Discussion
PD-associated gastrointestinal dysfunction, neurological dysfunctions, gastrointestinal symptoms, irritable bowel syndrome, PD symptoms, mood disorders, functional gastrointestinal disorders, gastrointestinal disorders, constipation, Alzheimer’s disease, PD, dysbiosis, greasy, autism spectrum disorders, aggravate disease
DISEASE PROGRESSION, IRRITABLE BOWEL SYNDROME, GASTROINTESTINAL DISEASE, NEURODEGENERATIVE DISEASE, AMYOTROPHIC LATERAL SCLEROSIS, DISEASE, MOTOR DISORDERS, MULTIPLE SYSTEM ATROPHY, FUNCTIONAL GASTROINTESTINAL DISORDER, GASTROINTESTINAL DISORDERS
Increasing reports showed that dysbiosis in the gut microecological system promotes altered host-microbial interactions and might aggravate disease progression in many neurological conditions, such as PD, autism spectrum disorders, Alzheimer’s disease, multiple system atrophy, and amyotrophic lateral sclerosis.In the present work, we carried out an RCT study on the effects of FMT on patients with PD. We used freeze-dried fecal microbiota powder capsules, this preparation is much more acceptable and accessible for patients than conventional endoscopic routes such as colonoscopy or gastrointestinal tube, which require advanced endoscopists or radiological equipment, capsule preparation allows patients get FMT at home or through distant delivery. Herein, we demonstrated that oral FMT significantly improved the effect of conventional PD medications on PD-associated symptoms. Before the intervention started, participants in FMT and placebo group demonstrated similar clinical characteristics regarding the evaluation for PD, at the end of this trial, FMT participants demonstrated a significantly greater change in MDS-UPDRS total score, showing that PD symptoms were alleviated.It has been generally realized that the gut microbiota is crucial in the physiological processes of CNS, including neurogenesis, myelination, microglial activation, etc. Similar cross talk exists between the CNS and gut microbiota in the progression of neurodegenerative disease, which involves not only motor symptoms but also non-motor symptoms (ie, cognition, mood, constipation, and many other aspects). Our data showed that non-motor experiences in the daily life of patients (assessed by the MDS-UPDRS part 1 scale) were significantly improved by FMT, which supports our previous hypothesis that FMT is efficient in improving the quality of life for PD patients. Previous report showed that FMT significantly improved constipation in PD patients,In addition, during the follow-up, a high placebo response to gastrointestinal symptoms was observed, which was in accordance with numerous reports of interventional studies of patients with gastrointestinal disease. Patients with functional gastrointestinal disorders tend to be sensitive to placebo treatment.Specifically, compared with the placebo arm, the FMT arm had a more significant decrease in MDS-UPDRS part 1 score at week 4 and week 12, showing that patients had a significantly better quality of life. Common knowledge on Parkinson’s Disease often focusses on motor dysfunction, but the poor life quality that greatly affects patients’ daily life. Moreover, the associated heavy burden for caregivers and social cost has now become an attractive issue in PD treatment. Since the MDS-UPDRS part 2 score represents the motor experiences in daily life, and the change of it could be an indicator for evaluating clinical improvement in PD patientsDysbiosis in the gut microecological system promotes altered host-microbial interactions and might aggravate the disease progression in many neurological dysfunctions like PD, autism spectrum disorders, Alzheimer’s disease, multiple system atrophy, amyotrophic lateral sclerosis.Based on these results, we hypothesize that the effectiveness of FMT on PD symptoms is contributed by the alteration of gut microbiota. Interestingly, we observed distinct responses from participants in the FMT arm, where some showed significant improvement in symptoms while others did not. We speculated this outcome might be related to the efficacy of FMT in altering the gut microbiota as well. This hypothesis was then confirmed by subgroup comparison between responders and non-responders to FMT therapy. Metagenomic analysis reveals that some butyrate-produced bacteria from the phylum Firmicutes, such as On the other hand, we observed that the FMT.R group had a more closely connected microbiota network compared with FMT.NR group. Similar outcomes were also reported in other studies. For example, Holvoet et al. reported that FMT induced different responses in patients with irritable bowel syndrome due to different features in gut microbiota.This study showed a promising result for FMT in improving the effectiveness of conventional PD medication. However, there are certain major limitations in this study, which might reduce the generalizability of this trial. The sample size is small and investigators were not masked from the participants’ allocation, which would introduce an imbalance in demographic or clinical characteristics in groups even though randomization was carried out. In addition, the comparability of the total MDS-UPDRS score for the two arms is marginal at baseline (with a p-value of 0.06), indicating a possible imbalance of disease severity between the two groups, meanwhile, there was also significant difference for MDS-UPDRS part 2 score at baseline, we speculate that this might be led by the small sample size of our trial, which is a major limitation of this work.To present the result more objectively, the unstructured correlation has been used in generalized estimating equations to assess the interaction of group and time, then minimize the re-testing bias, but there is still some bias that we cannot avoid in interpreting this. A larger cohort with a double- or triple-blind design of FMT on improving PD medication is still needed for further exploring the effectiveness. Another major limitation of this study is that 3 months of follow-up for PD patients is relatively short, our study only demonstrated the short-term effectiveness and safety in patients, based on current data, we may have a better understanding in future exploration of the efficacy of FMT on PD patients.Our clinical data showed that dietary guidance might also improve PD-associated gastrointestinal dysfunction, motor disorders, cognition, and mood disorders, which implied that the placebo might serve as a helpful treatment. This trial was performed in southwest China, where irritating food (mostly greasy and spicy food) is common in people’s daily lives, after enrollment, patients were asked to follow a specific regular and healthy diet, with limited protein intake and high-fiber diet, which may affect their composition of gut microbiota. Unfortunately, we did not record the dietary information during the intervention and follow-up, so we can only assume that dietary guidance affected gastrointestinal disorders and the quality of life of participants. In this study, we did not assess whether geological factors had an impact on the therapeutic outcomes in patients with PD, so further multicenter studies involving patients from different regions would be beneficial. Another major limitation of this study is that we did not perform a longer follow-up on participants. The current data only revealed a relatively short outcome in PD patients.In conclusion, this trial demonstrated that the oral FMT capsule was well-tolerated in patients with PD, it was effective in restoring the gut micro-ecology in PD patients, improving gastrointestinal symptoms and quality of life in PD patients, and was promising in improving the efficacy of conventional treatment for PD symptoms and cognitive function. We provided evidence that oral FMT
capsules can be safely and feasibly engrafted in these patients, demonstrating the promising potential of FMT in improving current PD medications. Our study also suggested that gut microbiota could serve as a biomarker to predict the response to FMT intervention in PD.