Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice

The use of Akkermansia muciniphila as potential therapeutic intervention is receiving increasing attention. Health benefits attributed to this bacterium include an improvement of metabolic disorders and exerting anti-inflammatory effects. The abundance of A. muciniphila is associated with a healthy gut in early mid- and later life. However, the effects of A. muciniphila on a decline in intestinal health during the aging process are not investigated yet. We supplemented accelerated aging Ercc1-/Δ7 mice with A. muciniphila for 10 weeks and investigated histological, transcriptional and immunological aspects of intestinal health. The thickness of the colonic mucus layer increased about 3-fold after long-term A. muciniphila supplementation and was even significantly thicker compared to mice supplemented with Lactobacillus plantarum WCFS1. Colonic gene expression profiles pointed towards a decreased expression of genes and pathways related to inflammation and immune function, and suggested a decreased presence of B cells in colon. Total B cell frequencies in spleen and mesenteric lymph nodes were not altered after A. muciniphila supplementation. Mature and immature B cell frequencies in bone marrow were increased, whereas B cell precursors were unaffected. These findings implicate that B cell migration rather than production was affected by A. muciniphila supplementation. Gene expression profiles in ileum pointed toward a decrease in metabolic- and immune-related processes and antimicrobial peptide production after A. muciniphila supplementation. Besides, A. muciniphila decreased the frequency of activated CD80+CD273- B cells in Peyer’s patches. Additionally, the increased numbers of peritoneal resident macrophages and a decrease in Ly6Cint monocyte frequencies in spleen and mesenteric lymph nodes add evidence for the potentially anti-inflammatory properties of A. muciniphila. Altogether, we show that supplementation with A. muciniphila prevented the age-related decline in thickness of the colonic mucus layer and attenuated inflammation and immune-related processes at old age. This study implies that A. muciniphila supplementation can contribute to a promotion of healthy aging. Overall design: The effects of 10-wk bacterial supplementation of Akkermansia muciniphila on gut barrier and immunity was investigated in 16-week-old accelerated aging Ercc1-/Δ7 mice, which have a median lifespan of ~20wk. Distal ileum and proximal colon tissues were subjected to gene expression profiling.

嗜黏蛋白阿克曼菌（Akkermansia muciniphila）作为潜在治疗干预手段的相关研究正受到越来越多的关注。该菌所具备的健康益处包括改善代谢紊乱以及发挥抗炎作用。嗜黏蛋白阿克曼菌的丰度与生命早、中、晚期的健康肠道状态密切相关。然而，目前尚未有研究探讨嗜黏蛋白阿克曼菌对衰老过程中肠道健康衰退的影响。我们对加速衰老型Ercc1-/Δ7小鼠灌胃嗜黏蛋白阿克曼菌，持续10周，并从组织学、转录组学及免疫学层面探究其肠道健康状况。长期灌胃嗜黏蛋白阿克曼菌后，小鼠结肠黏液层厚度增加约3倍，且相较于灌胃植物乳杆菌（Lactobacillus plantarum）WCFS1的小鼠，其结肠黏液层厚度显著更厚。结肠基因表达谱显示，与炎症及免疫功能相关的基因和通路表达水平下调，且结肠内B细胞的浸润量有所减少。灌胃嗜黏蛋白阿克曼菌后，小鼠脾脏及肠系膜淋巴结中的总B细胞频率未发生显著变化。骨髓中成熟与未成熟B细胞的频率有所升高，而B细胞前体的数量未受影响。上述结果表明，嗜黏蛋白阿克曼菌灌胃主要影响B细胞的迁移而非其生成。回肠基因表达谱显示，灌胃嗜黏蛋白阿克曼菌后，与代谢及免疫相关的生物学过程以及抗菌肽的产生均出现下调。此外，嗜黏蛋白阿克曼菌可降低派尔集合淋巴结（Peyer’s patches）中活化型CD80+CD273- B细胞的频率。此外，小鼠腹腔常驻巨噬细胞数量增多，脾脏及肠系膜淋巴结中Ly6Cint单核细胞频率降低，这些结果进一步为嗜黏蛋白阿克曼菌潜在的抗炎特性提供了证据。综上，本研究证实，灌胃嗜黏蛋白阿克曼菌可阻止衰老相关的结肠黏液层厚度衰退，并缓解老年小鼠的炎症反应及免疫相关生物学过程异常。本研究表明，灌胃嗜黏蛋白阿克曼菌有助于促进健康衰老。实验整体设计：本研究以中位寿命约20周的16周龄加速衰老型Ercc1-/Δ7小鼠为模型，探究为期10周的嗜黏蛋白阿克曼菌灌胃对肠道屏障及免疫功能的影响。对小鼠的回肠远端与结肠近端组织进行了基因表达谱分析。