Personalized treatment of gut health to combat levodopa-resistance in persons with Parkinson’s disease
Main applicant: Prof. Marcel Verbeek
Affiliation(s): Radboud university medical center, Nijmegen (NL)
Abstract: Many persons with PD develop small intestinal bacterial overgrowth (SIBO), which negatively affects their quality of life by causing abdominal pains, constipation, bloating, nausea, diarrhea and excessive flatulation. Recent work indicates that SIBO can cause additional problems for persons with PD. Specifically, SIBO is likely associated with overgrowth of specific bacterial subcultures, which produce an excessive amount of the enzyme tyrosine decarboxylase (TDC) in the gut. This TDC enzyme breaks down levodopa (the most important symptomatic drug to treat PD) before it can enter the brain, thus providing a peripheral obstacle that can explain why a significant proportion of patients respond much less favorably to levodopa than others, and why some patients even appear to become resistant to levodopa. This causes tremendous problems in daily clinical practice, because treatment failure of levodopa typically blocks any further attempts to try alternative treatments, thus causing considerable yet avoidable disability. In this project, we aim to: (1) examine whether quantifying levels of the TDC enzyme in the gut may serve as an objective biomarker that would objectively indicate the presence of such a peripheral blockade to levodopa; and (2) evaluate whether two innovative treatment strategies can help to alleviate this ‘peripheral levodopa resistance’. Specifically, our first approach is to seek proof-of-concept evidence that treatment with the antibiotic rifaximin can restore microbiome health and – by reducing gut TDC levels – restore the responsiveness to levodopa. We also expect vancomycin treatment to alleviate the debilitating complaints associated with SIBO. Our second and completely complimentary approach is to leave the gut itself untouched, but instead we aim to bypass the gut blockade by administering the potent dopamine receptor agonist apomorphine via a subcutaneous delivery. We expect that patients who have become partially or completely resistant to oral levodopa due to high TDC activity in the gut will show a gratifying response to apomorphine treatment. If proven to be correct, this could lead to timely instalment of dopamine agonist treatment in daily practice, including subcutaneous apomorphine, but also using less invasive approaches such as subcutaneous patch treatments. Our study will provide critical new insights into the role of peripheral levodopa resistance. Our findings can potentially have important clinical implications, since adequate tackling of this phenomenon using either vancomycin, a subcutaneous dopamine agonist or a combination thereof, could avoid the typically prolonged and time-consuming process of gradual further dose increases in levodopa (which is now common in daily practice). Timely instalment of these new treatment strategies could provide significant benefits to many patients with PD worldwide.
Related Publications: Personalized Response of Parkinson’s Disease Gut Microbiota to Nootropic Medicinal Herbs In Vitro: A Proof of Concept.