Stanford University Neurofiber Study

Rationale:

Parkinson's disease (PD) is a progressive neurological disorder, and the biological drivers of disease progression remain poorly defined. Gastrointestinal (GI) dysfunction is among the earliest and most common non-motor features of PD, and constipation, dysbiosis, and an altered gut microbial composition are reported in up to ~80% of people with PD (PWP). PWP show reduced abundance of commensal taxa that produce metabolites, notably short-chain fatty acids (SCFAs), that are involved in intestinal motility, epithelial barrier integrity, and mucosal immune homeostasis. SCFAs are generated by microbial fermentation of dietary fiber. SCFA supplementation has been associated with cognitive changes in animal models and in a small pilot cohort of PWP. Greater non-motor symptom burden, as measured by MDS-UPDRS Part I, is associated with increased risk of dementia in PD, which is one reason the gut is of interest in PD research.

In the general population, fiber supplementation is associated with increased stool frequency and bowel regularity, and it has been proposed as a way to support bowel function and the gut microbiome in PWP. Response to fiber depends on baseline microbiome composition and function, but the responsiveness (flexibility) of the PD microbiome to fiber has not been characterized, and the time course over which fiber changes bowel function or gut inflammation in PWP has not been systematically studied. This study addresses that gap.

Animal studies support a role for the gut microbiome in Parkinson's disease. In a genetically modified mouse model of Parkinson-like disease, germ-free mice showed fewer movement problems and less brain inflammation than mice with a normal microbiome, even though both groups had the same genetic risk. When germ-free mice received gut bacteria from people with Parkinson's disease, their symptoms worsened, whereas bacteria from healthy human donors did not worsen movement symptoms (Sampson et al., 2016). This suggests that gut bacteria may be involved in the disease process and not only accompany it.

Study design:

SUNs is a 4-month, open-label, two-arm interventional study with three longitudinal timepoints: baseline (no supplementation), the end of a 3-month fiber supplementation period, and one month after cessation. PWP are enrolled together with a cohabitating control (household partner), and both receive the same intervention. Dyad-based enrollment is intended to reduce environmental and dietary confounding of the gut microbiome. Participants are recruited from an existing Stanford biobank of 79 PWP/cohabitating control dyads, so baseline characterization already exists for the candidate pool.

The intervention is a prebiotic fiber bar containing 11 g of fiber, manufactured by Sorridi Therapeutics, at a dose of one bar per day as recommended by the study dietitian. Participants may choose one flavor (Lemon Cranberry or Dark Chocolate Cherry) or receive an equal shipment of both. Tolerability was previously assessed in an open-label, single-arm pilot (NCT07127120); in a sponsor-reported summary, 18 adults with Parkinson's disease ate one bar daily for 28 days, all completed the study, and no serious adverse events were reported. SUNs extends daily exposure to 90 days. The NeuroFiber bars are donated by Sorridi Therapeutics.

Specific aims and hypotheses:

Aim 1: Determine whether fiber supplementation changes fecal inflammatory protein levels over time in PWP. We hypothesize that Neurofiber supplementation will change fecal inflammatory protein levels (e.g., TNF-α, IL-6, CRP), and that the persistence of these changes after cessation will differ between controls and PWP.

Aim 2: Determine the rate at which initiation and cessation of fiber supplementation affects bowel function in PWP. We hypothesize that bowel function (Bristol Stool Form Scale, defecation frequency, and bowel symptoms) will change in both PWP and controls during supplementation, and that these measures will return toward baseline at different rates in PWP and controls after cessation. Bowel symptoms and bowel-related quality of life (PAC-SYM and PAC-QoL) are assessed longitudinally in parallel.

Biospecimen collection and processing:

Stool is collected remotely by participants using commercial stool collection kits (DNA Genotek, Zymo, and OMNImet Gut collection tubes) and returned by mail to Stanford, where samples are preserved for downstream protein isolation and quantification. Collecting at home enables the repeated longitudinal sampling this design requires and supports retention. We will also preserve these samples for downstream metagenomic and metabolomic analysis.

Protein quantification:

Fecal proteins will be isolated and quantified in collaboration with the Stanford Human Immune Monitoring Center (HIMC). Inflammatory protein levels will be measured using the NULISA (NUcleic acid Linked Immuno-Sandwich Assay) platform, a proximity-ligation immunoassay with DNA-barcoded antibodies and sequencing or qPCR readout that allows highly sensitive, multiplexed protein detection from very small sample volumes.

Analysis:

Longitudinal changes in fecal inflammatory proteins and in questionnaire-based bowel measures will be compared across the three timepoints within participants and between PWP and cohabitating controls.

Significance and future directions:

The study will define the extent and time course of PD gut microbiome adaptation to fiber and test whether adaptation is associated with changes in bowel function and gut inflammation. These data are intended to inform future research on diet, the gut microbiome, and the gut-brain axis.