Stimulation of the inflammatory reflex (IR) is a promising strategy for treating systemic inflammatory disorders. Recent studies suggest oral sodium bicarbonate (NaHCO3) as a potential activator of the IR, offering a safe and cost-effective treatment approach. However, the mechanisms underlying NaHCO3-induced anti-inflammatory effects remain unclear. We investigated whether oral NaHCO3’s immunomodulatory effects are mediated by the splenic nerve. Female rats received NaHCO3 or water (H2O) for four days, and splenic immune markers were assessed using flow cytometry. NaHCO3 led to a significant increase (p < 0.05, and/or partial eta squared > 0.06) in anti-inflammatory markers, including CD11bc + CD206 + (M2-like) macrophages, CD3 + CD4 + FoxP3 + cells (Tregs), and Tregs/M1-like ratio. Conversely, proinflammatory markers, such as CD11bc + CD38 + TNFα + (M1-like) macrophages, M1-like/M2-like ratio, and SSChigh/SSClow ratio of FSChighCD11bc + cells, decreased in the spleen following NaHCO3 administration. These effects were abolished in spleen-denervated rats, suggesting the necessity of the splenic nerve in mediating NaHCO3-induced immunomodulation. Artificial neural networks accurately classified NaHCO3 and H2O treatment in sham rats but failed in spleen-denervated rats, highlighting the splenic nerve's critical role. Additionally, spleen denervation independently influenced Tregs, M2-like macrophages, Tregs/M1-like ratio, and CD11bc + CD38 + cells, indicating distinct effects from both surgery and treatment. Principal component analysis (PCA) further supported the separate effects. Our findings suggest that the splenic nerve transmits oral NaHCO3-induced immunomodulatory changes to the spleen, emphasizing NaHCO3’s potential as an IR activator with therapeutic implications for a wide spectrum of systemic inflammatory conditions.

中文翻译：

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口服 NaHCO3 的免疫调节作用是由脾神经介导的：人工神经网络揭示的多变量影响

刺激炎症反射（IR）是治疗全身炎症性疾病的一种有前景的策略。最近的研究表明口服碳酸氢钠 (NaHCO3) 作为 IR 的潜在激活剂，提供了一种安全且具有成本效益的治疗方法。然而，NaHCO3 诱导的抗炎作用的机制仍不清楚。我们研究了口服 NaHCO3 的免疫调节作用是否是由脾神经介导的。雌性大鼠接受 NaHCO3 或水 (H2O) 四天，并使用流式细胞术评估脾脏免疫标记物。 NaHCO3 导致抗炎标记物显着增加（p < 0.05，和/或部分 eta 平方 > 0.06），包括 CD11bc + CD206 +（M2 样）巨噬细胞、CD3 + CD4 + FoxP3 + 细胞 (Treg) 和Tregs/M1 样比率。相反，给予 NaHCO3 后，脾脏中的促炎标记物，例如 CD11bc + CD38 + TNFα +（M1 样）巨噬细胞、M1 样/M2 样比率以及 FSChighCD11bc + 细胞的 SSChigh/SSClow 比率减少。这些作用在去脾神经的大鼠中被消除，表明脾神经在介导 NaHCO3 诱导的免疫调节中的必要性。人工神经网络在假大鼠中准确地分类了 NaHCO3 和 H2O 治疗，但在去脾神经的大鼠中却失败了，这凸显了脾神经的关键作用。此外，脾去神经独立影响 Tregs、M2 样巨噬细胞、Tregs/M1 样比率和 CD11bc + CD38 + 细胞，表明手术和治疗的效果不同。主成分分析 (PCA) 进一步支持了单独的效应。我们的研究结果表明，脾神经将口服 NaHCO3 诱导的免疫调节变化传递至脾脏，强调了 NaHCO3 作为 IR 激活剂的潜力，对广泛的全身炎症性疾病具有治疗意义。