In biological responses, fatty acids (FA) are absorbed and metabolized in the form of substrates for energy production. The molecular structures (number of double bonds and chain length) and composition of dietary FA impact digestion, absorption and metabolism, and the biological roles of FA. Recently, increasing evidence indicates that FA are essentially utilized as an energy source and are signaling molecules that exert physiological activity of gut microbiota and immune responses. In addition, FA could serve as natural ligands for orphan G protein-coupled receptors (GPCR), also called free fatty acid receptors (FFAR), which intertwine metabolic and immune systems via multiple mechanisms. The present review explores the recent findings on FA absorption and its impact on gut health, particularly addressing the mechanism by which dietary FA potentially influences intestinal microbiota and epithelial functions. Also, this work attempts to uncover research ideas for devising future strategies for manipulating the composition of dietary FA to regulate gut health and support a normal immune system for metabolic and immune disorders.

This study investigated the effects of dietary C. butyricum ZJU-F1 on the apparent digestibility of nutrients, intestinal barrier function, immune response, and microflora of weaned piglets, with the aim of providing a theoretical basis for the application of Clostridium butyricum as an alternative to antibiotics in weaned piglets. A total of 120 weanling piglets were randomly divided into four treatment groups, in which piglets were fed a basal diet supplemented with antibiotics (CON), Bacillus licheniformis (BL), Clostridium butyricum ZJU-F1 (CB), or Clostridium butyricum and Bacillus licheniformis (CB-BL), respectively. The results showed that CB and CB-BL treatment increased the intestinal digestibility of nutrients, decreased intestinal permeability, and increased intestinal tight junction protein and mucin expression, thus maintaining the integrity of the intestinal epithelial barrier. CB and CB-BL, as exogenous probiotics, were also found to stimulate the immune response of weaned piglets and improve the expression of antimicrobial peptides in the ileum. In addition, dietary CB and CB-BL increased the proportion of Lactobacillus. The levels of butyric acid, propionic acid, acetic acid, and total acid were significantly increased in the ceca of piglets fed CB and CB-BL. Furthermore, we validated the effects of C. butyricum ZJU-F1 on the intestinal barrier function and immune response in vitro and found C. butyricum ZJU-F1 improved intestinal function and enhanced the TLR-2-MyD88-NF-κB signaling.

The innate immune response is the host’s first line of defense, promptly activated upon pathogen invasion. Its precise and rapid activation relies on innate immune cells (IICs). Upon recognizing danger signals postinfection or injury, they release various innate immune effectors to eliminate invading pathogens or damaged cells, thus supporting the host’s immune homeostasis. Epigenetic modifications, by shaping chromatin structures, orchestrate specific gene transcription patterns to regulate the lineage development, differentiation, and activation of IICs. This intricate process ultimately contributes to effective pathogen clearance and IICs’ healthy development and differentiation. To thoroughly elucidate the epigenetic mechanisms underlying the development and differentiation of IICs, this review first introduces the fundamental concepts and latest advancements in this field. We then delve into how the immune microenvironment or other signaling molecules shape the epigenetic landscapes of distinct IIC subsets during their lineage development and differentiation. Furthermore, we summarize how different epigenetic modification profiles mediate specific transcriptional patterns, thereby influencing the lineage development, differentiation, and activation of IICs in response to infections or injuries. Finally, we discuss several unresolved critical issues from the perspective of targeting epigenetic modifications to modulate the innate immune response. In summary, this review aims to uncover the molecular mechanisms underlying the development, differentiation, and activation of IICs from an epigenetic perspective, providing theoretical foundations for scientific and medical researchers pursuing disease treatments.

Probiotics are widely used as dietary additives to strengthen gut barrier function, shape microbiota composition, regulate host metabolism, and promote overall health. To enhance probiotic delivery and microbial viability, this study evaluated a liquid feeding system supplemented with a probiotic consortium (Bifidobacterium infantis, Lactobacillus plantarum, and Pediococcus acidilactici) in nursery piglets. A 60-day trial involving 270 piglets (16.84 ± 0.12 kg) compared three diets: solid feed (Dry), liquid feed (Liq), and probiotic-enriched liquid feed (Pro). Compared to the Dry and Liq groups, probiotic supplementation significantly improved growth performance, with the average daily gain increasing by over 17.86% (p < 0.01) and the average daily feed intake increasing by more than 6.08% (p < 0.05). The feed conversion ratio was reduced by up to 8.08% (p < 0.05), indicating improved feed efficiency. The Pro group also exhibited elevated tight junction protein expression (p < 0.05), increased colonic short-chain fatty acid levels (p < 0.01), and decreased serum biomarkers of intestinal permeability (p < 0.05). The 16 S rRNA sequencing indicated the probiotic-driven colonization of B. infantis and L. plantarum and the suppression of opportunistic pathogens. Metabolomic analyses revealed enhanced colonic tryptophan metabolism, evidenced by elevated kynurenic and xanthurenic acid levels. Additionally, serum-targeted metabolomics and in vitro experiments confirmed that B. infantis and L. plantarum effectively converted tryptophan into indole-3-lactic acid, promoting its accumulation in piglet serum and colons. These results deepen our understanding of the mechanisms by which probiotics and tryptophan metabolism enhance intestinal health, providing a foundational platform for the application of probiotic-based interventions in livestock production.

Berberine, a benzyl isoquinoline alkaloid, is used in food for its diverse spectrum of biological activities. Inflammatory bowel disease (IBD) is a widespread condition characterized by frequent occurrence and limited therapeutic success. Berberine has been shown to alleviate colitis through enhancement of the intestinal barrier and modulation of gut microbial balance. However, the further mutualistic balance mechanism between microbes and the mucus of berberine in alleviating IBD still needs to be clarified. Our findings demonstrated a strong association between berberine’s therapeutic efficacy and alterations in the gut microbiota. This includes enhancements in the level of IgA-coated bacteria, Zg16, Reg3g, and Pla2g2a, all of which contribute to microbiota homeostasis. Moreover, the beneficial effect on gut barrier function of berberine was mostly attributed to Akkermansiam and Bacteriodes-associated mucin–SCFA metabolism. This study lays a critical groundwork for the development of berberine-based functional food additives that harness its nutraceutical potential.

Background: The early-life gut microbiota plays a critical role in programming intestinal barrier function and immune homeostasis, with profound implications for long-term host health. However, the effects of early-life compound probiotic intervention on the maturation of intestinal barrier function and the underlying molecular mechanisms remain incompletely understood, particularly in large-animal models relevant to human physiology. Methods: In this preclinical study, 3627 neonatal piglets—a well-established translational model for human infant gut development—were orally administered a novel compound probiotic formulation comprising Bifidobacterium longum subsp. infantis BZ, Lactobacillus plantarum LZ, and Pediococcus acidilactici PZ during early life. A total of 1512 fecal samples collected at seven time points from birth to day 180 were analyzed by 16S rRNA sequencing, and 525 samples from three developmental windows (days 10, 25, and 70) were subjected to LC-MS-based metabolomics. The candidate metabolite indole-3-lactic acid (ILA) was further mechanistically validated in a DSS-induced colitis mouse model and in IPEC-J2 cells. Results: Early-life probiotic intervention significantly enhanced intestinal barrier integrity, as evidenced by improved intestinal morphology and upregulated expression of tight junction proteins—zonula occludens-1 (ZO-1), occludin (OCLN), and Claudin-1 (CLDN1)—in the jejunum (p < 0.05). Notably, intervention at birth was more effective than post-weaning administration, and two administrations (birth + weaning) yielded superior outcomes compared with a single administration (p < 0.05). Microbiome analysis revealed enhanced microbial diversity and enrichment of beneficial genera during the juvenile-to-adult transition (p < 0.05). Metabolomic profiling identified ILA as a signature metabolite consistently elevated by probiotic supplementation. Conclusions: These findings provide evidence that early-life compound probiotic intervention is associated with improved intestinal barrier maturation, with ILA identified as a key candidate metabolite that may mediate this effect, as supported by functional validation in murine and cellular models. This provides a mechanistic rationale for probiotic-based strategies to support intestinal health in human infants during critical developmental windows.