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<p><i>Lactobacillus helveticus</i> LH76 is a candidate strain with potential probiotic properties, but its safety and functional effects have not been comprehensively characterized. In this study, we systematically evaluated the safety profile and potential immunomodulatory and gut microbiota-modulating effects of LH76 through integrated genomic, preclinical, and clinical approaches. Preclinical safety assessment included whole-genome sequencing and bioinformatics analyses (AMRFinder, CARD, ResFinder, VFDB, and PathogenFinder), in vitro assays of hemolysis, biogenic amine production, and cytotoxicity in Caco-2 cells, as well as a 14-day acute oral toxicity study in mice. An 8-week randomized, double-blind, placebo-controlled trial was subsequently conducted in healthy adults to assess safety, immune-related biomarkers (IgA, IgM, IgG, C3, C4, LL-37, and calprotectin), and gut microbiota composition by 16&#xa0;S rRNA sequencing. LH76 showed no detectable antibiotic resistance or classical virulence genes, no hemolytic activity, negligible biogenic amine production, and no detectable cytotoxicity in vitro, while no adverse effects or pathological abnormalities were observed in vivo. In the clinical trial, LH76 was well tolerated and was not associated with adverse changes in hematological, biochemical, or metabolic parameters. Compared with placebo, LH76 supplementation was associated with increased serum IgM and C3 levels, decreased C4 and LL-37 levels, increased microbial richness, and relative enrichment of genera including <i>Blautia</i> and <i>Bifidobacterium</i>. PICRUSt2-based analysis further suggested shifts in predicted microbial metabolic pathways, although these findings remain inferential. Overall, LH76 demonstrated a favorable safety profile, was well tolerated in healthy adults at the administered daily dose of 3 × 10¹⁰ CFU/day for 8 weeks and showed an acute oral LD<sub>50</sub> exceeding 2 × 10¹⁰ CFU/kg in mice. These findings support further investigation of LH76 in larger and more mechanistic studies.</p>

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Immunomodulatory and Gut Microbiota-Regulating Effects of Lactobacillus helveticus LH76 in Healthy Adults: Preclinical Safety Assessment and a Randomized, Double-Blind, Placebo-Controlled Trial

  • 期刊论文

  • 发表日期：

    2026年6月22日

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  • Shuai Song,
  • Limin Ding,
  • Taisong Yang,
  • Jiamin Liu,
  • Zhe Wang,
  • Yunkun Qin,
  • Xiangyi Tan,
  • Fei Xu,
  • Tingying Liang

摘要

Lactobacillus helveticus LH76 is a candidate strain with potential probiotic properties, but its safety and functional effects have not been comprehensively characterized. In this study, we systematically evaluated the safety profile and potential immunomodulatory and gut microbiota-modulating effects of LH76 through integrated genomic, preclinical, and clinical approaches. Preclinical safety assessment included whole-genome sequencing and bioinformatics analyses (AMRFinder, CARD, ResFinder, VFDB, and PathogenFinder), in vitro assays of hemolysis, biogenic amine production, and cytotoxicity in Caco-2 cells, as well as a 14-day acute oral toxicity study in mice. An 8-week randomized, double-blind, placebo-controlled trial was subsequently conducted in healthy adults to assess safety, immune-related biomarkers (IgA, IgM, IgG, C3, C4, LL-37, and calprotectin), and gut microbiota composition by 16 S rRNA sequencing. LH76 showed no detectable antibiotic resistance or classical virulence genes, no hemolytic activity, negligible biogenic amine production, and no detectable cytotoxicity in vitro, while no adverse effects or pathological abnormalities were observed in vivo. In the clinical trial, LH76 was well tolerated and was not associated with adverse changes in hematological, biochemical, or metabolic parameters. Compared with placebo, LH76 supplementation was associated with increased serum IgM and C3 levels, decreased C4 and LL-37 levels, increased microbial richness, and relative enrichment of genera including Blautia and Bifidobacterium. PICRUSt2-based analysis further suggested shifts in predicted microbial metabolic pathways, although these findings remain inferential. Overall, LH76 demonstrated a favorable safety profile, was well tolerated in healthy adults at the administered daily dose of 3 × 10¹⁰ CFU/day for 8 weeks and showed an acute oral LD50 exceeding 2 × 10¹⁰ CFU/kg in mice. These findings support further investigation of LH76 in larger and more mechanistic studies.