Neurobiota Research Center, College of Pharmacy, Kyung Hee University, Seoul, Korea.
Neurobiota Research Center, College of Pharmacy, Kyung Hee University, Seoul, Korea; School of Pharmacy, Jeonbuk National University, Jeonju-si, Korea.
Brain Behav Immun. 2024 May;118:136-148. doi: 10.1016/j.bbi.2024.02.031. Epub 2024 Feb 28.
Gut microbiota communicates bidirectionally with the brain through the nervous, immune, and endocrine systems of the gut. In our preliminary study, the fecal microbiota of volunteers with mild cognitive impairment (Fmci) exhibited a higher abundance of Escherichia fergusonii (NK2001), Veillonella infantium (NK2002), and Enterococcus faecium (NK2003) populations compared with those of healthy volunteers. Therefore, we examined the effects of Fmci, NK2001 (gram-negative), NK2002 (gram-negative-like), and NK2003 (gram-positive) on cognitive impairment-like behavior, neuroinflammation, and colitis in mice with or without antibiotics. Fmci transplantation increased cognitive impairment-like behavior, hippocampal tumor necrosis factor (TNF)-α expression, and the size of toll-like receptor (TLR)4Iba1, TLR2Iba1, and NF-κBIba1 cell populations independent of antibiotic treatment. Oral gavage of NK2001, NK2002, or NK2003, which induced TNF-α expression in Caco-2 cells, significantly increased cognitive impairment-like behavior and hippocampal TNF-α expression and Iba1-positive cell populations and decreased brain-derived neurotrophic factor (BDNF) expression in mice. Celiac vagotomy significantly decreased NK2001- or NK2002-induced cognitive impairment-like behavior and hippocampal Iba1 cell population and TNF-α expression and increased NK2001- or NK2002-suppressed hippocampal BDNF expression. However, NK2003-induced cognitive impairment-like behavior and hippocampal Iba1 cell population and TNF-α expression were partially, but not significantly, attenuated by celiac vagotomy. Furthermore, celiac vagotomy did not affect NK2001-, NK2002-, or NK2003-induced lipopolysaccharide (LPS) levels in the blood and feces and TNF-α expression and NF-κB-positive cell population in the colon. In conclusion, LPS-producing NK2001 and NK2002 and LPS-nonproducing NK2003 may induce NF-κB-mediated neuroinflammation through the translocation of byproducts such as LPS and peptidoglycan into the brain through gut-blood/vagus nerve-brain and gut-blood-brain pathways, respectively, resulting in cognitive impairment.
肠道微生物群通过肠道的神经、免疫和内分泌系统与大脑双向交流。在我们的初步研究中，与健康志愿者相比，轻度认知障碍（Fmci）志愿者的粪便微生物群中埃希氏菌弗格森ii（NK2001）、婴儿韦荣球菌（NK2002）和粪肠球菌（NK2003）的丰度更高。因此，我们研究了 Fmci、NK2001（革兰氏阴性）、NK2002（革兰氏阴性样）和 NK2003（革兰氏阳性）对有或没有抗生素的小鼠认知障碍样行为、神经炎症和结肠炎的影响。Fmci 移植增加了认知障碍样行为、海马肿瘤坏死因子（TNF）-α表达以及 TLR4Iba1、TLR2Iba1 和 NF-κBIba1 细胞群的大小，而与抗生素治疗无关。口服 NK2001、NK2002 或 NK2003 会诱导 Caco-2 细胞中 TNF-α 的表达，显著增加了认知障碍样行为和海马 TNF-α 表达以及 Iba1 阳性细胞群，并降低了小鼠脑源性神经营养因子（BDNF）的表达。腹腔迷走神经切断术显著降低了 NK2001 或 NK2002 诱导的认知障碍样行为和海马 Iba1 细胞群及 TNF-α 表达，并增加了 NK2001 或 NK2002 抑制的海马 BDNF 表达。然而，腹腔迷走神经切断术部分但并非显著减弱了 NK2003 诱导的认知障碍样行为和海马 Iba1 细胞群及 TNF-α 表达。此外，腹腔迷走神经切断术不影响 NK2001、NK2002 或 NK2003 诱导的血液和粪便中 LPS 水平以及结肠中 TNF-α 表达和 NF-κB 阳性细胞群。总之，产 LPS 的 NK2001 和 NK2002 以及不产 LPS 的 NK2003 可能通过 LPS 和肽聚糖等副产物通过肠道-血液/迷走神经-大脑和肠道-血液-大脑途径转移到大脑中，引起 NF-κB 介导的神经炎症，从而导致认知障碍。
