{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T05:17:46Z","timestamp":1787807866241,"version":"build-2784847793"},"reference-count":62,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100022963","name":"Key R&D Program of Zhejiang Province","doi-asserted-by":"crossref","award":["2024C02004"],"award-info":[{"award-number":["2024C02004"]}],"id":[{"id":"10.13039\/100022963","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Zhejiang Provincial San Nong Jiu Fang Project","award":["2025SNJF005"],"award-info":[{"award-number":["2025SNJF005"]}]},{"name":"Zhejiang Provincial Animal Husbandry Industry Technology Project"},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"crossref","award":["226-2025-00029"],"award-info":[{"award-number":["226-2025-00029"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"crossref","award":["226-2024-00239"],"award-info":[{"award-number":["226-2024-00239"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32472950"],"award-info":[{"award-number":["32472950"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32472950"],"award-info":[{"award-number":["32472950"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"China Agriculture Research System","award":["CARS-34"],"award-info":[{"award-number":["CARS-34"]}]},{"award":["CARS-34"],"award-info":[{"award-number":["CARS-34"]}],"id":[{"id":"https:\/\/ror.org\/03p5eky76","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Center of Technology Innovation for Pigs"},{"DOI":"10.13039\/100007421","name":"Li Ka Shing Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007421","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01g6g9h28","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>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\u2014a well-established translational model for human infant gut development\u2014were 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\u2014zonula occludens-1 (ZO-1), occludin (OCLN), and Claudin-1 (CLDN1)\u2014in the jejunum (p &lt; 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 &lt; 0.05). Microbiome analysis revealed enhanced microbial diversity and enrichment of beneficial genera during the juvenile-to-adult transition (p &lt; 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.<\/jats:p>","DOI":"10.3390\/nu18172776","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:27:19Z","timestamp":1787657239000},"page":"2776","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early-Life Compound Probiotic Intervention Programs Intestinal Barrier Maturation Through Indole-3-Lactic Acid in a Porcine Model"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1370-0864","authenticated-orcid":false,"given":"Mingzhi","family":"Yang","sequence":"first","affiliation":[{"name":"College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China"},{"name":"National Engineering Research Center of Green Feed and Healthy Breeding, Hangzhou 310058, China"},{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"He","sequence":"additional","affiliation":[{"name":"College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China"},{"name":"National Engineering Research Center of Green Feed and Healthy Breeding, Hangzhou 310058, China"},{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5596-8391","authenticated-orcid":false,"given":"Jie","family":"Fu","sequence":"additional","affiliation":[{"name":"College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China"},{"name":"National Engineering Research Center of Green Feed and Healthy Breeding, Hangzhou 310058, China"},{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixin","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China"},{"name":"National Engineering Research Center of Green Feed and Healthy Breeding, Hangzhou 310058, China"},{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Li","sequence":"additional","affiliation":[{"name":"College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China"},{"name":"National Engineering Research Center of Green Feed and Healthy Breeding, Hangzhou 310058, China"},{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixia","family":"Kai","sequence":"additional","affiliation":[{"name":"College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China"},{"name":"National Engineering Research Center of Green Feed and Healthy Breeding, Hangzhou 310058, China"},{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5445-4532","authenticated-orcid":false,"given":"Caihong","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou 310058, China"},{"name":"National Engineering Research Center of Green Feed and Healthy Breeding, Hangzhou 310058, China"},{"name":"Zhejiang Key Laboratory of Nutrition and Breeding for High-Quality Animal Products, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2690-429X","authenticated-orcid":false,"given":"Jie","family":"Feng","sequence":"additional","affiliation":[{"name":"College of Animal Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Key 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