Microbiology Department, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
Endocrinology and Nutrition Service, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.
Int J Mol Sci. 2024 Aug 14;25(16):8856. doi: 10.3390/ijms25168856.
Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), is a rare lysosomal disease caused by congenital enzymatic deficiencies in heparan sulfate (HS) degradation, leading to organ dysfunction. The most severe hallmark of MPS III comprises neurological alterations, although gastrointestinal symptoms (GISs) have also been shown to be relevant in many patients. Here, we explored the contribution of the gut microbiota to MPS III GISs. We analyzed the composition and functionality of the gut microbiota in two MPS III siblings with the same mutation (c.544C > T, c.1080delC, in the SGSH gene) and the same diet, but with differences in their GISs, including recurrent diarrhea in one of them. Using 16S sequencing, we observed that the MPS III patients exhibited decreased alpha diversity and a lower abundance of and accompanied by a higher abundance of the and families than the healthy control subjects. Comparing siblings, we found an increased abundance of and a lower abundance of and in the GIS-free patient. This patient also had a higher relative abundance of genes (, , , ) involved in glycosaminoglycan metabolism. We found higher HS levels in the stool of the two MPS III patients than in healthy volunteers, particularly in the patient with GISs. Functionally, whole fecal metabolites from the patient with GISs induced oxidative stress in vitro in healthy monocytes. Finally, the strain isolated from MPS III stool samples exhibited HS degradation ability. Overall, our results reveal different microbiota compositions and functionalities in MPS III siblings, who exhibited differential gastrointestinal symptomatology. Our study may serve as a gateway to explore the impact of the gut microbiota and its potential to enhance the quality of life in Sanfilippo syndrome patients.
黏多糖贮积症 III 型（Sanfilippo 综合征，MPS III）是一种罕见的溶酶体疾病，由先天性硫酸乙酰肝素（heparan sulfate，HS）降解酶缺乏引起，导致器官功能障碍。MPS III 最严重的特征包括神经功能改变，尽管胃肠道症状（gastrointestinal symptoms，GISs）在许多患者中也被认为具有相关性。在这里，我们探讨了肠道微生物群对 MPS III GISs 的影响。我们分析了两个具有相同基因突变（SGSH 基因 c.544C > T，c.1080delC）和相同饮食的 MPS III 兄弟姐妹的肠道微生物群的组成和功能，但他们的 GISs 存在差异，其中一人反复出现腹泻。通过 16S 测序，我们观察到 MPS III 患者的 alpha 多样性降低， 和 的丰度降低，而 和 家族的丰度升高，与健康对照组相比。比较兄弟姐妹，我们发现 GIS 无患者的 和 的丰度增加，而 和 的丰度降低。该患者还具有参与糖胺聚糖代谢的 基因（ ， ， ， ）的相对丰度较高。我们发现两个 MPS III 患者的粪便中 HS 水平高于健康志愿者，特别是在 GISs 患者中。功能上，来自 GISs 患者的整个粪便代谢物在体外诱导健康单核细胞的氧化应激。最后，从 MPS III 粪便样本中分离出的 菌株具有 HS 降解能力。总的来说，我们的研究结果揭示了 MPS III 兄弟姐妹之间存在不同的微生物群组成和功能，他们表现出不同的胃肠道症状。我们的研究可能为探索肠道微生物群的影响及其改善 Sanfilippo 综合征患者生活质量的潜力提供了一个切入点。
