Wong Giselle C, Jung Yewon, Lee Kevin, Fourie Chantelle, Handley Kim M, Montgomery Johanna M, Taylor Michael W
School of Biological Sciences, University of Auckland, Auckland, New Zealand.
Centre for Brain Research, University of Auckland, Auckland, New Zealand.
Front Microbiol. 2025 Aug 12;16:1607045. doi: 10.3389/fmicb.2025.1607045. eCollection 2025.
Shank gene variants are implicated in ~1% of people with autism, and mice lacking exhibit autism-like behaviours. Zinc deficiency and gastrointestinal problems can be common among people with autism, and zinc is a key element required for SHANK protein function and gut development. In mice, a supplementary zinc diet reverses autism-like behaviours. We hypothesise that dietary zinc may alter the gut microbiome, potentially affecting the gut-microbiome-brain axis, which may contribute to changes in autism-like behaviours. To test this, four types of gastrointestinal samples (ileum, caecum, colon, faecal) were collected from wild-type and knock-out mice on either control or supplemented-zinc diets, enabling us to examine the influence of-and interactions between-dietary zinc, the gut microbiome, and ASD-linked host genotype. Cage, genotype, and zinc diet each contributed significantly to bacterial community variation (accounting for 12.8, 3.9, and 2.3% of the variation, respectively). Fungal diversity was significantly lower in compared with wild-type mice on the control zinc diet, with specific fungal biota signatures detected among gut locations. Host metabolic genes, which may be regulated by the gut microbiota, and host genes involved in antimicrobial interactions were more highly expressed in mice. Metagenomic analyses revealed differential abundance of bacterial fatty acid biosynthesis and transporters (including zinc transport and neurotransmitter receptors) among our experimental groups. Overall these suggested increased activity of, or a switch towards, metabolic and microbial-host interactions that may benefit both host and microbe, in the presence of zinc. This raises the potential of manipulating both dietary zinc and the gut microbiota itself to ameliorate ASD-related behaviours and associated gastrointestinal issues. These data broaden understanding of the gut microbiome in autism and pave the way towards potential microbial therapeutics for gastrointestinal problems in people with autism.
SHANK基因变异在约1%的自闭症患者中存在，缺乏该基因的小鼠表现出自闭症样行为。锌缺乏和胃肠道问题在自闭症患者中较为常见，而锌是SHANK蛋白功能和肠道发育所需的关键元素。在小鼠中，补充锌的饮食可逆转自闭症样行为。我们推测，饮食中的锌可能会改变肠道微生物群，潜在地影响肠道微生物群-脑轴，这可能导致自闭症样行为的改变。为了验证这一点，我们从野生型和基因敲除小鼠中收集了四种胃肠道样本（回肠、盲肠、结肠、粪便），这些小鼠分别食用对照饮食或补充锌的饮食，从而使我们能够研究饮食锌、肠道微生物群和与自闭症相关的宿主基因型之间的影响及相互作用。饲养笼、基因型和锌饮食对细菌群落变异均有显著贡献（分别占变异的12.8%、3.9%和2.3%）。与食用对照锌饮食的野生型小鼠相比，基因敲除小鼠的真菌多样性显著降低，在不同肠道部位检测到特定的真菌生物群特征。可能受肠道微生物群调节的宿主代谢基因以及参与抗菌相互作用的宿主基因在基因敲除小鼠中表达更高。宏基因组分析显示，我们的实验组中细菌脂肪酸生物合成和转运蛋白（包括锌转运和神经递质受体）的丰度存在差异。总体而言，这些结果表明，在锌存在的情况下，代谢和微生物-宿主相互作用的活性增加或发生转变，这可能对宿主和微生物都有益。这增加了通过调节饮食锌和肠道微生物群本身来改善自闭症相关行为及相关胃肠道问题的可能性。这些数据拓宽了我们对自闭症中肠道微生物群的理解，并为自闭症患者胃肠道问题的潜在微生物治疗方法铺平了道路。
