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Lactobacillus acidophilus potentiates oncolytic virotherapy through modulating gut microbiota homeostasis in hepatocellular carcinoma

ABSTRACT: Oncolytic viruses (OVs) hold promise for cancer treatment. However, the antitumor efficacy is limited. Microbiota plays a pivotal role in cancer treatment and its impact on oncolytic virotherapy is unknown. Here, we show that VSVΔ51 has higher antitumor efficacy for hepatocellular carcinoma in the absence of microbiota in female mouse models. VSVΔ51 infection causes microbiota dysbiosis, increasing most of the gut bacteria abundance, while decreasing the commensal Lactobacillus. VSVΔ51 reduced intestinal expression of SLC20A1 that binds to Lactobacillus acidophilus (L. acidophilus) CdpA cell wall protein through IL6-JAK-STAT3 signaling, thereby attenuating attachment and colonization of L. acidophilus. L. acidophilus supplementation confers sensitivity to VSVΔ51 through restoring gut barrier integrity and microbiota homeostasis destroyed by VSVΔ51. In this work, we show that targeting microbiota homostasis holds substantial potential in improving therapeutic outcomes of oncolytic virotherapy

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic, Liquid Chromatography MS - alternating - reverse phase

PROVIDER: MTBLS12297 | MetaboLights | 2025-03-14

REPOSITORIES: MetaboLights

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Project description:Background In large-scale poultry farming, broilers of the same breed, sharing a common genetic background and identical management conditions, nevertheless exhibit considerable individual variation in body weight. Multitudinous stressors can profoundly influence the host microbiota, thereby modulating overall health and growth. This study employed multi-omics approaches to elucidate the underlying factors contributing to the disparities between high- and low-weight broilers and to evaluate the effects of Lactobacillus aerosolization on growth performance and systemic inflammation in these animals.Results This study identified distinct plasma proteomic profiles between high- and low-weight broilers, with the latter exhibiting a systemic inflammatory response. Gut microbiota differences were minimal, and fecal microbiota transplantation did not alter broiler body weight. However, lung microbiota analysis revealed a higher relative abundance of Lactobacillus in high-weight broilers, linked to altered plasma tryptophan metabolism. Aerosolized Lactobacillus reuteri C501, Lacticaseibacillus rhamnosus UA260, and their combination enhanced growth and mitigated LPS-induced inflammation. This intervention increased L-Tryptophan (L-Trp), indoleacrylic acid (IAA), and indole-3-carboxaldehyde (I3C) levels in plasma and bronchoalveolar lavage fluid (BALF). Mechanistic studies showed that IAA and I3C activated the AHR pathway, promoting SOCS3 expression in macrophages, inhibiting JAK2/STAT3 signaling, and alleviating LPS-induced inflammation.Conclusions Aerosolization of Lactobacillus enhances broiler performance and alleviates LPS-induced stress responses. This effect is mediated through the modulation of tryptophan metabolism, which interacts with the AHR/SOCS3 axis to inhibit JAK2/STAT3 signaling, thereby reducing both pulmonary and systemic inflammation. Our findings provide insights into the interaction between poultry production and lung microbiota, establishing Lactobacillus aerosolization as a promising strategy to combat systemic inflammation and improve poultry health and performance.

Project description:Familial Mediterranean fever (FMF) is an inflammatory genetic disease characterized by elevated systemic reactivity against commensal gut microbiota and high levels of gut Candida albicans. The current study investigated the effects of Lactobacillus acidophillus INMIA 9602 Er 317/402 strain (probiotic “Narine”) on the relative abundance of gut enteric bacteria, lactobacilli, Staphylococcus aureus, and Enteroccocus faecalis in Candida albicans-carrier and non-carrier FMF patients in remission with the main MEFV mutation patterns M694V/V726A- the prevalent MEFV gene mutation within FMF patients in the Armenian cohort. Our data revealed that M694V/V726A mutations in PURIN inflammasome leading to FMF disease brought to gender specific differences in microbial community structure in FMF patients. Possibly, long-term colchicine use suppresses the PURIN inflammasome/inhibits NLRP3 inflammasome-dependent IL-1β release influencing on overgrowth of C. albicans in gut microbiota of FMF patients. The comparison of Operational Taxonomic Units (OTUs) of enteric bacteria in C. albicans-carrier and non-carrier female patients revealed the statistically significant increase in OTUs of enterobacteria in C. albicans-carriers. In contrast to this, there were no differences in abundance of Enteroccocus faecalis between female FMF C. albicans-carriers compared with non-carriers, while male FMF C. albicans-carriers have increased abundance of E. faecalis in their gut microbiota compared with that of male patients with none carriers. The gut microbiota of FMF patients (both male and female) with C. albicans below baseline level contains high abundance of lactobacilli compared with C. albicans-carriers. The adoption of Lactobacillus acidophilus INMIA 9602 Er 317/402 leads to changes in gut microbiota composition of FMF patients. It reduces, in particularly, the abundance of enterobacteria in females, and Enteroccocus faecalis in men parallel with reducing the numbers of yeast in gut microbiota of FMF patients. We hypothesize that colchicine treatment changes the already-altered gut microbiota of FMF patients, thereby affecting the regulation of immune system by inhibition of NLRP3 inflammasome. Colchicine could lead to overgrowth of C. albicans in gut microbiota of FMF patients, whereas the Lactobacillus acidophilus INMIA 9602 Er 317/402 works on activation of inflammasome by new changes in gut microbiota of patients.

			Action	DRS
	Control-12.mzml	Mzml
	Control-2.mzml	Mzml
	Control-3.mzml	Mzml
	Control-5.mzml	Mzml
	QC-1.mzml	Mzml

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Lactobacillus acidophilus potentiates oncolytic virotherapy through modulating gut microbiota homeostasis in hepatocellular carcinoma

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