Synergistic Modulation of the Gut–Brain–Immune Axis by a Dual Lactobacillus Combination in a Murine IBS Model
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The gut microbiota is a key regulator of immune and neuroendocrine pathways along the gut–brain axis. Disruption of this bidirectional communication contributes to irritable bowel syndrome (IBS), a multifactorial disorder associated with gastrointestinal dysfunction and psychiatric comorbidities. Although microbiota-targeted therapies are promising, most current studies rely on single-strain interventions with limited efficacy, and the bioactive components as well as their host-mediated mechanisms remain insufficiently characterized. Here, we demonstrate that oral co-administration of Lactobacillus paracasei KBL382 and Lactobacillus plantarum KBL396 synergistically ameliorates IBS-like symptoms in a zymosan-induced mouse model. The combination therapy outperformed individual strains in reducing colonic shortening, abnormal cecal morphology, mucosal inflammation, and anxiety-like behaviors. These effects were accompanied by bidirectional neurobiological changes, including downregulation of colonic brain derived neurotrophic factor (BDNF) and serotonin 3A (5- HT3A), and restoration of hippocampal serotonergic signaling. Immunologically, the treatment decreased pro-inflammatory M1 macrophages and inflammatory dendritic cells (DCs), while increasing tolerogenic DCs and regulatory T cells in mesenteric lymph nodes. Furthermore, >100 kDa macromolecular fractions isolated from both strains enhanced the IL-10/IL-6 ratio and serotonin transporter (SERT) expression in vitro. These effects were abolished by protease or mutanolysin treatment, implicating structurally integrated peptidoglycan–protein complexes as key immunoregulatory and neuroactive components. The complexes engaged MyD88-dependent signaling pathways, promoting regulatory immune phenotypes. Importantly, therapeutic effects were preserved in microbiota-depleted mice, demonstrating a microbiota-independent, host-targeted mechanism. These findings demonstrate that defined Lactobacillus strains synergistically modulate neuroimmune pathways via bioactive macromolecules, offering a host-directed strategy for managing the multifactorial symptoms of IBS.
Abstract
The gut microbiota is a key regulator of immune and neuroendocrine pathways along the gut–brain axis. Disruption of this bidirectional communication contributes to irritable bowel syndrome (IBS), a multifactorial disorder associated with gastrointestinal dysfunction and psychiatric comorbidities. Although microbiota-targeted therapies are promising, most current studies rely on single-strain interventions with limited efficacy, and the bioactive components as well as their host-mediated mechanisms remain insufficiently characterized. Here, we demonstrate that oral co-administration of Lactobacillus paracasei KBL382 and Lactobacillus plantarum KBL396 synergistically ameliorates IBS-like symptoms in a zymosan-induced mouse model. The combination therapy outperformed individual strains in reducing colonic shortening, abnormal cecal morphology, mucosal inflammation, and anxiety-like behaviors. These effects were accompanied by bidirectional neurobiological changes, including downregulation of colonic brain derived neurotrophic factor (BDNF) and serotonin 3A (5- HT3A), and restoration of hippocampal serotonergic signaling. Immunologically, the treatment decreased pro-inflammatory M1 macrophages and inflammatory dendritic cells (DCs), while increasing tolerogenic DCs and regulatory T cells in mesenteric lymph nodes. Furthermore, >100 kDa macromolecular fractions isolated from both strains enhanced the IL-10/IL-6 ratio and serotonin transporter (SERT) expression in vitro. These effects were abolished by protease or mutanolysin treatment, implicating structurally integrated peptidoglycan–protein complexes as key immunoregulatory and neuroactive components. The complexes engaged MyD88-dependent signaling pathways, promoting regulatory immune phenotypes. Importantly, therapeutic effects were preserved in microbiota-depleted mice, demonstrating a microbiota-independent, host-targeted mechanism. These findings demonstrate that defined Lactobacillus strains synergistically modulate neuroimmune pathways via bioactive macromolecules, offering a host-directed strategy for managing the multifactorial symptoms of IBS.