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Untargeted metabolomic profiling of colonic contents

ABSTRACT:

Pre-IBD is a transitional state between irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), in which chronic high-fat diet intake and antibiotic exposure significantly increase intestinal inflammatory susceptibility. However, the underlying mechanisms and effective therapeutic strategies remain inadequately understood. Milk-derived extracellular vesicles (mEVs) have emerged as promising nanotherapeutic agents for alleviating gut disorders. In this study, we found that pre-IBD mice exhibited profound gut microbiota dysbiosis, and treatment with mEVs significantly alleviated intestinal inflammation by modulating MAPK-mediated M1/M2 macrophage polarization and restoring microbiota balance. Mechanistically, mEVs treatment led to a reduction in lysophosphatidylcholine (LPC) levels and an enrichment of Lactobacillus murinus (L. murinus), which exerted opposing effects on intestinal inflammation in both in vivo and in vitro models. Specifically, LPC exacerbated intestinal inflammation and structural alterations, whereas L. murinus treatment mitigated these pathological changes. Notably, both LPC and L. murinus interact with TLR2 but activate distinct downstream signaling pathways. LPC activates the TLR2/MAPK/NF-κB axis, promoting M1 polarization, whereas L. murinus binding to TLR2 induces M2 polarization. These findings demonstrate that mEVs reprogram the TLR2-mediated immune response by modulating the levels of L. murinus and LPC, thereby mitigating gut inflammation and contributing to the attenuation of pre-IBD pathology.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS14400 | MetaboLights | 2026-04-29

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14400_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS14400_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14400_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS14400_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Inflammation is the natural defensive response of the immune system to an injury or infection and is regulated by small molecule mediators triggering different phases of the inflammatory process. In particular, lipid mediators (LM) and cytokines exhibit crucial regulatory functions in the progression and resolution of inflammation. Macrophages play a central role in this process and can adopt distinct phenotypes with specialized functions depending on their microenvironment: inflammatory M1 macrophages drive inflammation by the release of pro-inflammatory cytokines and LMs, like prostaglandins (PG) and leukotrienes (LT), while resolving M2 macrophages promote inflammation resolution and tissue regeneration by production of anti-inflammatory cytokines and specialized pro resolving mediators (SPM). Aging is associated with chronic and unresolved, low-grade inflammation (“inflammaging”) and aging-related dysfunction of macrophages in the resolution of inflammation and tissue maintenance has been reported. Yet, the underlying molecular mechanisms and functional consequences of latter processes remain poorly understood. Here, we show that polarization of peritoneal macrophages (PM) from geriatric mice towards an M2-like phenotype is impaired versus adult mice, resulting in aberrant LM formation and cytokine release. In PMs isolated from adult mice (PM-A) we observed a shift in LM formation from PGs and LTs to SPMs already after 4 h of polarization towards M2 with interleukin (IL) 4. In contrast, PMs from geriatric mice (PM-G) produced mainly LTs and PGs upon polarization. This pattern persists over the course of 48 h of polarization. Proteomic profiling revealed that polarization of PM A towards M2 yields a more distinct phenotype, clearly separated from M1, when compared to PM-G. We observed similar aging-related changes in the lipidome and cytokine profile of spleen, lung and liver tissue from mice. Hence, we hypothesize that during aging macrophage polarization towards M2 is impaired, which in turn drives chronic inflammation and disturbs tissue maintenance. By combining state-of-the art lipidomic and proteomic profiling we aim to uncover new molecular targets for pharmaceutical interventions to improve therapeutic strategies for elderly patients with chronic inflammatory diseases.

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Untargeted metabolomic profiling of colonic contents

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