the relationship between MR2938 and gut microbiota. The inflammatory factor levels were performed by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Alcian blue staining and immunofluorescence were used to estimate the intestinal barrier. Results: The 16S rRNA sequencing revealed microbiota modulation by MR2938. Compared with the model group, the 100 mg/kg MR2938 group was associated with higher abundances of Entercoccus and a lower abundance of Staphylococcus, while the 50 mg/kg MR2938 group was associated with higher abundances of Lactobacillus and a lower abundance of Staphylococcus. The antibiotic-mediated microbiota depletion experiments demonstrated that the gut microbiota primarily contributed to barrier function protection, with little impact on inflammatory factor levels during the MR2938 treatment. Conclusions: These findings suggest that intestinal flora play a crucial role in MR2938's therapeutic mechanism for alleviating colitis.

The potential role of Klebsiella pneumoniae (K.pn) in hypertension development has been emphasized, although the specific mechanisms have not been well understood. Bacterial extracellular vesicles (BEVs) released by Gram-negative bacteria modulate host cell functions by delivering bacterial components to host cells. Endothelial dysfunction is an important early event in the pathogenesis of hypertension, yet the impact of K.pn-secreted EVs (K.pn EVs) on endothelial function remains unclear. This study aimed to investigate the effects of K.pn EVs on endothelial function and to elucidate the underlying mechanisms.

K.pn EVs were purified from the bacterial suspension using ultracentrifugation and characterized by transmission electron microscopy nanoparticle tracking analysis, and EV marker expression. Endothelium-dependent relaxation was measured using a wire myograph after in vivo or ex vivo treatment with K.pn EVs. Superoxide anion production was measured by confocal microscopy and HUVEC senescence was assessed by SA-β-gal activity. SIRT1 overexpression or activator was utilized to investigate the underlying mechanisms.

Our data showed that K.pn significantly impaired acetylcholine-induced endothelium-dependent relaxation and increased superoxide anion production in endothelial cells in vivo. Similarly, in vivo and ex vivo studies showed that K.pn EVs caused significant endothelial dysfunction, endothelial provocation, and increased blood pressure. Further examination revealed that K.pn EVs reduced the levels of SIRT1 and p-eNOS and increased the levels of NOX2, COX-2, ET-1, and p53 in endothelial cells. Notably, overexpression or activation of SIRT1 attenuated the adverse effects and protein changes induced by K.pn EVs on endothelial cells.

This study reveals a novel role of K.pn EVs in endothelial dysfunction and dissects the relevant mechanism involved in this process, which will help to establish a comprehensive understanding of K.pn EVs in endothelial dysfunction and hypertension from a new scope.

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals that mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. The natural history of IBD progression begins with early subclinical stages of disease that occur before clinical diagnosis. Improved understanding of those early subclinical stages could lead to new or improved strategies for IBD diagnosis, prognostication, or prevention. Here, we review our current understanding of the early subclinical stages of IBD in humans including studies from first-degree relatives of patients with IBD and members of the general population who go on to develop IBD. We also discuss representative mouse models of IBD that can be used to investigate disease dynamics and host-microbiota relationships during these early stages. In particular, we underscore how mouse models of IBD that develop disease later in life with variable penetrance may present valuable opportunities to discern early subclinical mechanisms of disease before histological inflammation and other severe symptoms become apparent.

LEfSe is a widely used Python package and Galaxy module for metagenomic biomarker discovery and visualization, utilizing the Kruskal-Wallis test, Wilcoxon Rank-Sum test, and Linear Discriminant Analysis. R/Bioconductor provides a large collection of tools for metagenomic data analysis but has lacked an implementation of this widely used algorithm, hindering benchmarking against other tools and incorporation into R workflows. We present the lefser package to provide comparable functionality within the R/Bioconductor ecosystem of statistical analysis tools, with improvements to the original algorithm for performance, accuracy, and reproducibility. We benchmark the performance of lefser against the original algorithm using human and mouse metagenomic datasets.

Our software, lefser, is distributed through the Bioconductor project (https://www.bioconductor.org/packages/release/bioc/html/lefser.html), and all the source code is available in the GitHub repository https://github.com/waldronlab/lefser.

The gut microbiota (GM) has proven to be essential for both physical health and mental wellbeing, yet the forces that ultimately shape its composition remain opaque. One critical force known to affect the GM is the social environment. Prior work in humans and free-ranging non-human primates has shown that cohabitation and frequent social interaction can lead to changes in GM composition. However, it is difficult to assess the direction of causation in these studies, and interpretations are complicated by the influence of uncontrolled but correlated factors, such as shared diet.

We performed a 15-month longitudinal investigation wherein we disentangled the impacts of diet and social living conditions on GM composition in a captive cohort of 13 male cynomolgus macaques. The animals were in single housing for the first 3 months of the study initially with a variable diet. After baseline data collection they were placed on a controlled diet for the remainder of the study. Following this diet shift the animals were moved to paired housing for 6 months, enabling enhanced social interaction, and then subsequently returned to single housing at the end of our study. This structured sequencing of diet and housing changes allowed us to assess their distinct impacts on GM composition. We found that the early dietary adjustments led to GM changes in both alpha and beta diversity, whereas changes in social living conditions only altered beta diversity. With respect to the latter, we found that two particular bacterial families - Lactobacillaceae and Clostridiaceae - demonstrated significant shifts in abundance during the transition from single housing to paired housing, which was distinct from the shifts we observed based on a change in diet. Conversely, we found that other bacteria previously associated with sociality were not altered based on changes in social living conditions but rather only by changes in diet.

Together, these findings decouple the influences that diet and social living have on GM composition and reconcile previous observations in the human and animal literatures. Moreover, the results indicate biological alterations of the gut that may, in part, mediate the relationship between sociality and wellbeing.

The gut microbiome, composed of the colonic microbiota and their host environment, is important for many aspects of human health. A gut microbiome imbalance (gut dysbiosis) is associated with major causes of human morbidity and mortality. Despite the central part our gut microbiome plays in health and disease, mechanisms that maintain homeostasis and properties that demarcate dysbiosis remain largely undefined. Here we discuss that sorting taxa into meaningful ecological units reveals that the availability of respiratory electron acceptors, such as oxygen, in the host environment has a dominant influence on gut microbiome health. During homeostasis, host functions that limit the diffusion of oxygen into the colonic lumen shelter a microbial community dominated by primary fermenters from atmospheric oxygen. In turn, primary fermenters break down unabsorbed nutrients into fermentation products that support host nutrition. This symbiotic relationship is disrupted when host functions that limit the luminal availability of host-derived electron acceptors become weakened. The resulting changes in the host environment drive alterations in the microbiota composition, which feature an elevated abundance of facultatively anaerobic microbes. Thus, the part of the gut microbiome that becomes imbalanced during dysbiosis is the host environment, whereas changes in the microbiota composition are secondary to this underlying cause. This shift in our understanding of dysbiosis provides a novel starting point for therapeutic strategies to restore microbiome health. Such strategies can either target the microbes through metabolism-based editing or strengthen the host functions that control their environment.

In the first days of life, the newborns' intestinal microbiota develops simultaneously with the intestinal gut barrier and follows intestinal immunity. The mode of delivery shows significant impact on microbial development and, thus, the initiation of the tryptophan catabolism pathway. Further antibiotics (ATB) treatment of mothers before or during delivery affects the microbial and tryptophan metabolite composition of stool of the caesarean- and vaginal-delivered newborns. The determination of microbiome and levels of tryptophan microbial metabolites in meconium and stool can characterize intestinal colonization of a newborn. From 134 samples from the Central European Longitudinal Studies of Parents and Children: The Next Generation (CELSPAC: TNG) cohort study, 16S rRNA gene sequencing was performed, and microbial tryptophan metabolites were quantified using ultra-high-performance liquid chromatography with triple-quadrupole mass spectrometry. Microbial diversity and concentrations of tryptophan metabolites were significantly higher in stool compared to meconium. Treatment of mothers with ATB before or during delivery affects metabolite composition and microbial diversity in stool of vaginal- and caesarean-delivered newborns. Correlation of microbial and metabolite composition shows significant positive correlations of indol-3-lactic acid, N-acetyl-tryptophan and indol-3-acetic acid with Bifidobacterium, Bacteroides and Peptoclostridium. The positive effect of vaginal delivery on newborns' microbiome development is degraded when mother is treated with ATB before or during delivery. KEY POINTS: • Antibiotic treatment diminishes the positive effects of vaginal delivery. • Antibiotic treatment affects metabolite and microbial composition in newborns. • Bifidobacterium and Peptoclostridium could be the producer of indole-lactic acid.

IL-33, a pleiotropic cytokine, has been associated with a plethora of immune-related processes, both inflammatory and anti-inflammatory. T regulatory (Treg) cells, the main leukocyte population involved in immune tolerance, can be induced by the administration of IL-33, the local microbiota, and its metabolites. Here, we demonstrate that IL-33 drastically induces the production of intestinal metabolites involved on tryptophan (Trp) metabolism.

naïve mice were treated with IL-33 for 4 days and leukocyte populations were analyzed by flow cytometry, and feces were processed for microbiota and intestinal metabolites studies. Using a murine skin transplantation model, the effect of Kynurenic acid (KA) on allograft survival was tested.

Under homeostatic conditions, animals treated with IL-33 showed an increment in Treg cell frequencies. Intestinal bacterial abundance analysis indicates that IL-33 provokes dysbiosis, demonstrated by a reduction in Enterobacteria and an increment in Lactobacillus genera. Furthermore, metabolomics analysis showed a dramatic IL-33 effect on the abundance of intestinal metabolites related to amino acid synthesis pathways, highlighting molecules linked to Trp metabolism, such as kynurenic acid (KA), 5-Hydroxyindoleacetic acid (5-HIAA), and 6-Hydroxynicotinic acid (6-HNA), which was supported by an enhanced expression of Ido and Kat mRNA in MLN cells, which are two enzymes involved on KA synthesis. Interestingly, animals receiving KA in drinking water and subjected to skin transplantation showed allograft acceptance, which is associated with an increment in Treg cell frequencies.

Our study reveals a new property for IL-33 as a modulator of the intestinal microbiota and metabolites, especially those involved with Trp metabolism. In addition, we demonstrate that KA favors Tregs in vivo, positively affecting skin transplantation survival.

Bacterial infections pose a significant global health threat, accounting for an estimated 7.7 million deaths. Hospital outbreaks driven by multi-drug-resistant pathogens, notably Klebsiella pneumoniae (K. pneumoniae), are of grave concern. This opportunistic pathogen causes pneumonia, urinary tract infections, and bacteremia, particularly in immunocompromised individuals. The rise of hypervirulent K. pneumoniae adds complexity, as it increasingly infects healthy individuals. Recent epidemiological data suggest that asymptomatic gastrointestinal carriage serves as a reservoir for infections in the same individual and allows for host-to-host transmission via the fecal-oral route. This review focuses on K. pneumoniae's gastrointestinal colonization, delving into epidemiological evidence, current animal models, molecular colonization mechanisms, and the protective role of the resident gut microbiota. Moreover, the review sheds light on in vivo high-throughput approaches that have been crucial for identifying K. pneumoniae factors in gut colonization. This comprehensive exploration aims to enhance our understanding of K. pneumoniae gut pathogenesis, guiding future intervention and prevention strategies.

Intestinal inflammation modifies host physiology to promote the occurrence of colorectal cancer (CRC), as seen in colitis-associated CRC. Gut microbiota is crucial in cancer progression, primarily by inducing intestinal chronic inflammatory microenvironment, leading to DNA damage, chromosomal mutation, and alterations in specific metabolite production. Therefore, there is an increasing interest in microbiota-based prevention and treatment strategies, such as probiotics, prebiotics, microbiota-derived metabolites, and fecal microbiota transplantation. This review aims to provide valuable insights into the potential correlations between gut microbiota and colitis-associated CRC, as well as the promising microbiota-based strategies for colitis-associated CRC.

Persistent colonization and outgrowth of potentially pathogenic organisms in the intestine can result from long-term antibiotic use or inflammatory conditions, and may perpetuate dysregulated immunity and tissue damage1,2. Gram-negative Enterobacteriaceae gut pathobionts are particularly recalcitrant to conventional antibiotic treatment3,4, although an emerging body of evidence suggests that manipulation of the commensal microbiota may be a practical alternative therapeutic strategy5-7. Here we isolated and down-selected commensal bacterial consortia from stool samples from healthy humans that could strongly and specifically suppress intestinal Enterobacteriaceae. One of the elaborated consortia, comprising 18 commensal strains, effectively controlled ecological niches by regulating gluconate availability, thereby re-establishing colonization resistance and alleviating Klebsiella- and Escherichia-driven intestinal inflammation in mice. Harnessing these activities in the form of live bacterial therapies may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant Enterobacteriaceae infection.

The intestinal barrier maintained by various types of columnar epithelial cells, plays a crucial role in regulating the interactions between the intestinal contents (such as the intestinal microbiota), the immune system, and other components. Dysfunction of the intestinal mucosa is a significant pathophysiological mechanism and clinical manifestation of inflammatory bowel disease (IBD). However, current therapies for IBD primarily focus on suppressing inflammation, and no disease-modifying treatments specifically target the epithelial barrier. Given the side effects associated with chronic immunotherapy, effective alternative therapies that promote mucosal healing are highly attractive. In this review, we examined the function of intestinal epithelial barrier function and the mechanisms of behind its disruption in IBD. We illustrated the complex process of intestinal mucosal healing and proposed therapeutic approaches to promote mucosal healing strategies in IBD. These included the application of stem cell transplantation and organ-like tissue engineering approaches to generate new intestinal tissue. Finally, we discussed potential strategies to restore the function of the intestinal barrier as a treatment for IBD.

Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis.

Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts.

Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract.

Inflammatory bowel disease (IBD) is an idiopathic and persistent inflammatory illness of the bowels, leading to a substantial burden on both society and patients due to its high incidence and recurrence. The pathogenesis of IBD is multifaceted, partly attributed to the imbalance of immune responses toward the gut microbiota. There is a correlation between the severity of the disease and the imbalance in the oral microbiota, which has been discovered in recent research highlighting the role of oral microbes in the development of IBD. In addition, various oral conditions, such as angular cheilitis and periodontitis, are common extraintestinal manifestations (EIMs) of IBD and are associated with the severity of colonic inflammation. However, it is still unclear exactly how the oral microbiota contributes to the pathogenesis of IBD. This review sheds light on the probable causal involvement of oral microbiota in intestinal inflammation by providing an overview of the evidence, developments, and future directions regarding the relationship between oral microbiota and IBD. Changes in the oral microbiota can serve as markers for IBD, aiding in early diagnosis and predicting disease progression. Promising advances in probiotic-mediated oral microbiome modification and antibiotic-targeted eradication of specific oral pathogens hold potential to prevent IBD recurrence.

Colorectal cancer (CRC) is one of the most common cancers worldwide, ranking third in terms of incidence and second as a cause of cancer-related death. There is growing scientific evidence that the gut microbiota plays a key role in the initiation and development of CRC. Specific bacterial species and complex microbial communities contribute directly to CRC pathogenesis by promoting the neoplastic transformation of intestinal epithelial cells or indirectly through their interaction with the host immune system. As a result, a protumoural and immunosuppressive environment is created conducive to CRC development. On the other hand, certain bacteria in the gut microbiota contribute to protection against CRC. In this chapter, we analysed the relationship of the gut microbiota to CRC and the associations identified with specific bacteria. Microbiota plays a key role in CRC through various mechanisms, such as increased intestinal permeability, inflammation and immune system dysregulation, biofilm formation, genotoxin production, virulence factors and oxidative stress. Exploring the interaction between gut microbiota and tumourigenesis is essential for developing innovative therapeutic approaches in the fight against CRC.

Recent advancements in genomics, transcriptomics, and metabolomics have significantly advanced our understanding of the human gut microbiome and its impact on the efficacy and toxicity of anti-cancer therapeutics, including chemotherapy, immunotherapy, and radiotherapy. In particular, prebiotics, probiotics, and postbiotics are recognized for their unique properties in modulating the gut microbiota, maintaining the intestinal barrier, and regulating immune cells, thus emerging as new cancer treatment modalities. However, clinical translation of microbiome-based therapy is still in its early stages, facing challenges to overcome physicochemical and biological barriers of the gastrointestinal tract, enhance target-specific delivery, and improve drug bioavailability. This review aims to highlight the impact of prebiotics, probiotics, and postbiotics on the gut microbiome and their efficacy as cancer treatment modalities. Additionally, we summarize recent innovative engineering strategies designed to overcome challenges associated with oral administration of anti-cancer treatments. Moreover, we will explore the potential benefits of engineered gut microbiome-modulating approaches in ameliorating the side effects of immunotherapy and chemotherapy.

The immune response induced by respiratory syncytial virus (RSV) infection is closely related to changes in the composition and function of gastrointestinal microorganisms. However, the specific mechanism remains unknown and the pulmonary-intestinal axis deserves further study. In this study, the mRNA levels of ROR-γt and Foxp3 in the lung and intestine increased first and then decreased. IL-17 and IL-22 reached the maximum on the third day after infection in the lung, and on the second day after infection in the small intestine and colon, respectively. RegⅢγ in intestinal tissue reached the maximum on the third day after RSV infection. Moreover, the genus enriched in the RSV group was Aggregatibacter, and Proteus was reduced. RSV infection not only causes Th17/Treg cell imbalance in the lungs of mice but also leads to the release of excessive IL-22 from the lungs through blood circulation which binds to IL-22 receptors on the intestinal surface, inducing RegⅢγ overexpression, impaired intestinal Th17/Treg development, and altered gut microbiota composition. Our research reveals a significant link between the pulmonary and intestinal axis after RSV infection.

RSV is the most common pathogen causing acute lower respiratory tract infections in infants and young children, but the complex interactions between the immune system and gut microbiota induced by RSV infection still requires further research. In this study, it was suggested that RSV infection in 7-day-old BALB/c suckling mice caused lung inflammation and disruption of Th17/Treg cells development, and altered the composition of gut microbiota through IL-22 induced overexpression of RegⅢγ, leading to intestinal immune injury and disruption of gut microbiota. This research reveals that IL-22 may be the link between the lung and gut. This study may provide a new insight into the intestinal symptoms caused by RSV and other respiratory viruses and the connection between the lung and gut axis, as well as new therapeutic ideas for the treatment of RSV-infected children.

This study aimed to examine the potential impact of the intervention of Lactiplantibacillus plantatum HFY11 (LP-HFY11) on colitis using in vivo animal trials. The impact of LP-HFY11 intervention on colitis was determined by measuring the levels of relevant indicators in the intestine, colon, and blood after oxazolone-induced colitis in BALB/c mice. The results of the trial show that LP-HFY11 improved the colon weight-to-length ratio, reduced the colitis-induced colon length shortening, and reduced colonic abstinence. Furthermore, it decreased the levels of myeloperoxidase, nitric oxide, and malondialdehyde activities while increasing the glutathione content in the colon tissue of colitis-affected animals. LP-HFY11 lowered the interleukin-10 (IL-10) level and increased the IL-2 level in the serum of colitis mice. LP-HFY11 also upregulated the expression of neuronal nitric oxide synthase, endothelial nitric oxide synthase, c-Kit, and stem cell factor (SCF), and downregulated the expression of IL-8, C-X-C chemokine receptor type 2 (CXCR2), and inducible nitric oxide synthase (iNOS) in the colon tissue of mice with colitis. LP-HFY11 decreased the expression of Firmicutes in the gut while increasing the expression of Bacteroidetes, Bifidobacteria, and Lactobacillus. This indicates that LP-HFY11 could control physiological alterations in the serum and colon tissue, as well as the expression of gut microorganism.

This review examines the complex connection between commensal microbiota and the development of opportunistic infections. Several underlying conditions, such as metabolic diseases and weakened immune systems, increase the vulnerability of patients to opportunistic infections. The increasing antibiotic resistance adds significant complexity to the management of infectious diseases. Although commensals have long been considered beneficial, recent research contradicts this notion by uncovering chronic illnesses linked to atypical pathogens or commensal bacteria. This review examines conditions in which commensal bacteria, which are usually beneficial, contribute to developing diseases. Commensals' support for opportunistic infections can be categorized based on factors such as colonization fitness, pathoadaptive mutation, and evasion of host immune response. Individuals with weakened immune systems are especially susceptible, highlighting the importance of mucosal host-microbiota interaction in promoting infection when conditions are inappropriate. Dysregulation of gut microbial homeostasis, immunological modulation, and microbial interactions are caused by several factors that contribute to the development of chronic illnesses. Knowledge about these mechanisms is essential for developing preventive measures, particularly for susceptible populations, and emphasizes the importance of maintaining a balanced gut microbiota in reducing the impact of opportunistic infections.

Fermented foods play a significant role in the human diet for their natural, highly nutritious and healthy attributes. Our aim was to study the effect of yeast extract, a fermented substance extracted from natural yeast, on colonic motility to better understand its potential therapeutic role. A yeast extract was given to rats by gavage for 3 days, and myogenic and neurogenic components of colonic motility were studied using spatiotemporal maps made from video recordings of the whole colon ex vivo. A control group received saline gavages. The yeast extract caused excitation of the musculature by increasing the propagation length and duration of long-distance contractions, the major propulsive activity of the rat colon. The yeast extract also evoked rhythmic propulsive motor complexes (RPMCs) which were antegrade in the proximal and mid-colon and retrograde in the distal colon. RPMC activity was evoked by distention-induced neural activity, but it was myogenic in nature since we showed it to be generated by bethanechol in the presence of tetrodotoxin. In conclusion, ingestion of yeast extract stimulates rat colon motility by exciting neurogenic and myogenic control mechanisms.

In recent years, an increasing attention has given to the intricate and diverse connection of microorganisms residing in our gut and their impact on brain health and central nervous system disease. There has been a shift in mindset to understand that drug addiction is not merely a condition that affects the brain, it is now being recognized as a disorder that also involves external factors such as the intestinal microbiota, which could influence vulnerability and the development of addictive behaviors. Furthermore, stress and social interactions, which are closely linked to the intestinal microbiota, are powerful modulators of addiction. This review delves into the mechanisms through which the microbiota-stress-immune axis may shape drug addiction and social behaviors. This work integrates preclinical and clinical evidence that demonstrate the bidirectional communication between stress, social behaviors, substance use disorders and the gut microbiota, suggesting that gut microbes might modulate social stress having a significance in drug addiction.

FMF is the most common monogenic autoinflammatory disease associated with MEFV mutations. Disease phenotype and response to treatment vary from one patient to another, despite similar genotype, suggesting the role of environmental factors. The objective of this study was to analyse the gut microbiota of a large cohort of FMF patients in relation to disease characteristics.

The gut microbiotas of 119 FMF patients and 61 healthy controls were analysed using 16 s rRNA gene sequencing. Associations between bacterial taxa, clinical characteristics, and genotypes were evaluated using multivariable association with linear models (MaAslin2), adjusting on age, sex, genotype, presence of AA amyloidosis (n = 17), hepatopathy (n = 5), colchicine intake, colchicine resistance (n = 27), use of biotherapy (n = 10), CRP levels, and number of daily faeces. Bacterial network structures were also analysed.

The gut microbiotas of FMF patients differ from those of controls in having increased pro-inflammatory bacteria, such as the Enterobacter, Klebsiella and Ruminococcus gnavus group. Disease characteristics and resistance to colchicine correlated with homozygous mutations and were associated with specific microbiota alteration. Colchicine treatment was associated with the expansion of anti-inflammatory taxa such as Faecalibacterium and Roseburia, while FMF severity was associated with expansion of the Ruminococcus gnavus group and Paracoccus. Colchicine-resistant patients exhibited an alteration of the bacterial network structure, with decreased intertaxa connectivity.

The gut microbiota of FMF patients correlates with disease characteristics and severity, with an increase in pro-inflammatory taxa in the most severe patients. This suggests a specific role for the gut microbiota in shaping FMF outcomes and response to treatment.

The myriad microorganisms that live in close association with humans have diverse effects on physiology, yet the molecular bases for these impacts remain mostly unknown1-3. Classical pathogens often invade host tissues and modulate immune responses through interactions with human extracellular and secreted proteins (the 'exoproteome'). Commensal microorganisms may also facilitate niche colonization and shape host biology by engaging host exoproteins; however, direct exoproteome-microbiota interactions remain largely unexplored. Here we developed and validated a novel technology, BASEHIT, that enables proteome-scale assessment of human exoproteome-microbiome interactions. Using BASEHIT, we interrogated more than 1.7 million potential interactions between 519 human-associated bacterial strains from diverse phylogenies and tissues of origin and 3,324 human exoproteins. The resulting interactome revealed an extensive network of transkingdom connectivity consisting of thousands of previously undescribed host-microorganism interactions involving 383 strains and 651 host proteins. Specific binding patterns within this network implied underlying biological logic; for example, conspecific strains exhibited shared exoprotein-binding patterns, and individual tissue isolates uniquely bound tissue-specific exoproteins. Furthermore, we observed dozens of unique and often strain-specific interactions with potential roles in niche colonization, tissue remodelling and immunomodulation, and found that strains with differing host interaction profiles had divergent interactions with host cells in vitro and effects on the host immune system in vivo. Overall, these studies expose a previously unexplored landscape of molecular-level host-microbiota interactions that may underlie causal effects of indigenous microorganisms on human health and disease.

Polygonatum sibiricum is a plant with medicinal and nutritional properties. Saponins are the important biologically active components of Polygonatum sibiricum. In this study, the specific components of Polygonatum sibiricum saponins (PSS) were analyzed, and the regulation effect of PSS on intestinal flora in patients with ulcerative colitis (UC) was investigated by inducing male Kunming mice with dextran sulfate sodium (DSS). PSS could ameliorate the symptoms of weight loss, high DAI score and colon length reduction compared to DSS-induced treatment. Colonic fragments were taken for H&E staining and histopathological scoring. PSS could significantly improve the pathological abnormality of colitis mice. 16S rRNA analysis showed that the intestinal microbial community of mice treated with DSS was significantly damaged. PSS could restore the richness and diversity of intestinal microbial flora, reduce the number of pathogenic bacteria, and increase the abundance of Lactobacillus spp. and Muribaculaceae, and improve the intestinal microbial flora disorder. Generally, PSS had an obvious effect in relieving colitis in mice. This study confirmed that Polygonatum sibiricum saponins play a therapeutic and palliative role in ulcerative colitis by regulating the microbiome balance.

Unbalanced gut microbiota is considered as a pivotal etiological factor in colitis. Nevertheless, the precise influence of the endogenous gut microbiota composition on the therapeutic efficacy of probiotics in colitis remains largely unexplored.

In this study, we isolated bacteria from fecal samples of a healthy donor and a patient with ulcerative colitis in remission. Subsequently, we identified three bacterial strains that exhibited a notable ability to ameliorate dextran sulfate sodium (DSS)-induced colitis, as evidenced by increased colon length, reduced disease activity index, and improved histological score. Further analysis revealed that each of Pediococcus acidilactici CGMCC NO.17,943, Enterococcus faecium CGMCC NO.17,944 and Escherichia coli CGMCC NO.17,945 significantly attenuated inflammatory responses and restored gut barrier dysfunction in mice. Mechanistically, bacterial 16S rRNA gene sequencing indicated that these three strains partially restored the overall structure of the gut microbiota disrupted by DSS. Specially, they promoted the growth of Faecalibaculum and Lactobacillus murinus, which were positively correlated with gut barrier function, while suppressing Odoribacter, Rikenella, Oscillibacter and Parasutterella, which were related to inflammation. Additionally, these strains modulated the composition of short chain fatty acids (SCFAs) in the cecal content, leading to an increase in acetate and a decrease in butyrate. Furthermore, the expression of metabolites related receptors, such as receptor G Protein-coupled receptor (GPR) 43, were also affected. Notably, the depletion of endogenous gut microbiota using broad-spectrum antibiotics completely abrogated these protective effects.

Our findings suggest that selected human-derived bacterial strains alleviate experimental colitis and intestinal barrier dysfunction through mediating resident gut microbiota and their metabolites in mice. This study provides valuable insights into the potential therapeutic application of probiotics in the treatment of colitis.

Inflammatory bowel disease (IBD) is one of the most prevalent chronic inflammations of the gastrointestinal tract (GIT). The gut microbial population, the cytokine milieu, the aryl hydrocarbon receptor (AHR) expressed by immune and nonimmune cells and the intrinsic pathway of Th-cell differentiation are implicated in the immunopathology of IBD. AHR activation requires a delicate balance between regulatory and effector T-cells; loss of this balance can cause local gut microbial dysbiosis and intestinal inflammation. Thus, the study of the gut microbiome in association with AHR provides critical insights into IBD pathogenesis and interventions. This review will focus on the recent advancements to form conceptional frameworks on the benefits of AHR activation by commensal gut bacteria in IBD.

Patients with Crohn's disease (CD) exhibit great heterogeneity in disease presentation and treatment responses, where distinct gut bacteria and immune interactions may play part in the yet unresolved disease aetiology. Given the role of antibodies in the barrier defence against microbes, we hypothesised that gut bacterial antibody-coating patterns may influence underlying disease-mediated processes.

Absolute and relative single and multicoating of gut bacteria with IgA, IgG1, IgG2, IgG3 and IgG4 in patients with CD and healthy controls were characterised and compared with disease activity. IgG2-coated and non-coated taxa from patients with severe CD were identified, profiled for pathogenic characteristics and monitored for enrichment during active disease across cohorts.

Patients with severe CD exhibited higher gut bacterial IgG2-coating. Supervised clustering identified 25 bacteria to be enriched in CD patients with high IgG2-coating. Sorting, sequencing and in silico-based assessments of the virulent potential of IgG2-coated and bulk stool bacteria were performed to evaluate the nature and pathogenicity of IgG2-coated and non-coated bacteria. The analyses demonstrated IgG2-coating of both known pathogenic and non-pathogenic bacteria that co-occurred with two non-coated pathobionts, Campylobacter and Mannheimia. The two non-coated pathobionts exhibited low prevalence, rarely coincided and were strongly enriched during disease flares in patients with CD across independent and geographically distant cohorts.

Distinct gut bacterial IgG2-coating was demonstrated in patients with severe CD and during disease flares. Co-occurrence of non-coated pathobionts with IgG2-coated bacteria points to an uncontrolled inflammatory condition in severe CD mediated via escape from antibody coating by two gut pathobionts.

Canonically, the complement system is known for its rapid response to remove microbes in the bloodstream. However, relatively little is known about a functioning complement system on intestinal mucosal surfaces. Herein, we report the local synthesis of complement component 3 (C3) in the gut, primarily by stromal cells. C3 is expressed upon commensal colonization and is regulated by the composition of the microbiota in healthy humans and mice, leading to an individual host's specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut ensures that C3 deposition does not result in the lysis of commensals. Pathogen infection triggers the immune system to recruit neutrophils to the infection site for pathogen clearance. Basal C3 levels directly correlate with protection against enteric infection. Our study reveals the gut complement system as an innate immune mechanism acting as a vigilant sentinel that combats pathogens and spares commensals.

Through a pilot study, we performed whole gut metagenomic analysis in 17 Lynch syndrome (LS) families, including colorectal cancer (CRC) patients and their healthy first-degree relatives. In a second asymptomatic LS cohort (n=150) undergoing colonoscopy-screening program, individuals with early precancerous lesions were compared to those with a normal colonoscopy. Since bacteria are organized into different networks within the microbiota, we compared related network structures in patients and controls.

Fecal prokaryote DNA was extracted prior to colonoscopy for whole metagenome (n=34, pilot study) or 16s rRNA sequencing (validation study). We characterized bacteria taxonomy using Diamond/MEGAN6 and DADA2 pipelines and performed differential abundances using Shaman website. We constructed networks using SparCC inference tools and validated the construction's accuracy by performing qPCR on selected bacteria.

Significant differences in bacterial communities in LS-CRC patients were identified, with an enrichment of virulent bacteria and a depletion of symbionts compared to their first-degree relatives. Bacteria taxa in LS asymptomatic individuals with colonic precancerous lesions (n=79) were significantly different compared to healthy individuals (n=71). The main bacterial network structures, constructed based on bacteria-bacteria correlations in CRC (pilot study) and in asymptomatic precancerous patients (validation-study), showed a different pattern than in controls. It was characterized by virulent/symbiotic co-exclusion in both studies and illustrated (validation study) by a higher Escherichia/Bifidobacterium ratio, as assessed by qPCR.

Enhanced fecal virulent/symbiotic bacteria ratios influence bacterial network structures. As an early event in colon carcinogenesis, these ratios can be used to identify asymptomatic LS individual with a higher risk of CRC.

Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer.

Previous studies suggested that microbial communities can harbour keystone species whose removal can cause a dramatic shift in microbiome structure and functioning. Yet, an efficient method to systematically identify keystone species in microbial communities is still lacking. Here we propose a data-driven keystone species identification (DKI) framework based on deep learning to resolve this challenge. Our key idea is to implicitly learn the assembly rules of microbial communities from a particular habitat by training a deep-learning model using microbiome samples collected from this habitat. The well-trained deep-learning model enables us to quantify the community-specific keystoneness of each species in any microbiome sample from this habitat by conducting a thought experiment on species removal. We systematically validated this DKI framework using synthetic data and applied DKI to analyse real data. We found that those taxa with high median keystoneness across different communities display strong community specificity. The presented DKI framework demonstrates the power of machine learning in tackling a fundamental problem in community ecology, paving the way for the data-driven management of complex microbial communities.

Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) is a significant threat to public health worldwide. The primary reservoir for CR-Kp is the intestinal tract. There, the bacterium is usually present at low density but can bloom following antibiotic treatment, mostly in hospital settings. The impact of disturbances in the intestinal environment on the fitness, survival, expansion, and drug susceptibility of this pathogen is not well-understood, yet it may be relevant to devise strategies to tackle CR-Kp colonization and infection. Here, we adopted an in vivo model to examine the transcriptional adaptation of a CR-Kp clinical isolate to immune activation in the intestine. We report that as early as 6 hours following host treatment with anti-CD3 antibody, CR-Kp underwent rapid transcriptional changes including downregulation of genes involved in sugar utilization and amino acid biosynthesis and upregulation of genes involved in amino acid uptake and catabolism, antibiotic resistance, and stress response. In agreement with these findings, treatment increased the concentration of oxidative species and amino acids in the mouse intestine. Genes encoding for proteins containing the domain of unknown function (DUF) 1471 were strongly upregulated, however their deletion did not impair CR-Kp fitness in vivo upon immune activation. Transcription factor enrichment analysis identified the global regulator cAMP-Receptor Protein, CRP, as a potential orchestrator of the observed transcriptional signature. In keeping with the recognized role of CRP in regulating utilization of alternative carbon sources, crp deletion in CR-Kp resulted in strongly impaired gut colonization, although this effect was not amplified by immune activation. Thus, following intestinal colonization, which occurs in a CRP-dependent manner, CR-Kp can rapidly respond to immune cues by implementing a well-defined and complex transcriptional program whose direct relevance toward bacterial fitness warrants further investigation. Additional analyses utilizing this model may identify key factors to tackle CR-Kp colonization of the intestine.