Excessive intake of added sugars is a global public health concern, given its established links with cardiometabolic disease and other chronic conditions. Emerging evidence suggests that the gut microbiota might mediate the harms of high sugar intake. In this review, we summarize evidence from animal and human studies regarding the impact of added sugar intake on gut microbiota diversity and composition, and discuss potential mechanisms linking sugar-induced microbial changes to health outcomes. Added sugars, including glucose, fructose, and sucrose, can alter gut microbial diversity, enrich sugar-utilizing taxa, and deplete short-chain fatty acid-producing bacteria. These microbial changes may impair gut barrier integrity, increase luminal oxygen and alternative electron acceptors under inflammatory conditions, reduce short-chain fatty acid production, alter bile acid and amino acid metabolism, and promote translocation of endotoxin across the gut barrier into the bloodstream. Collectively, these pathways may link added sugar intake to irritable bowel syndrome, obesity, liver steatosis, diabetes, and cardiovascular diseases. However, inconsistent results on alterations in the gut microbiota related to added sugar intake were observed across studies, which may be due to differences in sugar dose and form (liquid vs. solid), as well as population variation in background diet, host genetics, and gut microbial ecology. Future research should focus on mechanistic investigations, characterization of inter-individual variability in response to added sugar intake, and clinical studies to assess whether dietary or therapeutic interventions can reverse sugar-induced gut microbial changes and improve host health outcomes.

Obesity and the metabolic syndrome (MetS) are global health challenges. The gut microbiome, particularly its fermentation products, short-chain fatty acids (SCFAs), is increasingly recognized as a key modulator of cardiometabolic health. Growing evidence suggests that exercise may play a critical role in SCFA production. This study presents a pooled analysis of data from three randomized controlled trials to examine the effects of low-volume high-intensity (HIGH-EX) versus moderate-intensity (MOD-EX) interval training, each combined with single-set resistance training, on SCFAs and cardiometabolic health in obese MetS patients.

MICOMWeb is a user-friendly website for modeling microbial community metabolism in the human gut. This website tackles three constraints when generating metagenome-scale metabolic models: i) the prior Python user knowledge for metabolic modeling using flux balance analysis with the MICOM Python package, ii) predefined and user-defined diets to generate metabolic models, and iii) the high-throughput computational infrastructure required to obtain the simulated growth and metabolic exchange fluxes, using real abundance from metagenomic shotgun or 16S amplicon sequencing; we present MICOMWeb's features to easily run experiments as a functional hypothesis generator for experimental validation on three previously published databases. MICOMWeb has a constant run-time independent of the number of samples provided and database complexity. In practical terms, this behavior is upper-bounded by the sample with the greatest microbiota diversity, i.e., the sample with the largest metabolic reconstruction model size. The evidence suggests that the bigger the database, the better the MICOMWeb performs compared to MICOM in terms of consumed RAM (from 3.52 up to 7.13 folds) and total execution time (from 10.87 up to 205.05 folds).

The small intestine is a key site for nutrient sensing and host-microbiota interactions, yet how it functionally adapts to dietary changes remains poorly understood. Using a translational porcine model, we investigated the impact of moderate dietary fat increase on the gut microbiota and metabolome across five locations in the digestive tract. Pigs were fed either a low-fat (3%) or a medium-fat (12%) diet for 12 weeks without developing obesity. Multiomics profiling revealed significant dietary effects on bile and duodenojejunal metabolomic profiles, particularly lipid and stachydrine, with notable sex-specific responses. These metabolite shifts were accompanied by segment- and sex-specific changes in microbial communities, including the depletion of metabolically beneficial taxa (e.g., and ) and the enrichment of bacteria linked to metabolic dysfunction (e.g., ). In the small intestine lumen, multiple bacterial-metabolite associations correlated with host metabolic markers, suggesting early diet-induced alterations with potential relevance for metabolic disease onset. Our findings position the small intestine as a critical site for early diet-induced microbial and metabolic remodeling, potentially influencing metabolic disease risk and shaping the downstream intestinal environment. This study also underscores the importance of considering both region- and sex-specific responses in diet-microbiota-metabolome research.

Excessive ultra-processed foods (UPFs) consumption has been reported to increase the risk of inflammatory bowel disease (IBD). However, the specific mechanisms involved remain unclear. As an important ingredient of UPFs, 7-ketositosterol (KS) is synthesized mainly from high-temperature heated oils. We found that KS intake is higher in IBD patients and is related to disease activity. KS exacerbates colitis in a gut microbiota-dependent manner in mice, altering the gut microbiota composition and increasing the abundance of potential pathogenic bacteria, especially (SL). Moreover, SL aggravates DSS-induced colitis. Mechanically, KS upregulates the expression of PDZ and LIM domain 3 (PDLIM3). SL-derived lysin motif peptidoglycan-binding domain-containing protein (LPDP) interacts with PDLIM3 and activates the p38MAPK/NF-κB signaling pathway. Furthermore, tubuloside B, which is selected by high-throughput screening, blocks the interaction of PDLIM3 and LPDP, and ameliorates SL-aggravated colitis. Our study reveals that KS exposure promotes colitis via the gut microbiota and PDLIM3 interaction, providing evidence of IBD pathogenesis and a potential therapeutic strategy for IBD treatment.

Vegan and omnivorous diets differ markedly in composition, but their effects on the gut microbiome, metabolome, and lipidome across populations remain insufficiently characterized. While both diet and country of origin influence these molecular layers, the relative contribution of diet versus country-specific factors has not yet been systematically evaluated within a multi-omics framework.In this cross-sectional, bicentric, observational study, we profiled healthy vegans ( = 100) and omnivores ( = 73) from the Czech Republic and Italy using integrated microbiome, metabolome, and lipidome analyses. Findings were subsequently validated in an independent cohort ( = 142).Significant differences across all omics layers were observed for both country and diet. The predictive models confirmed diet-associated separation, with validation cohort AUCs of 0.99 (lipidome), 0.89 (metabolome), and 0.87 (microbiome). Functional metagenome analysis revealed enrichment of amino acid biosynthesis, inositol degradation, and the pentose phosphate pathway in vegans, while omnivores presented greater potential for amino acid fermentation, fatty acid biosynthesis, and propanoate metabolism. Linear models identified a robust, country-independent "vegan signature" consisting of 27 lipid metabolites, five non-lipid metabolites, and 11 bacterial species. Several lipid features associated with an omnivorous diet were inversely related to the duration of vegan diet adherence. Some of the vegan-associated metabolites and bacteria have been previously linked to favorable cardiometabolic profiles, although causality remains to be established.These findings demonstrate that vegan diets are associated with reproducible, country-independent molecular and microbial signatures. Our results highlight diet-driven shifts in host-microbiota interactions and provide a framework for understanding how dietary patterns relate to host-microbiota interactions.

Osteoporosis is an age-related disease. The relationship between gut microbiota (GM) homeostasis and bone health is well established, but the mechanism of GM dysbiosis contributes to senile osteoporosis remains elusive. The objective of this study is to investigate the relationship between GM, bile acids (BAs) and their effects on bone mass.

Sterols play an indispensable role in maintaining cell membrane stability, regulating hormone synthesis, and preserving physiological homeostasis. Recently, the function of the gut microbiota in modulating host sterol metabolism has become the focus of extensive research. Nonetheless, the specific functions carried out by the gut microbiota in sterol metabolism and their health implications remain unclear due to a lack of comprehensive synthesis and analysis. This review aims to consolidate current perspectives regarding the sources and metabolic mechanisms of sterols, with an emphasis on the involvement of gut microbiota in the biotransformation of zoosterols, phytosterols, and mycosterols. Additionally, it explores the pathological implications of sterol metabolism disorders in diseases such as Alzheimer's disease and cancer. Finally, the review highlights the potential of dietary interventions to reshape gut microbiota composition and restore sterol metabolic homeostasis, presenting novel strategies for disease prevention and therapy through targeted modulation of sterol metabolism.

Crohn's disease (CD), a chronic inflammatory bowel disorder, often progresses to intestinal fibrosis and stricture, yet no effective anti-fibrotic treatments exist. This study reveals dipeptidyl peptidase 4 (DPP4) as a pivotal driver of fibrosis through bioinformatics analysis, clinical samples, and experimental models. Elevated DPP4 expression was observed in stenotic intestinal tissues of CD patients and dextran sodium sulfate (DSS)-induced fibrotic mice. Mechanistically, both membrane-bound DPP4 and soluble DPP4 (sDPP4) activated human intestinal myofibroblasts (HIMFs) via the PI3K-AKT pathway, stimulating migration, proliferation, and extracellular matrix deposition. Importantly, metagenomic sequencing revealed enrichment of microbial genes in fecal samples from CD patients with stenosis, and colonization with engineered overexpressing microbial DPP4 exacerbated fibrotic remodeling, confirming microbiota-derived DPP4 (mDPP4) as a pathogenic driver. Furthermore, pharmacological inhibition of host DPP4 (sitagliptin) or selective blockade of mDPP4 (Dau-d4) attenuated fibrosis in murine models, with combined therapy showing enhanced efficacy. These findings underscore the roles of DPP4, originating from both host and microbiota, and existing in membrane-bound and soluble forms, in promoting CD-associated intestinal fibrosis. This study identifies DPP4 as a novel therapeutic target, proposing dual-source inhibition as a promising strategy to prevent stricture formation in CD patients, thereby addressing a critical unmet clinical need.

The gut microbiota plays a crucial role in lipid metabolism in both humans and animals. However, the specific contributions of gut microbiota and their associated metabolites to fat deposition, as well as the underlying mechanisms, remain largely unexplored. In this study, we demonstrated that the intestinal microbiota mediated the heterogeneity of mesenteric fat index (MFI), as evidenced by fecal microbiota transplantation (FMT) experiments. Notably, analysis of the 16S rRNA gene amplicon sequencing of 44 samples revealed a significantly higher abundance of in the Low MFI group, with a positive correlation to reduced MFI. Serum metabolomics analysis confirmed that L-Carnitine emerged as the most differentially abundant metabolite in the Low MFI group and exhibited a strong positive correlation with abundance. Metagenomic analysis showed that microbial genes related to L-Carnitine biosynthesis were significantly enriched in the Low MFI group. Further, was isolated and cultured, and its subsequent monocolonization in germ-free zebrafish and tilapia demonstrated its lipid-lowering effects by enhancing mitochondrial fatty acid -oxidation. Whole genome sequencing demonstrated could encode the [EC:1.2.1.3] gene, which promotes the production of 4-trimethylammoniobutanoate, a precursor of L-Carnitine, thereby enhancing L-Carnitine biosynthesis by the host and gut microbiota, leading to the reduced fat deposition in Nile tilapia. In conclusion, , a core gut microbe with high abundance in aquatic teleost intestines, plays an important role in host lipid metabolism. This study advances our understanding of how core gut microbes shape host phenotypes and provides novel insights into manipulating core gut colonizers to reduce fat deposition.

Social relationships play a crucial role in shaping health. To better understand the underlying mechanisms, we explored the independent and interactive effects of perceived emotional support (PES) and marital status on body mass index (BMI), eating behaviors, brain reactivity to food images, plasma oxytocin, and alterations in the brain-gut microbiome (BGM) system. Brain responses to food stimuli, fecal metabolites, and plasma oxytocin levels were measured in 94 participants. Structural equation modeling was used to determine the integrated pathways linking social factors to obesity-related outcomes. Marital status and PES interact and independently influence lower BMI, healthier eating behaviors, increased oxytocin levels, food-cue reactivity in frontal brain regions involved in craving inhibition and executive control, and tryptophan-pathway metabolites related to inflammation, immune regulation, and energy homeostasis. These findings suggest that supportive human relationships, particularly high-quality marital bonds, may regulate obesity risk through oxytocin-mediated alterations in brain and gut pathways.

EspH is an effector protein secreted by the type III secretion system of various pathogenic strains, including enteropathogenic (EPEC). The ability of EspH to inhibit host RhoGTPases, disrupt the actin cytoskeleton, and induce host cell cytotoxicity has been well-documented. Mass spectrometry analysis of EspH translocated into EPEC-infected cells revealed that a lysine at position 106 (K106) is modified with ubiquitin. Immunoblotting using the FK2 anti-ubiquitin antibodies has confirmed these results, suggesting that EspH undergoes polyubiquitylation. Prediction algorithms have identified a single ubiquitylation site at K106 and a phosphodegron in EspH. Moreover, we show that wild-type (EspH), but not the EspH mutant, is subjected to degradation following translocation in an MG132-sensitive manner, indicating that the proteasome degrades the polyubiquitylated effector following translocation. Finally, we show that translocated EspH induces higher cytotoxicity than translocated EspH. EspH translocated into MG132-pretreated cells also displayed higher cytotoxicity levels than EspH in untreated cells. These data reinforce the idea that EspH is polyubiquitylated and that the host proteasome degrades the translocated effector, possibly limiting its ability to toxicate the host cells. Additional implications of these effects on bacterial-host interactions are discussed.

White adipose tissue plays a critical role in obesity, as its dysfunction can impair lipid homeostasis. We previously demonstrated that desaminotyrosine (DAT), a microbial metabolite, prevents high-fat diet (HFD)-induced body weight gain in mice, but the role of DAT on white adipocyte is unknown. Here, we investigated the role of DAT in host metabolic health and its therapeutic potentials in treating obesity.

Bacterial infection caused by intracellular pathogens such as is a rapidly increasing global health concern that requires urgent and necessary action. The dearth of licensed vaccines against shigellosis and the decline in susceptibility to conventional antibiotics has encouraged the development of new antibiotic principles and drugs. The treatment options are decreasing faster than the discovery rate of new antibacterial agents. Combinatorial approach of antibiotics with non-antibiotic adjuvants is a promising aspect to treat resistant bacterial infections. Asiatic acid, a membrane-disrupting triterpenoid with wide antimicrobial and immunomodulatory properties, can potentiate antibiotics, but the exact mechanisms remain broadly unexplored. Therefore, in this study, we screened the interaction of asiatic acid with several antibiotics. The results showed synergistic interactions of asiatic acid with antibiotics against susceptible and multidrug-resistant clinical isolates. Particularly important was the interaction of asiatic acid with the quinolone antibiotics ciprofloxacin and nalidixic acid. A detailed study showed that combined treatment of asiatic acid with ciprofloxacin inhibited biofilm formation and resistance development. An increase in membrane disruption and depolarization upon co-treatment was evident by surface electron and confocal microscopy. In addition, asiatic acid and ciprofloxacin synergism was identified to inhibit efflux activity and intracellular bacterial viability. However, asiatic acid showed no synergistic toxicity with ciprofloxacin towards mammalian cells. The antibacterial activity was further verified in a infected mice model. Therapeutic benefits were evident with reduced bacterial burden, recovery from intestinal tissue damage and increase in mice survivability. The results showed that this combination can target the bacterial membrane, efflux pump proteins and biofilm formation, thereby preventing resistance development. The combination treatment offers a proof of concept in targeting essential bacterial activities and might be developed into a novel and efficient treatment alternative against .

Staphylococcus (S.) aureus remains a frequent pathogen for neonatal late-onset bloodstream infections (BSIs). The impact of colonization screening on BSI incidence is less understood.

Antibiotics influence both gut microbial composition and immune regulation, but the detailed mechanisms are still undefined. Shifts in the microbiome caused by antibiotic exposure can modulate immune activity through various pathways. Therefore, we aimed to explore how antibiotics affect immune-inflammation by regulating Th17 cells through the gut microbiota of mice with experimental autoimmune prostatitis (EAP). Antibiotic-driven shifts in gut microbial communities and metabolite profiling in EAP mice were performed by integrating 16S rRNA sequencing with mass spectrometry-driven metabolomic analysis. Antibiotic cocktail (ABX) therapy mitigated EAP, modified the gut microbiome composition, and influenced bile acid metabolism. Fecal microbiota transplantation (FMT) using microbiota from ABX-treated feces into EAP mice effectively altered gut microbiome composition and alleviated disease symptoms, indicating that microbiome intervention reduces autoimmune inflammation and decreases deoxycholic acid (DCA) in mice. Subsequent experiments demonstrated that DCA suppresses farnesol X receptor (FXR) expression which can inhibit the NLRP3‒ IL17A axis, thus promoting Th17 cell development and exacerbating inflammatory cell infiltration of the prostate. Our initial clinical examination of patients with prostatitis and antibiotic treatment indicated that bile acid metabolism and Th17 cell development are affected by antibiotic therapy. This work revealed that antibiotic-induced gut microbiota dysbiosis decreases the bile acid metabolite DCA, further restraining Th17 cell differentiation via the FXR‒NLRP3 axis to alleviate autoimmune prostatitis. Our results reveal new perspectives regarding the interconnected dynamics of antibiotics, gut microbiota, bile acid metabolism, and immune regulation, with potential relevance for therapies targeting immune-mediated diseases.

Exposure to food antigens that can trigger aberrant type-2 immunity is ubiquitous. However, only a subset of individuals develops allergy, implicating environmental drivers of sensitization, among which diet- and antibiotic-induced changes in intestinal microbiome activity stand out for their ability to alter host-microbe interactions at the gut mucosa. While efforts seek microbial signatures and microbiome-based therapies, the same microbes or pathways may foster either tolerance or sensitization depending on host and environmental context, which must be considered when designing interventions. We synthesize recent molecular insights into mucosal host-microbiome crosstalk, focusing on regulatory T cells, the colonic mucus barrier, and host immunoglobulins (IgA and IgE). Using examples of microbiome functional duality in which diet-driven altered microbial activities and secreted molecules such as lipopolysaccharides and flagellins yield opposing effects, we discuss the context-dependent mechanisms by which microbes either protect against or promote food allergy.

Patients with Crohn's disease exhibit abnormal intestinal colonization by , particularly adherent-invasive (AIEC). These bacteria predominate in the mucus, adhere to epithelial cells, colonize them, and survive inside macrophages. We recently demonstrated that the AIEC strain LF82 adapts to phagolysosomal stress through a two-step process: initial replication arrest generating stress-tolerant persisters, followed by the resumption of replication, leading to the formation of intracellular bacterial communities (IBCs) embedded in a biofilm-like matrix. Given the significant genomic diversity among strains with the AIEC phenotype, we performed a comparative genomic and functional analysis of 13 AIEC isolates from Crohn's disease patients in France and Spain. Our results demonstrate that IBCs are replicative niches for all AIEC strains within THP-1 macrophages, yet their formation relies on distinct mechanisms, including variations in phagosome detoxification, biofilm architecture, and macrophage responses. Our study identifies a strong positive correlation between vacuole acidification and persister induction, which underlies the intracellular survival of the different strains. Furthermore, we revealed distinct AIEC dissemination strategies outside macrophages, potentially contributing to the propagation of inflammation in the human host. These findings highlight that research on pathogens and pathobionts with dynamic genomes should extend beyond classical bacterial models.

Next-generation sequencing (NGS) data usage is widespread, but its compositional nature poses challenges. We evaluated four normalization methods (relative abundance, CLR, TMM, DESeq2) for identifying true signals in compositional microbiota data using simulations. Two experiments were conducted: one with only increases in specific taxa, and a 1:1 increase/decrease in specific taxa. Simulated sequencing produced compositional data, which were normalized using the four methods. The study compared absolute abundance data and the normalized compositional data using variance explained and false discovery rates. All normalization methods showed decreased variance explained and increased false positives and negatives compared to absolute abundance data. CLR, TMM, and DESeq2 did not improve over relative abundance data and sometimes worsened false discovery rates. The study highlights that false positives and negatives are common in compositional NGS datasets, and current normalization methods do not consistently address these issues. Compositionality artefacts should be considered when interpreting NGS results and obtaining absolute abundances of features/taxa is recommended to distinguish biological signals from artefacts.

The development of extra-intestinal diseases is often accompanied by disruptions in intestinal microbiota and its metabolites, yet the mechanistic link between the gut microbiota and asthma remains unclear. We investigated whether intelectin-1 (ITLN1) mitigates allergic asthma through the gut‒bone‒lung axis as a regulator of gut microbial homeostasis.

is a flagellated lactic acid bacterium found in the intestines of various mammals, including humans. Although this species harbors a complete flagellar gene cluster, flagella formation has not been observed in human-derived strains, and the underlying regulatory mechanisms remain unknown. Here, we isolated a motility-acquired mutant of ATCC 25644 that exhibited full flagellation and a measurable chemotactic response under acidic conditions (pH 3.0). Whole-genome sequencing revealed a ~35 kb deletion encompassing multiple regulatory genes. Functional complementation identified a single response regulator, designated FpsR (flagellation-piliation switchover regulator), as a central switch that suppresses flagella formation while promoting pilus expression. The motility-acquired mutant displayed reduced pilus production, diminished adhesion to murine intestinal mucus and fibronectin, and increased susceptibility to acid (pH 3.0) and bile (0.25-0.5%), resulting in a complete loss of intestinal colonization in a murine model. Furthermore, while flagellin from the motile strain activated TLR5 and induced proinflammatory responses comparable to those of pathogenic bacteria, no such inflammation was observed in vivo, likely due to the strain's colonization failure. These findings reveal FpsR as a previously unrecognized genetic mechanism that coordinates motility and mucosal colonization in a human commensal bacterium and provide insight into how flagella are regulated and silenced in the gut environment to support host-microbe symbiosis.