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Background/Objectives: Inflammatory bowel disease (IBD) is a persistent inflammatory condition affecting the gastrointestinal tract, distinguished by the impairment of the intestinal epithelial barrier, dysregulation of the gut microbiota, and abnormal immune responses. Cajanus cajan (L.) Millsp., traditionally used in Chinese herbal medicine for gastrointestinal issues such as bleeding and dysentery, has garnered attention for its potential therapeutic benefits. However, its effects on IBD remain largely unexplored. Methods: In this study, the major compounds from Cajanus cajan leaf extract (CCLE) were initially characterized by LCMS-IT-TOF. The IBD model was developed in C57BL/6 mice by administering continuous 4% (w/v) dextran sodium sulfate (DSS) aqueous solution over a period of seven days. The body weight, colon length, disease activity index (DAI), and histopathological examination using hematoxylin and eosin (H&E) staining were performed in the IBD model. The levels of the main inflammatory factors, specifically TNF-α, IL-1β, IL-6, and myeloperoxidase (MPO), were quantified by employing enzyme-linked immunosorbent assay (ELISA) kits. Additionally, the levels of tight junction proteins (ZO-1, Occludin) and oxidative stress enzymes (iNOS, SOD1, CAT) were investigated by qPCR. Subsequently, flow cytometry was employed to analyze the populations of various immune cells within the spleen, thereby assessing the impact of the CCLE on the systemic immune homeostasis of IBD mice. Finally, 16S rDNA sequencing was conducted to examine the composition and relative abundance of gut microbiota across different experimental groups. In addition, molecular docking analysis was performed to assess the interaction between the principal components of CCLE and the aryl hydrocarbon receptor (AHR). Results: We identified seven bioactive compounds in CCLE: catechin, cajachalcone, 2-hydroxy-4-methoxy-6-(2-phenylcinyl)-benzoic acid, longistylin A, longistylin C, pinostrobin, amorfrutin A, and cajaninstilbene acid. Our results demonstrated that oral administration of CCLE significantly alleviates gastrointestinal symptoms in DSS-induced IBD mice by modulating the balance of gut-derived pro- and anti-inflammatory cytokines. This modulation is associated with a functional correction in M1/M2 macrophage polarization and the Th17/Treg cell balance in splenic immune cells, as well as shifts in the populations of harmful bacteria (Erysipelatoclostridium and Staphylococcus) and beneficial bacteria (Odoribacter, unidentified Oscillospiraceae, Lachnoclostridium, and Oscillibacter) in the gut. Furthermore, cajaninstilbene acid, longistylin A, and longistylin C were identified as potential AhR agonists. Conclusions: The present results suggested that CCLE, comprising stilbenes like cajaninstilbene acid, longistylin A, and longistylin C, protects the epithelial barrier’s structure and function against DSS-induced acute IBD by restoring gut microbiota balance and systemic immune response as AhR agonists. Overall, CCLE represents a promising natural product-based therapeutic strategy for treating IBD by restoring gut microbiota balance and modulating systemic immune responses.

In bacterial-based cancer therapy, while attenuated Salmonella treatment effectively inhibits tumor progression, single bacterial therapy struggles to completely suppress tumor growth and metastasis. Metformin, a natural compound derived from Galega officinalis L. and known for its antidiabetic properties, also demonstrates significant anti-tumor activity. However, the combined effect of metformin and attenuated Salmonella on tumor treatment has not been thoroughly investigated. In this study, we observed that metformin enhances attenuated Salmonella-mediated recruitment of tumor-infiltrating immune cells, such as NK cells, neutrophils, M1 macrophages, CD4+, and CD8+T lymphocytes in CT26 tumor-bearing mice. Furthermore, the combined treatment of metformin and attenuated Salmonella increases the protein expression of PEN2, PD1, and PD-L1. This finding is likely associated with the enhanced anti-tumor effects of S.t ΔppGpp by metformin, indicating that the combination of S.t ΔppGpp and metformin holds promise as a synergistic strategy for attenuated Salmonella-based immunotherapy.

Bacteria-mediated cancer immunotherapy (BCI) suppresses tumor progression in two ways: the bacteria themselves kill tumor cells, and they elicit robust host immune responses. However, this does not eradicate tumors completely or prevent metastasis. Therefore, the immune responses elicited by BCI must be backed up by other therapies such as chemotherapy. Zingerone has anticancer activity and modulates T cell-mediated immune responses. Here, we examined the antitumor effects of zingerone/BCI combination therapy. We show that that zingerone 1) enhances St.ΔppGpp-mediated antitumor effects, but reduces survival of tumor-colonizing bacteria by promoting recruitment of tumor-infiltrating neutrophils; 2) amplifies St.ΔppGpp-mediated immune responses by stimulating tumor infiltration by macrophages, natural killer cells, and CD4+ and CD8+ T cells; and 3) enhances St.ΔppGpp-mediated macrophage phagocytosis, leading to tumor eradication. These findings suggest that the zingerone/St.ΔppGpp combination has synergistic antitumor effects, making it a promising approach to cancer immunotherapy.

Abstract Background Bacteria-mediated cancer immunotherapy (BCI) robustly stimulates the immune system and represses angiogenesis, but tumor recurrence and metastasis commonly occur after BCI. The natural product Ilex kudingcha C. J Tseng enriched with ursolic acid has anti-cancer activity and could potentially augment the therapeutic effects of BCI. The objective of the present study was to determine potential additive effects of these modalities. Methods We investigated the anti-cancer activity of KDCE (Kudingcha extract) combined with S.t△ppGpp in the mice colon cancer models. Results In the present study, KDCE combined with S.t△ppGpp BCI improved antitumor therapeutic efficacy compared to S.t△ppGpp or KDCE alone. KDCE did not prolong bacterial tumor-colonizing time, but enhanced the antiangiogenic effect of S.t△ppGpp by downregulatingVEGFR2. We speculated that KDCE-induced VEGFR2 downregulation is associated with FAK/MMP9/STAT3 axis but not AKT or ERK. Conclusions Ursolic acid-enriched KDCE enhances the antitumor activity of BCI, which could be mediated by VEGFR2 downregulation and subsequent suppression of angiogenesis. Therefore, combination therapy with S.t△ppGpp and KDCE is a potential cancer therapeutic strategy.

Bacteria-mediated cancer immunotherapy (BCI) inhibits tumor progression and has a synergistic antitumor effect when combined with chemotherapy. The anti- or pro-tumorigenic effects of interferon-γ (IFN-γ) are controversial; hence, we were interested in the antitumor effects of IFN-γ/BCI combination therapy. Here, we demonstrated that IFN-γ increased the tumor cell killing efficacy of attenuated Salmonella by prolonging the survival of tumor-colonizing bacteria via blockade of tumor-infiltrating neutrophil recruitment. In addition, IFN-γ attenuated Salmonella-stimulated immune responses by stimulating tumor infiltration by M1-like macrophages and CD4+ and CD8+ T cells, thereby facilitating tumor eradication. Taken together, these findings suggest that combination treatment with IFN-γ boosts the therapeutic response of BCI with S. tΔppGpp, suggesting that IFN-γ/BCI is a promising approach to immunotherapy.

Lovastatin is a statin produced by Monascus purpureous-fermented pu-erh tea, which is used in the treatment of cardiovascular diseases and prostate cancer. Bacteria-mediated cancer immunotherapy (BCI), which is an effective antitumor strategy compared with conventional immunotherapies, targets neutrophil infiltration associated with tumor recurrence and metastasis. In mouse colon cancer models, combination treatment with lovastatin and BCI suppressed tumor progression by extending the survival of tumor-colonizing bacteria. We used zebrafish live imaging to show that lovastatin decreases the recruitment of neutrophils to the inflammatory site by inducing neutrophil apoptosis via phosphorylation of ERK and AKT. The present findings suggest that the combination of BCI with lovastatin or fermented pu-erh tea is an effective approach compared with conventional cancer immunotherapy.

Neutrophilic inflammation plays a vital role in cancer recurrence and metastasis. One therapeutic strategy is to clear neutrophils from the inflammatory site by inducing apoptosis or reverse migration. Bacteria-mediated cancer therapy (BCT) regulates neutrophil infiltration and shows robust anti-tumor activity. Chlorogenic acid, a natural compound found in coffee, shows anti-inflammatory activity. Here, we used live-cell imaging of zebrafish to show that chlorogenic acid clears neutrophils from inflammatory sites by inducing apoptosis and reverse migration. The effect is mediated by inhibiting phosphorylation of ERK and AKT. In addition, chlorogenic acid abrogates △ppGpp S. Typhimurium -induced neutrophil recruitment to tumors in a mouse model of colon cancer, thereby prolonging bacterial colonization.