Antibiotics are drugs regarded to influence gut microbiota composition by affecting both pathogenetic and beneficial microbes’ population (Fornai et al., 2016a; Becattini et al., 2016). In addition, besides targeting gut microbiota, antibiotics are also endowed with additional properties, such as anti-inflammatory and neuroprotective activities (Stoilova et al., 2013; Sultan et al., 2013; Fornai et al., 2016a; Santa-Cecília et al., 2019). In this context, a previous study by Zhou et al. showed how gut microbiota modulation via ceftriaxone, a third-generation cephalosporin active against both Gram-negative and positive bacteria, exerted beneficial effects in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice. Authors demonstrated that the administration of ceftriaxone in MPTP mice improved motor dysfunctions and maintained neuronal integrity by restoring brain-derived neurotrophic factor (BDNF) and glial derived neurotrophic factor (GDNF) expression levels in CNS. Such effects were associated with an anti-inflammatory activity, exerted by the downregulation of TLR4 and MyD88, locally restricted to the colon (Zhou et al., 2021). However, more investigations are needed to clarify if such effects depend only on the direct modulation of gut microbiota or also on systemic anti-inflammatory and neuroprotective effects induced by the antibiotic. Notably, a recent and pioneering study has tested antibiotic rifaximin, a poorly absorbed antibiotic with a wide spectrum of antibacterial activity, in PD animals at the early phases of the disease. In particular, Hong and colleagues reported that a 3-month rifaximin treatment protected MitoPark PD mice against neuronal loss and attenuated systemic inflammation, preventing BBB breakdown (Hong et al., 2022). Overall, these findings suggest that a gut-directed therapy aimed at modulating microbiota composition via particular antibiotics can halt disease progression and symptoms, representing a suitable therapeutic option for the management of this neurodegenerative disorder, but more researches are needed to identify the specific activity of any antibiotics and the more effective one.

Growing evidence highlights how dietary interventions can influence gut microbiota composition and, in turn, impact on neurological disorders, including PD (Larroya-García et al., 2019). Healthy diet habits have been found to exert neuroprotective effects, decreasing neuroinflammatory responses, oxidative stress, and mitochondrial dysfunctions in the brain (Muth and Park, 2021). Several studies have reported the beneficial effects mediated by different dietary interventions in PD animals. Among all the preclinical models, the rotenone model (which consists in the intravenous, oral, subcutaneous, or intraperitoneal administration of rotenone toxin) represents the most used one because it depicts as fully as possible all the PD features, including GI dysfunctions, olfactory deficits, dopaminergic cell death, neuronal oxidative stress and α-synuclein phosphorylation and aggregation (Radad et al., 2019) (see Table 1 for more detailed information about all the PD preclinical models). Indeed, Perez-Pardo et al. investigated the effect of a dietary intervention combining uridine and docosahexaenoic acid (DHA) in rotenone-induced PD mice (Perez-Pardo et al., 2018b). In particular, authors observed that the diet ameliorated motor coordination and exerted a neuroprotective effect, increasing the survival of DA neurons. Moreover, the enriched dietary intervention mitigated GI dysfunctions, α-synuclein accumulation and enhanced zonulin-1 expression in colonic tissues from rotenone-treated mice (Perez-Pardo et al., 2018b). Such effects were attributed both to uridine, a phospholipid precursor, able to increase synaptogenesis and to DHA, regarded to exert anti-inflammatory and antioxidant effects (Perez-Pardo et al., 2018b). Likewise, Zhang and colleagues proved that the dietary intake of α-ketoglutarate ameliorated central α-synuclein pathology, rescued DA neuron degeneration, and suppressed pro-inflammatory mediators such as IL-6, IL-1β and TNF in transgenic A53T α-syn mice via enhancing nigral DHA levels (Zhang et al., 2023). Nevertheless, more studies are needed to better clarify whether the effects resulting from uridine and DHA depend on a gut locally activity or on a direct effect in the brain, since uridine can be transported across cellular membranes in all tissues, including the CNS (Wurtman et al., 2010). Zhou et al. showed that a fasting mimicking diet, consisting in 3 days of fasting followed by 4 days of refeeding in MPTP PD mice, reshaped gut microbiota composition and attenuated neuroinflammation by decreasing IL-1β levels and increasing BDNF levels in the striatum, thus offering innovative perspectives for the treatment of PD (Zhou et al., 2019). Similar results were obtained in a very recent study by Jiang et al. in which the administration of a ketogenic diet, characterized by low carbohydrate, high fat, and moderate-protein levels, restructured gut microbiota composition and ameliorated motor dysfunctions in MPTP PD mice (Jiang et al., 2023). Overall, these findings suggest that dietary interventions ameliorate PD and related motor and GI symptoms by exerting anti-inflammatory and neuroprotective effects. However, the exact mechanisms by which such interventions may influence gut microbiota composition, and, in turn, PD progression remain still unclear.

Prebiotics are primarily indigestible dietary fibers that improve host’s health by selectively promoting the development and/or function of some bacteria in the gut (Davani-Davari et al., 2019). Soybeans, raw oats, unprocessed grains such as barley and wheat, indigestible sugars and oligosaccharides are the most prevalent sources of prebiotics (Markowiak and Ślizewska, 2017). The indigestible fibers, taken with the diet, reach the colon and are locally fermented by several bacteria strains, including Bifidobacteria (Hutkins et al., 2016). The final products of the fermentation include SCFAs (butyrate, acetate, and propionate), which promote beneficial activities to the host, such as inhibition of pro-inflammatory genes transcription (i.e., NF-kB, MAPK/ERK) and maintenance of gut barrier function and homeostasis (Blaak et al., 2020). Indeed, Srivastav et al. showed that the administration of sodium butyrate counteracted neurotoxicity, mitigated gliosis, and elevated neurotrophic factors levels in brain tissues from MPTP mice, confirming SCFAs as potent neuroprotective agents (Srivastav et al., 2019). Of note, sodium butyrate is in large part absorbed in the upper parts of GI tract and consequently its beneficial effects could be mainly addressed to a direct influence on the brain and, only in a lesser extent, to a gut-directed activity (Pellegrini et al., 2018). On these bases, prebiotic fibers targeting butyrogenic bacteria, such as chitin-glucan and β-glucan, able to promote butyrate production locally in the gut, are emerging for the treatment of PD (Cantu-Jungles et al., 2019). In this context, a recent study showed that the administration of four different monomers of chitosan oligosaccharide protected MPTP mice from DA neuron loss (Wang et al., 2022). Accordingly, several studies in PD mice have shown that non-digestible oligosaccharides such as galacto- and fructo-oligosaccharides (GOS and FOS, respectively) normalized motor and non-motor symptoms, including GI dysfunctions (Perez-Pardo et al., 2018a). The mechanisms underlying GOS and FOS effects resulted from a polarization of microbiota towards beneficial bacteria strain proliferation along with an improvement of synaptic functions in the ENS (Perez-Pardo et al., 2018a). Therefore, GOS and FOS supplementation might confer clinical benefits on PD patients, although more studies are essential to provide further insights on how FOS and GOS beneficially affect PD motor and non-motor symptoms.

Probiotics are live microorganisms able to induce benefits in the host and there are lot of evidence regarding their use in neurodegenerative disorders, including PD (Zommiti et al., 2022). Their beneficial activity results from different mechanisms, such as preservation of barrier integrity through the modulation of tight junctions’ expression (i.e., zonulin-1, occludin and claudin-1) and mucus production as well as reduction of enteric and systemic immune/inflammatory responses (Klaenhammer et al., 2012; Toscano et al., 2017; Sanders et al., 2019). Several efforts have been made to investigate the effects of probiotics and their metabolites in PD animal models, focusing the attention on their effects in halting or slowing down disease progression. Sun et al. showed that treatment with Clostridium butyricum (Cb) to MPTP mice reshaped gut microbiota composition, augmenting the relative abundance of SCFAs-producing bacteria such as Akkermansia, along with a normalization of SCFAs receptor expression, including GPR41/43, as well as an increase of GLP-1 in colonic tissues (Sun et al., 2021). Of note, GLP-1 can cross the BBB and, through the interaction with its receptor (GLP-1R) located with high density on SNpc neurons, astrocytes, and microglia, can, in turn, promote neurogenesis and reverse neuronal loss (Sun et al., 2021). In agreement with the previous results, Fang et al. showed how an engineered probiotic, carrying GLP-1 expression vector, ameliorated locomotor impairment, increased tyrosine hydroxylase levels in neurons and counteracted inflammation in MPTP mice, opening the way to implement genetically modified bacteria for the treatment of brain diseases (Fang et al., 2019). Other studies have evaluated the effects of Bifidobacterium and Lactobacillus in PD animals (Liao et al., 2020; Wang et al., 2022; Li et al., 2022). In particular, Li et al. showed that a 5-week supplementation with Bifidobacterium breve CCFM1067 suppressed pathogenic bacteria strains (e.g., Escherichia-Shigella), increased beneficial bacteria growth (e.g., Bifidobacterium and Akkermansia) and enhanced the expression of tight junction proteins, along with a decrease in pro-inflammatory cytokines levels in colon and brain tissues from MPTP mice (T. Li et al., 2022). Accordingly, a plethora of studies conducted in different animal model of CNS disorders showed that the assumption of probiotics increased intestinal tight junctions’ expression, restored colonic mucus cells loss, that, in turn, can reduce immune/inflammatory responses and alleviate central symptoms (Pellegrini et al., 2023). Another study by Ma and colleagues showed that Lactiplantibacillus plantarum PS128, administrated to rats with nigrostriatal dopaminergic neurodegeneration induced by 6-hydroxydopamine (6-OHDA), increased DA content in the striatum and attenuated dopaminergic neuronal loss (Ma et al., 2023), highlighting the neuroprotective effects of Lactobacillus supplementation. Interestingly, the neurotrophic effects of Lactobacillus and Bifidobacterium supplementation were tested in a study conducted by Castelli et al. in which SLAB51 (a probiotic mixture of Streptococcus thermophilus, Bifidobacterium longum, B. breve, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. Bulgaricus and Lactobacillus brevis) counteracted dopaminergic neuronal loss and modulated BDNF expression levels in the substantia nigra and in the striatum from 6-OHDA injected mice, by increasing peroxisome proliferator-activated receptor gamma (PPAR-γ) expression levels (Castelli et al., 2020). These findings suggest that the assumption of probiotics containing Bifidobacterium and Lactobacillus can represent a suitable therapeutical tool to manage PD via decreasing pro-inflammatory responses, counteracting oxidative stress and exerting neuroprotective effects (Magistrelli et al., 2019; Castelli et al., 2020; Xie and Prasad, 2020; Alipour Nosrani et al., 2021). Of interest, some probiotics displayed their potential to release neurotransmitters, including GABA, serotonin, acetylcholine, and noradrenaline that, successively, can influence brain functions. Accordingly, Pan et al. showed the ability of Pediococcus pentosaceus to counteract α-synuclein accumulation in SNpc, to maintain intracellular redox homeostasis and protect neurons from oxidative damage, through the increment of GABA levels in brain tissues from MPTP mice (Pan et al., 2022). However, whether P. pentosaceus-released GABA can influence indirectly brain functions through the maintenance of intestinal homeostasis, or rather it can migrate in the bloodstream and cross the BBB influencing the CNS, remain to be clarified.

In recent years, researchers are investigating the effects of “synbiotics”, the synergistic combination of pro- and prebiotics, in neurodegenerative disorders (Lye et al., 2018; Ton et al., 2020). In this context, Liu et al. tested the administration of Lacticaseibacillus rhamnosus GG (LGG) and polymannuronic acid (PM) either alone or in combination (PM + LGG) in MPTP mice (Liu et al., 2022). The results showed that all treatments protect MPTP mice from dopaminergic neuronal loss and neuroinflammation, with a more pronounced beneficial activity in those receiving PM + LGG. Interestingly, the underlying mechanisms of PM, LGG or PM + LGG seem to be different in protecting dopaminergic neurons. In particular, PM displayed an anti-inflammation activity in brain tissues via microbiota derived SCFAs, whereas LGG improved GDNF striatal expressions levels, emphasizing the hypothesis that the synergistic effects of synbiotics are closely dependent on the combination of a pro- and a prebiotic. However, the available preclinical data in PD models about the effectiveness of synbiotics are limited, and more studies are needed to define the most effective combination in slowing down the progression of PD.

Fecal microbiota transplantation (FMT) is a procedure that consists in the transplantation of a gut microbiota extract, obtained from the feces of a healthy donor, into the GI tract of a recipient (Bakken et al., 2013). FMT has been tested in different pathological settings (e.g., Clostridium difficile infection, ulcerative colitis, and others) because of its capacity to thoroughly and extensively regenerate gut microbiota, modifying intestinal microbial diversity and restoring atypical intestinal flora (Li et al., 2019; Kim et al., 2021). Several preclinical studies have explored the effect of FMT as a potential therapeutical strategy for the treatment of CNS disorders, including PD. In this regard, Zhao et al. showed that FTM improved both intestinal and motor dysfunctions in rotenone-treated mice and elicited a remarkable reduction of lipopolysaccharide levels in serum, colon, and CNS tissues, underlying how the reshaping of gut microbiota can ameliorate IEB integrity and, successively, reduce immune/inflammatory processes (Zhao et al., 2021). Moreover, based on another study by Sun et al., FMT significantly mitigated gut dysbiosis and reduced microglia and astrocyte activation, thus suggesting a significant neuroprotective effect (Sun et al., 2018). Overall, the above findings shed light on the possibility to take advantages through the modulation of MGB axis using FMT practice, although further investigations are necessary to better understand how identify healthy donors, long-term safety, delivery methods, and clinical benefits of FMT.

Among the numerous dietary regimens, the mediterranean diet (MD) is recognized as a dietary model able to improve health in several disorders, including cardiovascular diseases, cancer, and metabolic syndrome in both Mediterranean and non-Mediterranean populations (Sánchez-Sánchez et al., 2020). In particular, the beneficial effects mediated by the MD seem to be addressed to its content in anti-inflammatory and antioxidant compounds (such as β-carotene and ascorbic acid) and to its ability to control glycemic levels and improve endothelial functions, thus resulting in a normalization of blood pressure levels (Martín-Peláez et al., 2020). Moreover, it is well accepted that a diet intake is responsible for gut microbiota shaping, in terms of composition and function. In this regard, the MD has been observed to positively influence gut microbiota, thanks to its enrichment in dietary fibers and complex carbohydrates which, once fermented by gut microorganisms, lead to the consequent production of SCFAs, capable of regulating glucose and lipid metabolism in several tissues (Martín-Peláez et al., 2020). Recently, a new field of research has showed that a higher adherence to the MD is associated with a lower risk of mental and brain disorders (Aridi et al., 2017). Indeed, case-control studies reported that MD assumption was associated with a decreased risk to develop PD (Alcalay et al., 2012; Maraki et al., 2019). A recent randomized clinical trial examined the impact of the MD on cognitive performance in PD participants. In this study, authors observed that the diet improved cognitive and executive functions, as well as attention, memory, and language (Paknahad et al., 2020). The major source of fat in the MD is olive (Olea europaea L.) oil, containing monounsaturated fatty acids, which possesses antioxidant activity and can reduce α-synuclein aggregation (Mohammad-Beigi et al., 2019). Furthermore, the dietary vitamin E and carotene intake from MD were associated with a lower risk of PD, likely minimizing oxidative damage by neutralizing the effect of oxygen free radicals (Yang et al., 2017). Moreover, the ketogenic diet can activate dopaminergic nuclei of the CNS (Naneix et al., 2017) through the increased utilization of ketone bodies by the brain. After 12 weeks, the above effects ameliorate cognitive functions and alleviate both motor and non-motor symptoms in PD patients (Phillips et al., 2018), and improve the feeling of anxiety, described as a persistent condition of worry not connected to stressful events (Tidman et al., 2022). Overall, these findings underscore the potential of tailored nutritional strategies in mitigating the symptoms of PD (Baroni et al., 2011). Further research and understanding of the intricate relationship between diet and PD may pave the way for innovative approaches in the management of this neurodegenerative disorder.

The use of prebiotics in PD patients has been demonstrated to improve GI peristalsis, enhance immunological function, and alleviate constipation. In one small open-label investigation, a diet high in insoluble fibers (a typical prebiotic food source) ameliorated constipation, motor capacities and systemic L-dopa bioavailability (Astarloa et al., 1992). Furthermore, in an open-label trial enrolling 87 participants, the authors found that individuals with PD receiving resistant starch improved non-motor symptom ratings and had also substantially incremented fecal butyrate levels, as well as decreased fecal calprotectin levels, compared to patients that received dietary recommendations only (Becker et al., 2022). In another open-label study, the administration of a prebiotic mixture to PD patients determined the decrease in total UPRDS score and a reduction in both intestinal inflammation and circulating zonulin levels, a marker of IEB dysfunction (Hall et al., 2023). Therefore, prebiotics could have beneficial effect on PD by stimulating the production of SCFA-producing bacteria and their metabolites. However, there is currently scarce clinical data on prebiotics in PD patients, hence more trials are needed to adequately study the process.

Many studies evaluated the effect of multistrain probiotics in the treatment of PD constipation (Georgescu et al., 2016; Ibrahim et al., 2020; Tan et al., 2021; Du et al. 2022). Tan and colleagues observed a significant increase in bowel movements and constipation symptoms in PD patients treated with probiotic capsules containing strains of Lactobacillus, Bifidobacterium, and Enterococcus (Tan et al., 2021). In another study with a different formulation containing Lactobacillus, Bifidobacterium, and Enterococcus the researchers also found a significant reduction in Bristol stool scale (BSS) score, patient assessment of constipation quality of life questionnaire (PAC -QOL) score and degree of defecation effort score, associated with positive changes in the gut microbiota composition of PD patients (n = 46) (Du et al., 2022). Other studies have evaluated the effect of probiotics in motor and non-motor symptoms (Tamtaji et al., 2019; Yang et al., 2023). Tamtaji et al. in their randomized, double-blind trial (n = 60) observed that a 12-week treatment with probiotic capsules containing L. acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum determined a significant decrease in MDS-UPRDS, other than reducing inflammatory parameters and oxidative stress. In a recent research, involving 128 PD patients, a fermented milk containing Lacticaseibacillus paracasei strain Shirota was able to improve constipation-related symptoms but also ameliorate other non-motor symptoms (i.e., depression and anxiety) (Yang et al., 2023). Overall, probiotics are likely to represent a promising therapeutic strategy for the treatment of PD-related GI symptoms, but their safety needs to be further evaluated, as Enterococcus spp., often incorporated in probiotics, has shown significant levodopa breakdown capability (Rekdal et al., 2019), stressing the need for caution during its utilization.

Considering the association between GI symptoms and PD, FMT might represent a possible therapeutical strategy. Several trials (NCT04854291, NCT05204641 and NCT04837313 on ClinicalTrials.gov) are at present being conducted to explore the impact of FMT on both motor and non-motor symptoms in PD. In 2019, the first human case report including the employment of FMT in PD was published (Huang et al., 2019). FMT was performed in a 71-year-old man who had a 7-year history of PD. The patient got nearly immediate alleviation from constipation, and his tremor in his lower extremities was also significantly decreased and remained reduced at the 3-month follow-up (Huang et al., 2019). In a more recent study, Segal and colleagues examined a group of six PD patients who received FMT (Segal et al., 2021). Four weeks after FMT, most of patients showed improvements in their PD-related constipation and an amelioration in UPDRS-III and Non-Motor Symptoms Scale scores, with few adverse effects reported (Segal et al., 2021). FMT from healthy donors, administered via a nasoduodenal tube, has also demonstrated to elicit significant benefits for both motor and non-motor PD symptoms (Kuai et al., 2021). In another study conducted on 15 patients, at a 1-month follow-up, it was observed that FMT was linked with better sleep and overall quality of life, in addition to decreases in motor symptoms, anxiety, and depression scores (Xue et al., 2020). A 3-month follow-up of the same population revealed long-term gains among the 12 participants who remained in the trial. Interestingly, ten of the fifteen patients in the trial received colonic FMT, while the remaining five received FMT through a nasoduodenal tube. The latter group showed major improvements on several motor and non-motor PD-related evaluations, as compared with patients receiving FMT via the colonic method, indicating that method of delivery may be a significant variable in FMT success (Xue et al., 2020). The adverse effects observed in the previous studies were minor to mild and of short duration (Huang et al., 2019; Xue et al., 2020; Kuai et al., 2021; Segal et al., 2021). Overall, this research shows that FMT could represent a feasible treatment for PD. Still, given the different rates of response in relation to FMT delivery, more research is needed to determine the appropriate route of administration, the choice of proper endpoints, and the rate of administration required to sustain desired beneficial effects.

Among the antibiotics, rifaximin, has been used to treat small intestinal bacterial overgrowth (SIBO) also in PD. In a recent study, involving 33 PD patients, SIBO eradication with rifaximin resulted in lower GI motor fluctuations, but without ameliorating L-DOPA bioavailability (Fasano et al., 2013). Additional microbial-directed therapies having the potential to assist PD patients, such as postbiotics, small-molecules and biological drugs, have yet to be fully investigated in the clinical context. SCFAs administration and selective blocking of levodopa-metabolizing bacterial enzymes appear to offer special promises, although more testing in human interventional research is required. Other immunomodulatory and IEB-restoring therapies need more consideration. Anti-TNF treatment, which has been linked to a lower PD incidence in IBD patients (Peter et al., 2018), has been shown to change fecal microbiota composition, with fecal amounts of butyrate and SCFAs in general being linked to clinical remission (Aden et al., 2019). Another new frontiers could be targeting PD-related molecular pathogenesis (for example, involving α-synuclein or glucocerebrosidase) in the ENS. In an open label trial, orally administered squalamine (that seems to relocate α-synuclein aggregates from ENS neurons) was safe and significantly reduced the symptoms of constipation in patients with PD (Hauser et al., 2019).