The Peripheral Intestinal Trigger Hypothesis: Gut Lumen as the Origin of Neurodegeneration in GBA1/Ceruloplasmin Variant Carriers — A Novel Unified Framework on Bacterial Metal Sequestration, Copper-Zinc-Iron Imbalance, and Alpha-Synuclein Misfolding

We present an original hypothesis proposing that in patients carrying GBA1 geneheterozygosity and any variant of the ceruloplasmin (CP) gene, the intestinal lumen is theprimary site of initiation of a pathological cascade leading to neurodegeneration. A peripheralirritative stimulus — proposed to include latent herpesviruses such as Epstein-Barr virus (EBV)or cytomegalovirus (CMV), acting as gut-level triggers rather than central causative agents —activates the overgrowth of H2S-producing sulfate-reducing bacteria (SRB) within theintestinal lumen. The resulting H2S production captures luminal copper as insoluble coppersulfide (CuS) deposited on the intestinal wall, producing functional copper depletion that isinvisible to standard assays.This intestinal copper sequestration disrupts the copper-zinc-iron metabolic triad, impairingceruloplasmin ferroxidase activity, copper-zinc superoxide dismutase (SOD1) function,mitochondrial respiratory chain efficiency, and — through alpha-synuclein copper-dependentconformation — promoting misfolding and retrograde vagal propagation to the basal ganglia.The neurodegeneration of dopaminergic neurons is the final, distal consequence of thisperipheral, intestinal metabolic failure.We propose that mapping the total quantity of transition metals in the fecal compartment —using ICP-MS after complete acid digestion — combined with identification of H2S-producingbacteria at pathogenic abundance, serial anti-ZnT8 antibody measurement, and serumceruloplasmin, constitutes a novel diagnostic panel. The therapeutic strategy — dissolvingintestinal metal-sulfide complexes through targeted microbiota modulation — is proposed as adisease-modifying and potentially preventive intervention in genetically predisposedindividuals, acting upstream of all neurological manifestations