Atopic dermatitis (AD) is a prevalent inflammatory skin disorder with increasing incidence in early life. Bovine colostrum (BC), rich in diverse bioactive components, represents a promising functional dairy matrix for immune regulation. This study investigated the protective effects and underlying mechanisms of early-life BC supplementation (100 mg/kg) in a 2,4-dinitrofluorobenzene (DNFB)-induced murine AD model. BC intervention significantly ameliorated clinical and histological symptoms, including reduced skin thickness, erythema, and mast cell infiltration. It concurrently restored skin barrier integrity by upregulating key barrier genes (FLG, LOR, SPINK5) and rebalanced systemic immunity by suppressing Th2 cytokines (IL-4, IL-13) while promoting regulatory T cell (Treg) populations and IL-10 production. Crucially, BC exerted profound effects on the gut-skin axis by enhancing intestinal mucosal immunity, as evidenced by increased secretory immunoglobulin A (sIgA) and pIgR expression. 16S rRNA sequencing revealed that BC restored gut microbial diversity, enriched beneficial butyrate-producing genera (e.g., Lachnospiraceae NK4A136 group, Ruminiclostridium_9), and significantly elevated colonic butyrate levels. Correlation analysis identified butyrate as a key correlated mediator, linking gut microbiota remodeling to Treg expansion and Th2 inhibition. Our findings suggest that BC alleviates AD and is associated with a coordinated remodeling of the gut microbiota, increased butyrate production, and enhanced immune regulation, supporting its potential as a candidate dietary strategy for early-life atopic prevention.

Atopic dermatitis (AD) is a prevalent early childhood inflammatory skin disease frequently linked to gut dysbiosis. While Bifidobacterium longum subsp. infantis is a pioneer infant gut colonizer driving immune maturation, its role in AD prevention remains unclear. Here, we investigated early life intervention with B. longum subsp. infantis CCFM1269 using a 2,4-dinitrofluorobenzene (DNFB)-induced murine AD model. Oral administration of CCFM1269 significantly ameliorated AD symptoms, reducing skin/ear thickness, dermatitis scores, and serum IgE. Mechanistically, CCFM1269 modulated the systemic Th1/Th2 balance by downregulating TSLP, IL-4, and IL-13, while upregulating IFN-γ. Notably, CCFM1269 produced indole-3-lactic acid (ILA). Via the gut-skin axis, ILA activated the aryl hydrocarbon receptor (AHR) and its target CYP1A1 in skin tissues, strengthening the epidermal barrier. Additionally, AD mitigation was associated with gut microbiota reshaping. Ultimately, CCFM1269 alleviates AD primarily through the ILA- AHR signaling pathway, highlighting its potential as a functional food ingredient for early life AD prevention.

IntroductionNon-Western diets are increasingly studied for their relationship to gut microbiota composition and diversity, although most research in this area has focused on plant-based, fiber-rich diets. Here, we present a single-participant longitudinal study investigating gut microbiota dynamics during a transition from a Western diet to a 12-week Indigenous Arctic animal-based diet composed of minimally processed raw, dried, and fermented animal-source foods. During one month of this period, the participant consumed dried whole fish (ammassak), including intestinal contents, representing a form of gastrophagy, a practice common to the Arctic diet, that may increase exposure to food-associated microbes.MethodsFecal samples (n = 29) were collected before, during, and after the Arctic diet phase. 16S rRNA gene sequencing of the V3-V4 region was used to profile bacterial communities. Diversity metrics, Firmicutes/Bacteroidota (F/B) ratios, and taxonomic composition analyses were performed to assess compositional shifts across diet phases.ResultsAlpha diversity remained relatively steady throughout the study, with a tendency toward higher values during the Arctic diet. The F/B ratio increased from 1.31 to 2.12 during the Arctic diet phase and remained elevated (2.38) after returning to a Western diet. Beta diversity analysis revealed significant restructuring of the gut microbiota at the onset of the Arctic diet, followed by partial reversibility upon returning to a Western diet. Fiber-associated taxa like Prevotella 9 disappeared, and Bifidobacterium declined, while protein- and fat-associated taxa, including Bacteroides, Lachnoclostridium, and Alistipes, increased. Several genera appeared during the Arctic diet phase that were absent during the preceding Western diet phase, consistent with altered microbial exposure. Among those, Photobacterium was also detected in the ammassak, suggesting potential microbial exposure during the gastrophagy period.DiscussionThese results provide preliminary evidence that the gut microbiota can shift substantially during an Indigenous Arctic dietary transition. Because the Arctic diet also substantially overlapped with sustained high physical activity, the observed changes should be interpreted in the context of a combined dietary and lifestyle transition. These findings highlight the need for a better understanding of underrepresented dietary patterns, such as those of Arctic Indigenous communities, and their relationship with the gut microbiota.

While human milk oligosaccharides (HMOs) show promise in alleviating allergic diseases, the specific efficacy of individual structures remains unclear. This study aimed to systematically evaluate and compare the structure-specific effects of four representative HMOs-including the sialylated structures 6'-sialyllactose (6'-SL) and 3'-sialyllactose (3'-SL), and the neutral structures lacto-N-neotetraose (LNnT) and lacto-N-tetraose (LNT)-on ovalbumin (OVA)-induced food allergy. Using an OVA-sensitized mouse model, mice were supplemented with the respective HMOs, and their allergic responses were assessed through symptom scoring and serum levels of OVA-sIgE, mMCP-1, and cytokines (IFN-γ, IL-4). Intestinal barrier integrity was evaluated via tight junction protein expression, and immunomodulation was analyzed using flow cytometry for regulatory T cells (Tregs). Gut microbiota composition and short-chain fatty acid (SCFA) profiles were determined using 16S rRNA sequencing and GC-MS, respectively. At an equivalent dose, only 6'-SL significantly attenuated allergic symptoms. It uniquely reduced OVA-sIgE, mMCP-1, and IL-4 levels, suppressed the expression of other key Th2 cytokines (IL-5, IL-13), while increasing IFN-γ, enhanced intestinal barrier function by upregulating Occludin and ZO-1, and promoted Treg expansion. Although all HMOs modestly modulated the gut microbiota, only 6'-SL induced significant and beneficial shifts, specifically increasing the abundance of Faecalibaculum and Candidatus Saccharimonas, and significantly elevating the concentrations of acetate, butyrate, and valerate. 6'-SL exerts a unique protective effect against food allergy through integrated immunoregulatory and microbial mechanisms, notably by enhancing Treg activity and enriching SCFA-producing bacteria. These findings highlight the structure-dependent functionality of HMOs and position 6'-SL as a promising candidate for targeted dietary interventions against food allergy.

The infant gut microbiota, orchestrated by human milk oligosaccharides (HMOs), forms a critical foundation for lifelong health. Despite their recognized importance, the molecular strategies through which HMOs govern microbial competition and niche establishment remain poorly understood. Moving beyond ecological observations, this review synthesizes current mechanistic evidence on the molecular machinery of HMO metabolism in microbial assembly. We explore the specialized enzymes that confer competitive advantages and the metabolic networks fueled by HMO breakdown. Furthermore, we distinguish substrate-driven effects from the hypothesized signaling roles of intact HMOs in modulating host-microbe interactions, indicating where the evidence is associative versus causal. By integrating these pathways, we provide a blueprint for leveraging HMO biology to develop targeted nutritional interventions for preventing early-life disorders.

Atopic dermatitis (AD), a prevalent allergic skin disease characterized by a Th2-dominant inflammatory response, imposes a significant global health burden. Early-life serves as a pivotal period for intestinal microbial establishment, which critically influences immune system development and has lasting implications for health into later life. This study evaluated the therapeutic potential of early-life intervention with Bifidobacterium breve CCFM1078 on DNFB-induced atopic dermatitis in a murine model. Intervention with B. breve CCFM1078 significantly alleviated AD manifestations, such as ear swelling and epidermal hyperplasia. These improvements were associated with diminished inflammatory cell infiltration, lowered serum IgE levels, and reduced expression of key pro-inflammatory cytokines (IL-4, IL-13, CCL-22) in skin tissues, alongside elevated levels of IFN-γ and the anti-inflammatory cytokine IL-10. Additionally, the intervention boosted both IgA and secretory IgA (sIgA) levels in the colon. Mechanistically, B. breve CCFM1078 activated the aryl hydrocarbon receptor (AhR) signaling pathway, leading to the upregulation of CYP1A1, Gal-1, and Gal-3, and suppressed TSLP production. It also favorably altered gut microbiota composition by enriching beneficial bacterial taxa. In summary, early-life administration of B. breve CCFM1078 alleviates AD symptoms through concurrent modulation of the AhR pathway, restoration of Th1/Th2 immune balance, and beneficial restructuring of gut microbiota.

Abstract Bifidobacterium breve is recognized as an important member of the dominant gut microbiota early in life, playing a crucial role in intestinal immunity. Although B. breve can bioconvert linoleic acid (LA) into conjugated linoleic acid (CLA) to exert immunomodulatory effects, its region-specific immune functions and precise roles in shaping gut microbial composition remain elusive. Our study aimed to evaluate the immunomodulatory effects and microbiota-modulating properties of CLA-producing B. breve strains in lipopolysaccharide (LPS)-induced inflammation model using rat pups. LPS stimulation significantly alters the relative transcriptional levels of inflammatory cytokines in intestinal tissues. Interventions with different B. breve strains demonstrated efficacy in alleviating LPS-induced intestinal inflammation, with B. breve CCFM683 exhibiting particularly broad-spectrum immunomodulatory capacity and comprehensive therapeutic effects. B. breve CCFM683 modulates gut immunity in rat pups via increasing interleukin-10 (IL-10) level and reducing interleukin-1β (IL-1β), interleukin-6 (IL-6), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) mRNA expression. Furthermore, B. breve CCFM683 administration significantly altered the CLA level in the cecum and colon. Moreover, strain CCFM683 treatment can help restore gut homeostasis and promote beneficial alterations in gut microbiota composition by increasing the abundance of Ligilactobacillus. These results indicated that CLA-producing B. breve can alleviate LPS-induced inflammation, with B. breve CCFM683 had great functionality in regulating the intestinal immune responses.

Obesity is associated with profound immune dysregulation, driving chronic inflammation while compromising host defense against tumors. While trained immunity can enhance innate effector functions, it has thus far required parenteral administration of microbial ligands. Here, we show that incorporating a yeast-derived β-glucan supplement in mouse diets induces trained immunity via reprogramming of hematopoietic stem and progenitor cells. This dietary intervention leads to sustained production of metabolically enhanced monocytes and macrophages that rescue anti-tumor immunity in high-fat diet-induced obese mice, and corrects immune dysfunction sustained after weight loss. Our work reveals that yeast β-glucans act as functional "immuno-nutrients," which remodel innate immunity and identifies the mucosal/bone-marrow axis as a target for dietary manipulations to restore immune resilience without impacting metabolism.

Identification of reliable biomarkers in Hepato-pancreatico-biliary (HPBC) and gastric cancers (GC) has been extremely challenging, and no effective screening modality is currently available. There is an increasing appreciation that the gut microbiome may be altered in these diseases and act as a predictor of disease or disease outcome. To examine the gut microbiota in a cohort of treatment naïve, newly diagnosed pancreatic, biliary and gastric cancer patients and age matched controls. Stool samples from 37 treatment naïve, newly diagnosed HPBC and GC patients and 47 age-matched non-cancer controls were prospectively collected. Microbiota composition was determined by 16 S rRNA amplicon sequencing. Differences in the microbial composition of HC and HPBC patients were assessed using linear discriminant analysis effect size. Predictive functional profiling of microbial communities was obtained with PICRUSt. The gut microbiota of HPBC patients was significantly different compared to the non-cancer controls. Enterococcus, Enterobacter, Streptococcus and Lactobacillus, were significantly increased in HPBC, while numerous Lachnospiraceae, Ruminococcaceae_UCG014, Bacteroides and Faecalibacterium were significantly reduced in HPBC. Enterobacter and Enterococcus best discriminated the HPBC samples, while Butyrivibrio and Lachnospira best discriminated the non-cancer controls. There was a trend towards decreased diversity and richness in cancer patients with increasing severity of cancer stage. We report a significant difference in microbial composition in patients with pancreatic and biliary cancer compared to non-cancer controls, which is associated with an increase in pathogens and a decrease in potential beneficial bacteria. Our results support the potential for the gut microbiota to act as an early biomarker for these highly fatal and poorly diagnosed gastrointestinal cancers.

The early-life gut microbiome is tightly linked to different aspects of infant development. Microbial colonisation patterns have been repeatedly shown to play a role in a variety of paediatric outcomes, ranging from metabolism and immune function to neurodevelopment. Concomitantly, the identification of early-life biomarkers is crucial, especially considering that for various conditions, reliable diagnostic tools only emerge in early childhood. As such, microbiome data collected in the first two years of life may offer valuable prospects for early detection, prevention, quantification or even correction of adverse health trajectories. With the increasing availability of high-resolution microbiome data, researchers are leveraging both traditional statistical approaches and machine learning (ML) methods to analyse the evolution of these complex microbial communities. While statistical models are well-suited for identifying associations between microbiome features and health states, ML methods allow for predicting health outcomes from those features. This review explores the role of the early-life gut microbiome in infant health and development, with a focus on how data acquisition and analytical methods can shape current knowledge. We contrast statistical approaches with ML methods, summarising key findings on microbial succession and factors influencing it. By addressing current challenges and identifying areas for methodological refinement, we aim to discuss the potential of the microbiome in the assessment of current and future health states of an individual and aid in the development of more robust, clinically-relevant models for paediatric care.

Bacillus species are important in food biopreservation due to their bioactive metabolites-bacteriocins and lipopeptides-which hold great potential to combat foodborne pathogens like Listeria monocytogenes. These metabolites are promising candidates to replace conventional chemicals. This study focused on Bacillus pumilus APC 4184, isolated from apricot sticks, to identify and characterize its key antimicrobial metabolites. APC 4184 was screened against a range of foodborne pathogens and spoilage bacteria. The anti-Listeria metabolite was further analyzed using production kinetics, genome mining, MALDI-TOF mass spectrometry, and heterologous expression in Lactococcus lactis. Pumilacidins, a group of lipopeptides, were characterized by genome mining, partial purification, and antibacterial assessment. Results showed that APC 4184 exhibits a broad inhibitory spectrum, mainly against gram-positive bacteria. The novel circular bacteriocin pumilarin X (7045 Da) was produced during early growth phase and identified as the anti-Listeria metabolite. Genome analysis revealed the biosynthetic gene clusters of pumilarin X and pumilacidins (molecular masses of 1058, 1072, 1086, and 1100 Da). Purified pumilacidins exhibited specific activity against L. lactis HP but were inactive against Listeria and Staphylococcus. Our study offers valuable insights into the target specificity of Bacillus pumilus metabolites. We identify the traits of pumilarin X and pumilacidins as narrow-spectrum agents. These discoveries allow for the selective extraction of key metabolites from complex mixtures, supporting precise applications of bioactive agents in food systems.

Rheumatoid arthritis (RA) is an autoimmune disease with hallmark features of chronic synovial inflammation and progressive joint destruction, in which gut microbiota dysbiosis plays a significant pathogenic role. This study investigated the therapeutic potential of Lactobacillus helveticus CCFM1440 against RA. In rats with collagen-induced arthritis (CIA), administration of this strain alleviated joint swelling and pathological damage, while suppressing synovial hyperplasia and inflammatory infiltration. Mechanistically, treatment reduced serum levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-17A) and elevated the anti-inflammatory cytokine IL-10. It also downregulated matrix metalloproteinase expression (MMP-2, MMP-3, MMP-9) and modulated the RANKL/OPG balance by upregulating OPG and downregulating RANKL, thereby inhibiting osteoclast activity. Furthermore, CCFM1440 partially restored gut microbiota homeostasis, with a concomitant increase in beneficial genera like Lachnoclostridium, and enhanced the production of certain short-chain fatty acids. Collectively, these findings provide experimental support toward the development of L. helveticus CCFM1440 into a probiotic adjunct for RA, identifying its clinical evaluation as a necessary next step.

Food quality deterioration due to microbial contamination and consequent spoilage represents a major challenge for the food industry. This growing concern creates the need for sustainable, effective, and consumer-safe solutions. The increasing consumer awareness of the potential risks for human health of synthetic preservatives forces the demand for the use of natural alternatives. One promising solution involves the administration of natural biopreservatives, including microorganisms with Qualified Presumption of Safety (QPS) or Generally Recognized as Safe (GRAS) status, as well as antimicrobial compounds derived from such microbes. This review highlights the application of QPS- and GRAS-status microbial strains and/or the antimicrobials they produce in several food categories, such as dairy, meat, fish, fruits, vegetables, and baked products, as natural bioprotective cultures/peptides against spoilage and pathogenic microorganisms. Considering the increasing threat generated by foodborne pathogens carrying antibiotic resistance genes, we also explore the targeted use of antimicrobials, particularly bacteriocins, to selectively inhibit these harmful microbes in food products. Furthermore, we examine strategies to enhance the antimicrobial effectiveness of bacteriocins against Gram-negative and Gram-positive bacteria, using a combination of bacteriocins with membrane-permeabilizing agents like ethylenediaminetetraacetic acid (EDTA), high hydrostatic pressure (HHP), organic acids, essential oils, and chitosan-based coatings. Overall, this review aims to uncover the potential of replacing synthetic preservatives with natural, consumer-friendly safe cultures as preservatives and clean-label antimicrobials, offering a promising solution on reducing global food waste.

An unhealthy diet disrupts feeding behavior and the gut microbiota, but whether early-life dietary effects persist, or can be restored later in life, remains unclear. We investigated whether microbiota-targeted interventions (FOS + GOS or Bifidobacterium longum APC1472) could restore early-life high-fat/high-sugar (HFHS) diet-induced feeding alterations in adult female and male mice. HFHS exposure exclusively in early-life induced persistent, sex-specific feeding alterations in adult mice, despite normalized body weight. Early-life HFHS diet reduced hypothalamic cells expressing feeding-related markers (POMC, GHSR, PNOC, NOD2) in adult mice. Females were more vulnerable, with reduced LEPR+ cells and disrupted arginine/tryptophan metabolism, while males showed impaired peptidoglycan sensing and steroid metabolism. We show that microbiota interventions restore these effects via distinct mechanisms. FOS + GOS induced extensive microbiome compositional shifts and sex-specific restoration of gut-brain pathways, while B. longum APC1472 induced greater behavioral restoration with minimal microbiome compositional changes. These findings highlight sex-specific vulnerabilities and mechanism-dependent therapeutic potential of microbiota-based interventions after exposure to early-life unhealthy diets.

Bifidobacterium has been shown to regulate bone metabolism and maintain bone homeostasis. This study investigated the effects of Bifidobacterium longum subsp. infantis on bone growth in juvenile mice. Treatment with B. longum subsp. infantis CCFM1445 increased femur length, bone volume fraction, and cortical bone area in both female and male mice. Bone histomorphometry indicated that CCFM1445 elevated the height of the femoral growth plate, increased osteoblast numbers, and decreased osteoclast numbers. Furthermore, B. longum subsp. infantis CCFM1445 raised serum concentrations of bone formation markers, including osteoprotegerin (OPG), procollagen type I N-terminal propeptide (PINP), and bone alkaline phosphatase (BALP). Concurrently, it suppressed the levels of tartrate-resistant acid phosphatase type 5b (TRACP5b) and cross-linked N-telopeptide of type I collagen (NTX). Additionally, CCFM1445 upregulated the transcriptional network of key genes involved in osteogenesis and bone matrix synthesis. And intervention with CCFM1445 also significantly increased the relative abundance of Bifidobacterium, Alistipes, and [Eubacterium] xylanophilum group in the gut microbiota. Targeted metabolomic analysis showed that CCFM1445 modulated the arginine biosynthesis and metabolic pathway, characterized by decreased citrulline and increased levels of arginine and its downstream metabolites. Together, these results demonstrate that B. longum subsp. infantis CCFM1445 enhances bone formation, suppresses bone resorption, modulates gut microbiota composition, and influences arginine metabolism, thereby promoting longitudinal bone growth and increasing bone mass in growing mice.

Fungal contamination of food with yeast and molds is associated with major economic losses due to spoilage and also poses health risks in the form of mycotoxin production. The strain Pantoea agglomerans APC 4211 isolated from leaves of Ilex aquifolium (holly tree) has broad spectrum antifungal activity against a variety of food spoilage fungi. Genomic analysis of the strain confirmed the presence of biosynthetic gene clusters potentially encoding for the enzymatic machinery required for the production of the antifungal lipopeptide herbicolin A. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of the cell-free supernatant (CFS) confirmed the presence of molecular masses corresponding to herbicolin A (1300.8 Da), and herbicolin B (1138 Da). Purified herbicolin A has desirable properties for biotechnological applications, including potent antifungal activity against a range of spoilage fungi, thermal stability and resistance to proteases. The lipopeptide has low cytotoxicity against epithelial cell lines and has minimum inhibitory concentrations (MICs) lower than those of some commercial antifungal drugs (0.2-2.5 mg/L). In a model dairy system (10% skim milk), herbicolin A demonstrated excellent solubility and stability, effectively eliminating Aspergillus niger and Penicillium notatum at a concentration of 5 mg/L. Overall, the study determines herbicolin's A spectrum against food spoilage organisms and examines potential applications in food. In conclusion, herbicolin A is a potent, naturally occurring antifungal agent with the potential to be applied as a biopreservative in food systems, providing a safe, clean-label, and efficient compound for synthetic preservatives replacement.

The immunomodulatory properties of Bifidobacterium breve have garnered increasing interest. However, its dose-response relationship in alleviating immunosuppression remains incompletely understood. This study evaluated the alleviative effects of Bifidobacterium breve CCFM1310 on cyclophosphamide (CTX)-induced immunocompromised mice and elucidated its dose-response characteristics. Following prior strain screening, immunocompromised mice were administered daily doses of CCFM1310 ranging from 106 to 1010 CFU. The results revealed a clear threshold effect, with significant amelioration of immunosuppression observed at 109 and 1010 CFU/day for most endpoints. However, immunoglobulin responses were endpoint-specific: IgG increased only at 109 CFU/day, whereas IgA and IgM responded across a broader dose range. In contrast, doses of 106-108 CFU/day showed no restorative activity on most immune parameters. This improvement was reflected in the normalization of body weight, enhanced thymus and spleen indices, restored white blood cell and neutrophil counts, elevated serum immunoglobulin (IgA, IgM) levels, and improved hepatic antioxidant status (increased SOD and T-AOC, reduced MDA), but with no effect on CAT activity. Qualitative histological examination suggested that doses of 109 and 1010 CFU/day were associated with reduced morphological damage in splenic and intestinal tissues, promoted goblet cells proliferation, and increased intestinal secretory immunoglobulin A (sIgA) secretion. Mechanistically, 109 and 1010 CFU/day treatment reinforced the intestinal tight junction barrier by selectively upregulating tight junction protein expression, selectively modulated gut microbiota composition by enriching certain beneficial bacteria, and was associated with increased phosphorylation of MAPK pathway proteins (p38, JNK, ERK). In conclusion, Bifidobacterium breve CCFM1310 at doses of 109 CFU per day or higher effectively alleviates immunosuppression. This study provided essential preclinical dose-effect evidence to inform the potential application of this strain.

While the interplay between gestational diabetes mellitus (GDM) and the maternal-infant microbial axis is increasingly recognized, the specific pathways of influence remain unclear. This study comprehensively investigated the impact of GDM on the breast milk microbiota, human milk oligosaccharides (HMOs), and the subsequent development of the infant gut microbiota. We analyzed breast milk and paired infant fecal samples collected from healthy and GDM-affected mothers at two time points (0-7 and 42 days postpartum). The microbiota of both sample types was profiled by metagenomic sequencing, and HMOs in breast milk were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our findings revealed that GDM had a strong influence on the infant gut microbiota via reducing HMO concentrations than via direct alterations to the breast milk microbiota. These GDM-associated HMO alterations induced stage-specific shifts in the offspring's gut microbiota. Notably, the correlation between specific HMOs and gut bacteria reversed from the colostrum stage to the mature milk stage. This suggests that HMOs influence microbial colonization not only through direct utilization but also, and perhaps more importantly, via indirect ecological mechanisms such as cross-feeding. Collectively, our results identify maternal HMOs as a critical link between maternal metabolism and infant gut health, highlighting their potential as a promising nutritional target to improve long-term metabolic outcomes in GDM-exposed infants.

The neonatal development period from the time of birth can be considered the period of greatest physiological changes throughout the human lifespan. These changes are partly due to dietary or environmental factors and are also modulated by genetic, neuronal, and humoral influences. The focus of research is increasingly on the microbial colonization of the neonatal intestine, since the establishment of a healthy, symbiotic newborn microbiota not only corresponds closely with nutrient metabolism, immune functions, and growth, but also with the brain as part of the so-called "gut-brain axis". At the same time, a critical time window of opportunity opens up for the early infant microbiota, which is accessible to modulating approaches in favor of normal infant development. Although the definition of "normal" microbiota in infants still remains challenging, the microbiota of infants delivered at term can be discussed as the gold standard-provided they were exclusively breastfed and have not been exposed to antibiotics. Advances in sequencing technologies now also allow us to identify and characterize the microbiota at the strain level and to provide the scientific rationale for new approaches to modulate the early-life microbiome in a more targeted and personalized way-applicable also for formula-fed children who cannot be supplied with human milk. This review addresses the challenges associated with the "healthy" development of a newborn during the first weeks and months of life and discusses potentially modifiable external factors in light of the requirements for the establishment of a functional gut microbiota, gastrointestinal system, and gut-brain axis.

Alterations in the gut microbiome are associated with neurodevelopmental disorders, but causal mechanisms and therapeutic strategies remain undefined. Here, we demonstrate that human infant microbiomes isolated during the first six months of life drive behavioral impairments in mice and that microbiota-based interventions restore mice to normal behavior. Early-life microbiomes from twelve infants who later exhibited cognitive deficits at 2 years old (low-scoring) transferred adverse metabolic, brain, and behavioral phenotypes to mice, in contrast to microbiomes from twenty-three cognitively typical or high-scoring infants. Deficits in mice were rescued by fecal microbiota transplant from high-scoring infants or a rationally designed consortium that promoted amino acid levels. We confirmed lower fecal amino acid concentrations in low-scoring infants and replicated the association between early-life microbiome composition and cognitive outcomes in a second geographically independent infant cohort. Altogether, we discovered an early-life microbiome-mediated metabolic state causally linked to cognitive deficits and amenable to microbial intervention.