Umamahesan Chianna, Pilcicka Aleksandra, Yick Jennifer, Baker Kieran, Smith Melvyn, Taylor David, Ma Yun, Mullish Benjamin H, Marchesi Julian R, Gilbert Steven, Sadeghi Nasab Shervin D, Moyes David, Pavlidis Polychronis, Hayee Bu'Hussain, Dobbs Sylvia M, John Dobbs R, Charlett André
Host Microbiome Interaction: Clinical Pharmacology and Therapeutics, Institute of Pharmaceutical Science, King's College London, London, U.K.
The Maudsley Hospital, London, U.K.
Biochem J. 2025 Jun 11;482(12):807-21. doi: 10.1042/BCJ20240621.
Constipation is a forerunner to Parkinson's disease (PD) diagnosis, worsening thereafter. We explore the relationship of intestinal barrier dysfunction to constipation and whether intestinal fungal load is an aggravating factor. Fungal load was quantified by real-time PCR, using ITS1F-ITS2 primer set, on microbial DNA extract from stool in 68 participants with PD, 102 without. Fungal load was 60% higher per decade after age 60 years, with no PD status interaction with age. After age adjustment, it was associated inversely with dietary renal acid load. It was unrelated to the presence of constipation or barrier dysfunction. Neither consumption of antimicrobials nor of other targeted exogenous substances was associated. Enzyme-linked immunosorbent assays measured barrier dysfunction markers, faecal alpha-1 antitrypsin (AAT), zonulin and serum intestinal fatty acid-binding protein (I-FABP). Barrier dysfunction was associated with constipation and slower radiographic colonic transit. Functional constipation was 28% more frequent with a doubling of AAT concentration. More colonic-transit test markers were retained in the transverse colon, the higher the AAT and zonulin concentrations, anatomically spotlighting abnormality for the entire colon. In contrast, the concentration of the small intestinal barrier marker I-FABP was associated with looser stool consistency, which is consistent with secondary microbial overgrowth. By showing a relationship of intestinal barrier dysfunction to constipation, this study supports the hypothesis that dysfunction may be consequential. Dysfunction may be a necessary, but not sufficient, precursor to PD, in allowing inflammaging. Since ageing is the clearest risk for PD, a gut pathogen escalating in abundance from the sixth decade, integral to fungal load, and whose reproduction and virulence is favoured by alkalinity, tallies.
便秘是帕金森病（PD）诊断的先兆，且此后会加重。我们探讨肠道屏障功能障碍与便秘的关系，以及肠道真菌负荷是否为加重因素。使用ITS1F-ITS2引物对，通过实时PCR对68例PD患者和102例非PD患者粪便中的微生物DNA提取物进行真菌负荷定量。60岁以后，每十年真菌负荷增加60%，且真菌负荷与PD状态和年龄无交互作用。年龄调整后，真菌负荷与饮食肾酸负荷呈负相关。真菌负荷与便秘或屏障功能障碍的存在无关。抗菌药物或其他靶向外源物质的使用与真菌负荷均无关联。采用酶联免疫吸附测定法检测屏障功能障碍标志物，即粪便α-1抗胰蛋白酶（AAT）、闭合蛋白和血清肠脂肪酸结合蛋白（I-FABP）。屏障功能障碍与便秘及结肠造影传输减慢有关。AAT浓度翻倍时，功能性便秘的发生率增加28%。横结肠中保留的结肠传输试验标志物越多，AAT和闭合蛋白的浓度越高，从解剖学角度凸显了整个结肠的异常。相比之下，小肠屏障标志物I-FABP的浓度与粪便质地较稀有关，这与继发性微生物过度生长一致。本研究通过揭示肠道屏障功能障碍与便秘的关系，支持了功能障碍可能是后果的假说。功能障碍可能是PD发生的必要但非充分的先兆，因为它会导致炎症衰老。由于衰老显然是PD的最大风险因素，而一种肠道病原体从第六个十年开始数量不断增加，它是真菌负荷的组成部分，且其繁殖和毒力在碱性环境中更有利，这与上述情况相符。
