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Multicellular life arose in a world dominated by microorganisms, a reality that has imposed a constant and pervasive selective pressure on all subsequent complex organisms. The immune system has been historically defined by its role in pathogen clearance through resistance mechanisms. However, a complementary and equally critical strategy is to enable the peaceful and inevitable coexistence with microorganisms, allowing each host species to shelter a unique associated microbiome. The term tolerance holds multiple meanings in immunology, yet all underlie a balanced and cooperative host-microorganism relationship. Each represents a different aspect of how the immune system limits tissue damage while maintaining functionality in the presence of microbial or inflammatory stimuli. Using the intestinal mucosa as a paradigm, we explore how epithelial barrier integrity, toxin neutralization, tissue repair, and stress response underpin disease tolerance; how microbial exposure calibrates innate immunity via epigenetic and metabolic reprogramming (LPS tolerance); and how the gut microenvironment fosters the generation of tolerogenic antigen-presenting cells and microbe-specific regulatory T cells to enforce immunological tolerance. We further explore how the microbiota itself is a potent inducer of these tolerogenic pathways and highlight IL-10 as a major hub, connecting different tolerogenic circuits. Finally, we examine the hygiene hypothesis, arguing that lifestyle changes during the Anthropocene disrupt these finely tuned tolerance mechanisms, thereby contributing to the rising incidence of immune-mediated diseases. We posit that these tolerance programs are fundamental prerequisites for engendering host-microbiota symbiosis, a relationship forged over millennia of co-evolution and endangered in the contemporary world.

A small molecule metabolite DAT drives tuft cell hyperplasia and type 2 immunity in the small intestine. DAT-mediated tuft cell hyperplasia depends on HDAC3 and an intact microbiota; our findings reveal how small molecule metabolites fine-tune intestinal type 2 defenses against parasites.

This study establishes that Lactobacillus plantarum Lac16 alleviates DSS-induced colitis through gut microbiota-dependent mechanisms. Lac16 administration significantly ameliorated colitis symptoms while restoring intestinal barrier integrity, promoting anti-inflammatory macrophage polarization, and suppressing NLRP3 inflammasome overactivation. The pseudo-germ-free mouse model provided definitive evidence that Lac16’s suppression of NLRP3 inflammasome overactivation requires gut microbiota. Fecal microbiota transplantation verified the causal role of microbiota in mediating Lac16’s therapeutic benefits. Notably, Lac16 reshaped microbial composition, elevating beneficial genera ( Alloprevotella and Dubosiella ) while suppressing pathogenic genera ( Bacteroides and Helicobacter ). Crucially, Lac16 increased microbiota-derived short-chain fatty acids, particularly isobutyric acid. Both in vivo and in vitro experiments confirmed that isobutyric acid significantly contributes to anticolitic effects and suppresses NLRP3 activation. These findings elucidate a novel mechanism by which Lac16 ameliorates colitis via (i) microbiota-dependent NLRP3 inflammasome modulation and (ii) isobutyric acid-mediated protective effects. This work provides important insights into probiotic mechanisms and supports targeting microbial metabolic networks for IBD intervention.

This research marks an investigation into how specific microbiota, like Bacteroides , regulate host responses across different gut regions to influence systemic health. By dissecting the impact of Bacteroides across multiple regions of the intestinal tract, this study offers new insights into the localized and whole-body effects of this important immune-programming microbe. Such an understanding is crucial as it helps in unraveling the complex interplay between gut microbes and the host’s immune system. This research helps bridge the gap between local intestinal ecology and overall systemic health, addresses important questions relevant to the gut-lung axis, and helps pave the way for innovative therapies.

There is a limited amount of work examining the effects of oral lyophilized fecal microbiota transplantation (FMT) on the microbiome of patients with ulcerative colitis (UC), and less so studies examining species-level dynamics and functional changes using this form of FMT. We performed deep shotgun metagenomic sequencing to provide an in-depth species-genome bin-level analysis of the microbiome of patients with UC receiving oral lyophilized FMT from a single donor. We identified key taxonomic and functional features that transferred into patients and were associated with clinical response. We also determined how FMT impacts the resistome of patients with UC. We believe these findings will be important in ongoing efforts to not only improve the efficacy of FMT in UC but also allow for the transition to defined microbial therapeutics, foregoing the need for FMT donors.

This study investigates the gut-larynx axis, revealing how gut dysbiosis impacts immune responses in the larynx. Although laryngeal microbiota remained stable, significant immunological and cellular changes occurred following gut microbiota disruption. Transcriptomic alterations in epithelial integrity, immune signaling, and cell communication underscore the systemic impact of gut dysbiosis. The identification of integrin-mediated signaling as a key pathway in immune-epithelial interactions emphasizes the complexity of host-microbe dynamics. These findings suggest that gut health plays a critical role in shaping respiratory immunity, providing a foundation for future research into microbiota-driven immune modulation in the upper airway.

This study provides mechanistic and clinical insights into the therapeutic effects of fecal microbiota transplantation (FMT) in inflammatory bowel disease (IBD), particularly when combined with the anti-tumor necrosis factor (anti-TNF) biologic infliximab (IFX). While both FMT and IFX achieve response in approximately 60% of IBD patients, their combined influence on the gut microbial and metabolic landscape in refractory disease has been poorly understood. Here, we demonstrate that FMT monotherapy restores gut microbial diversity and reconfigures host-microbiota-metabolite networks, correlating with clinical and endoscopic remission in patients refractory to conventional treatments. Furthermore, in Crohn's disease patients unresponsive to either therapy alone, combined IFX-FMT induced more complete microbial and metabolic normalization and achieved remission where monotherapy had failed. These findings reveal ecosystem-level network rewiring as a central mechanism of FMT efficacy and establish the additive potential of combining microbiome-targeted and immunomodulatory therapies. This work supports the development of microbiome-informed adjunctive strategies for severe or refractory IBD, highlighting an actionable path toward personalized, mechanism-based treatment regimens. This study is registered with ClinicalTrials.gov as NCT07149441 .

Early-life microbial colonization is essential for gut and immune development. Human milk oligosaccharides (HMOs) support the growth of (BI). Here, we studied the individual and combined effects of BI and HMOs on the immune and colon transcriptomes and on serum and cecal metabolome. Germ-free mice were randomly assigned to four groups (10-14/group: HMO, BI, BI + HMO, and control [no HMO or BI]). HMO and BI + HMO groups received 5 mg/day each of 2'-fucosyllactose, lacto-N-tetraose, and 3'-sialyllactose for 14 days. BI and BI + HMO received BI ATCC 15,697 (1 × 10 CFU/day) on days 1, 4, and 9. Mono-colonization with BI increased monocytes, macrophages, B cells, CD4 T cells, and Treg cells in mesenteric lymph nodes (MLN) relative to controls. In the spleen, BI alone increased B cells, dendritic cells, Th17 cells, and ILC3 cells, and enriched serum amino acid metabolism pathways. Additionally, BI influenced colonocyte gene expression and modulated serum metabolites that regulate circadian rhythms. BI + HMO increased MLN Th17 cells and spleen monocytes compared with HMO alone. Collectively, the results of this study highlight the complex interplay among host-microbe-diet interactions and emphasize the importance of considering these interactions when designing strategies to modulate infant health during early life. Early life immune and gut microbiome development are shaped by human milk (HM). One of the most important drivers of these processes is the human milk oligosaccharides (HMOs). (BI) possesses a unique enzymatic system that enables efficient HMO uptake and intracellular metabolism, providing a competitive advantage over other microbial species in the breastfed infant gut. To date, the potential direct and synergistic effects of BI and HMO have not been fully explored. The knowledge generated herein identified the independent and synergistic effects of HMOs and BI on gut immune response, serum and cecal metabolites, and colonic gene expression.

Genetic-level evidence of gut microbiota causality in atopic dermatitis: this study established a causal relationship between specific gut microbiota and the risk of atopic dermatitis at the genetic level, providing strong genetic evidence for the “gut-skin axis” theory. GALE is identified as a novel therapeutic target with redefined methotrexate mechanism: molecular docking study unexpectedly found that GALE binding affinity of MTX was significantly higher than that of its classical target TYMS, suggesting that GALE may be an important but previously unrecognized target of MTX in the treatment of AD. Multi-omics integration framework reveals increased keratinocyte heterogeneity: integrating single-cell RNA sequencing and computational pharmacology provided a cellular and molecular basis for understanding the characteristics of chronicity and recurrence of the disease.

The intratumoral microbiota is a vital part of the tumor microenvironment, yet its interplay with host gene expression and immune regulation remains unclear. Based on a machine learning framework for the interaction analysis of intratumoral microbiota and host genes, as well as the construction of the Immune and Prognosis-Related Microbial Score, our findings suggest that intratumoral microbiota may influence gene expression by affecting host pathways, especially immune-related pathways. Moreover, immune-related intratumoral microbiota are significantly associated with patient survival and TME immunity and may influence prognosis by affecting immune cells, pathways, or gene expression, offering new perspectives and potential biomarkers for predicting personalized patient prognosis in the future.