Table 1 Evidence for and against the gut origin of PD

Epidemiological studies

Gastrointestinal symptoms usually precede the motor symptoms of PD [18].

CNS and PNS are simultaneously involved in PD, with peripheral symptoms appearing first owing to poorer compensatory mechanisms [19].

IBD increases the incidence of PD [20,21,22,23,24]. Effective treatment can reduce the risk of  PD [23, 25].

A retrospective study did not confirm that IBD increases the risk for PD [26]. The results of a Mendelian randomization study did not support that treating IBD could prevent PD [27].

Vagotomy and appendectomy can lower the risk of PD [28, 29].

A long-term follow-up study did not confirm that vagotomy reduces the risk of PD [30]. In most studies, appendectomy is not correlated with PD; rather it even slightly increases the risk of PD in some studies [31,32,33].

Neuropathological studies

Pathological changes in PD may first occur in the ENS [34].

Results of several clinicopathological studies do not support the peripheral origin of PD. The studies showed that α-syn histopathology of the PNS rarely precedes the CNS [35,36,37].

Increased intestinal permeability and decreased level of the tight junction protein occludin in PD [38,39,40].

Clinical studies

Intestinal flora dysbiosis can occur in the prodromal phase of PD [41].

Gut microbes are associated with motor and nonmotor PD phenotypes [42].

Microbial therapy can improve the clinical manifestations of PD [43].

Animal studies

Changes in intestinal flora produce abnormal metabolites and structural proteins, which may trigger α-syn accumulation [44, 45].

The origin of PD may be multifocal [19].

α-Syn originates in the gut and spreads to the CNS through a transsynaptic intercellular approach [46].

PD pathologies, such as α-syn overexpression, can also propagate from the CNS to the intestine [47,48,49,50,51].

Fecal microbiome transplantation can exacerbate or improve PD-like symptoms in animal models [45].