To (1) investigate the efficacy of multiple doses of an orally delivered probiotic bacteria Lactobacillus paracasei (LP) modified to express angiotensin (1–7) (LP-A) in altering physiologic parameters relevant to the gut-brain axis in older rats and to (2) compare this strategy with subcutaneous delivery of synthetic Ang(1–7) peptide on circulating Ang(1–7) concentrations and these gut-brain axis parameters. Male 24-month-old F344BN rats received oral gavage of LP-A, or subcutaneous injection of Ang(1–7) for 0×, 1×, 3×, or 7×/week over 4 weeks. Circulating RAS analytes, inflammatory cytokines, and tryptophan and its downstream metabolites were measured by ELISA, electrochemiluminescence, and LC-MS respectively. Microbiome taxonomic analysis of fecal samples was performed via 16S-based PCR. Inflammatory and tryptophan-related mRNA expression was measured in colon and pre-frontal cortex. All dosing regimens of LP-A induced beneficial changes in fecal microbiome including overall microbiota community structure and α-diversity, while the 3×/week also significantly increased expression of the anti-inflammatory species Akkermansia muciniphila. The 3×/week also increased serum serotonin and the neuroprotective analyte 2-picolinic acid. In the colon, LP-A increased quinolinate phosphoribosyltransferase expression (1×/week) and increased kynurenine aminotransferase II (1× and 3×/week) mRNA expression. LP-A also significantly reduced neuro-inflammatory gene expression in the pre-frontal cortex (3×/week: COX2, IL-1β, and TNFα; 7×/week: COX2 and IL-1β). Subcutaneous delivery of Ang(1–7) increased circulating Ang(1–7) and reduced angiotensin II, but most gut-brain parameters were unchanged in response. Oral—but not subcutaneous—Ang(1–7) altered physiologic parameters related to gut-brain axis, with the most effects observed in 3×/week oral dosing regimen in older rats.

(1) 研究多剂量口服益​​生菌副干酪乳杆菌的功效(LP) 修饰以表达血管紧张素 (1-7) (LP-A) 以改变与老年大鼠肠脑轴相关的生理参数，并 (2) 将此策略与皮下递送合成 Ang(1-7) 进行比较肽对循环 Ang(1-7) 浓度和这些肠脑轴参数的影响。雄性 24 个月大的 F344BN 大鼠在 4 周内每周接受 LP-A 灌胃或皮下注射 Ang(1–7) 0×、1×、3× 或 7×。分别通过 ELISA、电化学发光和 LC-MS 测量循环 RAS 分析物、炎性细胞因子和色氨酸及其下游代谢物。通过基于 16S 的 PCR 对粪便样本进行微生物组分类学分析。在结肠和前额叶皮质中测量了炎症和色氨酸相关的 mRNA 表达。Akkermansia muciniphila。每周 3 次还增加了血清素和神经保护分析物 2-吡啶甲酸。在结肠中，LP-A 增加了喹啉酸磷酸核糖基转移酶的表达（1×/周），并增加了犬尿氨酸氨基转移酶 II（1× 和 3×/周）的 mRNA 表达。LP-A 还显着降低了前额皮质中的神经炎症基因表达（3 次/周：COX2、IL-1β 和 TNFα；7 次/周：COX2 和 IL-1β）。皮下输送 Ang(1-7) 可增加循环中的 Ang(1-7) 并减少血管紧张素 II，但大多数肠-脑参数未发生变化。口服——但不是皮下注射——Ang(1–7) 改变了与肠-脑轴相关的生理参数，在老年大鼠中观察到的 3 次/周口服给药方案的影响最大。