Deletion of the nuclear hormone receptor small heterodimer partner (Shp) ameliorates the development of obesity and nonalcoholic steatohepatitis (NASH) in mice. Liver-specific SHP plays a significant role in this amelioration. The gut microbiota has been associated with these metabolic disorders, and the interplay between bile acids (BAs) and gut microbiota contributes to various metabolic disorders. Since hepatic SHP is recognized as a critical regulator in BA synthesis, we assessed the involvement of gut microbiota in the antiobesity and anti-NASH phenotype of Shp-/- mice. Shp deletion significantly altered the levels of a few conjugated BAs. Sequencing the 16S rRNA gene in fecal samples collected from separately housed mice revealed apparent dysbiosis in Shp-/- mice. Cohousing Shp-/- mice with WT mice during a Western diet regimen impaired their metabolic improvement and effectively disrupted their distinctive microbiome structure, which became indistinguishable from that of WT mice. While the Western diet challenge significantly increased lipopolysaccharide and phenylacetic acid (PAA) levels in the blood of WT mice, their levels were not increased in Shp-/- mice. PAA was strongly associated with hepatic peroxisome proliferator-activated receptor gamma isoform 2 (Pparg2) activation in mice, which may represent the basis of the molecular mechanism underlying the association of gut bacteria and hepatic steatosis. Shp deletion reshapes the gut microbiota possibly by altering BAs. While lipopolysaccharide and PAA are the major driving forces derived from gut microbiota for NASH development, Shp deletion decreases these signaling molecules via dysbiosis, thereby partially protecting mice from diet-induced metabolic disorders.

中文翻译：

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通过删除小鼠核激素受体 SHP，可以减少与脂肪性肝炎相关的微生物产物。

核激素受体小异二聚体伴侣 (Shp) 的缺失可改善小鼠肥胖和非酒精性脂肪性肝炎 (NASH) 的发展。肝脏特异性 SHP 在这种改善中发挥着重要作用。肠道微生物群与这些代谢紊乱有关，胆汁酸 (BA) 和肠道微生物群之间的相互作用导致了各种代谢紊乱。由于肝脏 SHP 被认为是 BA 合成的关键调节因子，因此我们评估了肠道微生物群在 Shp-/- 小鼠抗肥胖和抗 NASH 表型中的作用。Shp 缺失显着改变了一些缀合 BA 的水平。对单独饲养的小鼠粪便样本中的 16S rRNA 基因进行测序显示，Shp-/- 小鼠存在明显的生态失调。在西方饮食方案中，将Shp-/-小鼠与WT小鼠混养会损害​​它们的代谢改善，并有效破坏它们独特的微生物组结构，使其与WT小鼠无法区分。虽然西方饮食挑战显着增加了WT小鼠血液中的脂多糖和苯乙酸（PAA）水平，但它们的水平在Shp-/-小鼠中没有增加。PAA 与小鼠肝脏过氧化物酶体增殖物激活受体 γ 亚型 2 (Pparg2) 激活密切相关，这可能代表了肠道细菌与肝脏脂肪变性相关分子机制的基础。Shp 缺失可能通过改变 BA 来重塑肠道微生物群。虽然脂多糖和 PAA 是 NASH 发展的肠道微生物群的主要驱动力，但 Shp 缺失通过菌群失调减少了这些信号分子，从而部分保护小鼠免受饮食引起的代谢紊乱。