Ethanol extract of Astragali Radix inhibits M1 macrophage polarization to alleviate ulcerative colitis by promoting Lactobacillus reuteri-produced indole-3-carboxaldehyde and formononetin

TL;DR

Astragali Radix extract helps treat ulcerative colitis by boosting Lactobacillus reuteri, which produces compounds that reduce inflammation.

Contribution

The study reveals a novel mechanism where Astragali Radix extract alleviates UC by promoting Lactobacillus reuteri and its metabolites that inhibit M1 macrophage polarization.

Findings

AR ethanol extract reduces mucosal injury and proinflammatory cytokines in UC mice.

Lactobacillus reuteri growth is stimulated by AR extract, leading to increased indole-3-carboxaldehyde and formononetin.

Indole-3-carboxaldehyde and formononetin inhibit M1 macrophage polarization via distinct pathways.

Abstract

Astragali Radix (AR) is a traditional Chinese medicine used to treat ulcerative colitis (UC). However, the effectiveness of its ethanol extract in relieving UC and its mechanisms involved are not well comprehended. This study aimed to evaluate the therapeutic efficacy of AR ethanol extract on UC and explore the underlying mechanisms, focusing on its regulation of the intestinal microecology.

A UC model in mice was induced with 2.5% dextran sulfate sodium and then treated with AR ethanol extract, L. reuteri, or microbial metabolites indole-3-carboxaldehyde (IAId) and formononetin (FMN). Changes in tissue damage and inflammation were evaluated. Adjustments in gut microbiota were identified using 16S rRNA sequencing analysis. Changes in the fecal metabonomics were analyzed. Levels of polarized M1 macrophages in colon tissues was detected using immunofluorescence staining. The mRNA levels of proinflammatory cytokines in RAW264.7 cells was quantified by RT-PCR. The binding affinity between FMN and PGK1 (IAId and AHR) was assessed using surface plasmon resonance analysis.

AR ethanol extract relieved mucosal injury and decreased levels of proinflammatory cytokines in the colon. AR extract modulated the structure and composition of intestinal flora, specifically, it significantly increased the L. reuteri level, which facilitated the production of IAId and FMN. Moreover, Ononin was the key ingredient from AR to induce the L. reuteri growth. IAId and FMN could relieve UC symptoms, thereby improving the overall efficacy of AR extract on UC. Furthermore, IAId and FMN could inhibit M1 macrophages polarization, resulting in a reduction in TNF-α, IL-6, and IL-1β levels. IAId inhibited M1 macrophages polarization by AHR/NF-κB pathway, and FMN suppressed M1 macrophages via PGK1/NLRP3/NF-κB pathway, which exerts the synergistic effect on inflammatory responses.

AR ethanol extract can alleviate UC by inhibiting M1 macrophages activities via promoting L. reuteri-produced IAId and FMN.

The ethanol extract of Astragali Radix (AR) demonstrates therapeutic effects on ulcerative colitis (UC) in mice, primarily by promoting the proliferation of the gut bacterium Lactobacillus reuteri and inhibiting the polarization of M1 macrophages. 2.AR ethanol extract-induced increase in L. reuteri is essential for the production of indole-3-carboxaldehyde and formononetin, which consequently mitigates the inflammation of UC.3.Both indole-3-carboxaldehyde and formononetin inhibit the pro-inflammatory activities of M1 macrophages by modulating the PGK1/NLRP3/NF-κB and AHR/NF-κB pathways, respectively, thereby enhancing the overall therapeutic efficacy of against UC.

The ethanol extract of Astragali Radix (AR) demonstrates therapeutic effects on ulcerative colitis (UC) in mice, primarily by promoting the proliferation of the gut bacterium Lactobacillus reuteri and inhibiting the polarization of M1 macrophages.

AR ethanol extract-induced increase in L. reuteri is essential for the production of indole-3-carboxaldehyde and formononetin, which consequently mitigates the inflammation of UC.

Both indole-3-carboxaldehyde and formononetin inhibit the pro-inflammatory activities of M1 macrophages by modulating the PGK1/NLRP3/NF-κB and AHR/NF-κB pathways, respectively, thereby enhancing the overall therapeutic efficacy of against UC.

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