Diaphorobacter nitroreducens synergize with oxaliplatin to reduce tumor burden in mice with lung adenocarcinoma.

Lung adenocarcinoma (LADC) is the most common lung cancer and the leading cause of cancer-related deaths globally. Accumulating evidence suggests that the gut microbiota regulates the host response to chemotherapeutic drugs and can be targeted to reduce the toxicity of current chemotherapeutic agents. However, the effect of Diaphorobacter nitroreducens synergized with oxaliplatin on the gut microbiota and their impact on LADC have never been explored. This study aimed to evaluate the anti-cancer effects of D. nitroreducens, oxaliplatin, and their combined treatment on tumor growth in tumor-bearing mice. The composition of gut microbiota and the immune infiltration of tumors were evaluated by using 16S rRNA gene high-throughput sequencing and immunofluorescence, respectively. The inhibitory effect of the combination treatment with D. nitroreducens and oxaliplatin was significantly stronger than that of oxaliplatin alone in tumor-bearing mice. Furthermore, we observed that the combination treatment significantly increased the relative abundance of Lactobacillus and Akkermansia in the gut microbiota. Meanwhile, the combination treatment significantly increased the proportions of macrophage but decreased the proportion of regulatory T cells in the LADC tumor tissues of mice. These findings underscored the relationship between D. nitroreducens and the gut microbiota-immune cell-LADC axis, highlighting potential therapeutic avenues for LADC treatment. IMPORTANCE: Oxaliplatin is widely used as an effective chemotherapeutic agent in cancer treatment, but its side effects and response rate still need to be improved. Conventional probiotics potentially benefit cancer chemotherapy by regulating gut microbiota and tumor immune infiltration. This study was novel in reporting a more significant inhibitory effect of Diaphorobacter nitroreducens on lung adenocarcinoma (LADC) cells compared with common traditional probiotics and validating its potential as an adjuvant therapy for LADC chemotherapy in mice. This study investigated the impact of D. nitroreducens combined with oxaliplatin on the gut microbiota and immune infiltration of tumors as a potential mechanism to improve anticancer effects.

Stenotrophomonas maltophilia promotes lung adenocarcinoma progression by upregulating histone deacetylase 5.

Introduction: Lung cancer is the leading cause of cancer death worldwide, and lung adenocarcinoma (LADC) is the most common lung cancer. Lung cancer has a distinct microbiome composition correlated with patients' smoking status. However, the causal evidence of microbial impacts on LADC is largely unknown. Methods: We investigated microbial communities' differences in Formalin-Fixed Paraffin-Embedded tissues of ever-smoke (n = 22) and never-smoke (n = 31) patients with LADC through bacterial 16S rRNA gene high-throughput sequencing. Then nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer mouse model and A549 cells were used to study the effect of Stenotrophomonas maltophilia (S. maltophilia) in LADC. Results and Discussion: We found a significant increase of genus Stenotrophomonas in LADC tissues of patients with primary tumor size greater than 3 cm and never-smoker patients. We further found that intratracheal infection with S. maltophilia promoted tumor progression in the NNK-induced lung cancer mouse model. We performed RNA-seq analysis on lung tissues and found that S. maltophilia treatment drove inflammation and upregulated tumor associated cell signaling, including Apelin signaling pathway. Mechanistically, histone deacetylase 5 (HDAC5) gene expression was significantly upregulated in S. maltophilia treated groups, and was required for S. maltophilia induced cell proliferation and migration in LADC cell line A549. Therefore, we provide in vivo and in vitro evidence to demonstrate that S. maltophilia promotes LADC progression, in part, through HDAC5.

Specific γ-aminobutyric acid decomposition by gabP and gabT under neutral pH in recombinant Corynebacterium glutamicum.

OBJECTIVES: Corynebacterium glutamicum that expresses the exogenous L-glutamate decarboxylase (GAD) gene can synthesize γ-aminobutyric acid (GABA). To prevent GABA decomposition in the recombinant C. glutamicum GAD strain, GABA uptake and the GABA shunt pathway were blocked. RESULTS: GABA uptake is catalyzed by GABA permease encoded by gabP. The first reaction of the GABA shunt pathway is catalyzed by the GABA transaminase encoded by gabT. Initially, the effects of pH on GABA decomposition in recombinant C. glutamicum co-expressing two GAD genes (gadB1 and gadB2) were analyzed, demonstrating that GABA could be decomposed under neutral pH. Next, the gabP and gabT were individually deleted, and the GABA production of the related GAD strains was investigated by controlling the pH of the final fermentation stage at a neutral state. During this stage, the GABA concentration of the gabT-deleted GAD strain decreased from 23.9 ± 1.8 to 17.7 ± 0.7 g/l. However, the GABA concentration of the gabP-deleted GAD strain remained at 18.6-19.4 g/l. CONCLUSION: This study demonstrated that GABA was decomposed under neutral pH and that the deletion of gabP could effectively alleviate GABA decomposition in C. glutamicum.

Deletion of odhA or pyc improves production of γ-aminobutyric acid and its precursor L-glutamate in recombinant Corynebacterium glutamicum.

OBJECTIVES: To enhance γ-aminobutyric acid (GABA) production in recombinant Corynebacterium glutamicum, metabolic engineering strategies were used to improve the supply of the GABA precursor, L-glutamate. RESULTS: C. glutamicum ATCC13032 co-expressing two glutamate decarboxylase genes (gadB1 and gadB2) was constructed in a previous study Shi et al. (J Ind Microbiol Biotechnol 40:1285-1296, 2013) to synthesize GABA from endogenous L-glutamate. To improve its L-glutamate supply, new strains were constructed here. First, the odhA and pyc genes were deleted separately. Then, a gadB1-gadB2 co-expression plasmid was transferred into ΔodhA, Δpyc, and ATCC13032, resulting in recombinant strains SNW201, SNW202, and SNW200, respectively. After fermenting for 72 h, GABA production increased to 29.5 ± 1.1 and 24.9 ± 0.7 g/l in SNW201 and SNW202, respectively, which was significantly higher than that in SNW200 (19.4 ± 2.6 g/l). The GABA conversion ratios of SNW201 and SNW202 reached 0.98 and 0.96 mol/mol, respectively. CONCLUSION: The recombinant strains SNW201 and SNW202 can be used as candidates for GABA production.