Modulation of Gut Microbiota by Rifaximin in PD Patients

Gut microbiota is the largest microorganisms pool in the human body. The physiological roles of gut microbiota for digestion, metabolism, immune homeostasis, GI-tract infection prevention and anti-inflammation. The very first colonized gut microbiota of infant are from maternal vaginal fluid. Gut microbiota are strongly affected by the environment, diet and health status of host.

The alteration of gut microbiota (any microbial imbalance resulting in a shift (i.e., loss or overgrowth of a species) and/or reduction in microbial diversity), which is known as dysbiotic microbiota, is associated with numerous human diseases, including metabolic syndrome, diabetes, obesity, depression and autism. Among people with hypercholesterolemia, they tend to have lower richness and diversity of bacterial communities. In addition, patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. Gut microbiota are also the primary source of short-chain fatty acids (SCFAs). These molecules are known to significantly impact the gut environment and host metabolism and to exhibit potent anti-oxidant and anti-inflammatory properties.

Microbial dysbiosis also impacts on local and systemic inflammation, which are relevant to several human diseases. The gut is the main site for the generation of the two most important T cell populations, the inducible regulatory T cells (iTregs) and CD4IL17-producing cells (Th17). In physiological status, those T cells are responsible for immune tolerance, which avoid inducing immune reaction toward the antigens presented in the gut microbiota9. However, once the detrimental species of gut microbiota trigger the slow and persisted inflammatory process in the gut, intestinal lymphocytes release pro-inflammatory cytokine (IL-1β, IL-6 and TNF), which leads to the elevated intestinal permeability of mucosa. Inflammation induces the permeabilization of gut mucosa and subsequent intestinal leak (leaky gut syndrome). The leaking results in the entrance of large amount of bacterial toxins (such as LPS) into systemic circulation and elevated systemic inflammation.

Gut microbiota also play an important role in several neurological diseases due to the presence of gut-brain axis. Distinct gut microbiota are found in plenty of people with neurological diseases, such as autism, depression, Alzheimer's disease (AD) and Parkinson's disease (PD). Regarding to PD, a neurodegenerative disease with the most well-studied gut-brain axis, 70% people with PD (PwP) suffered from gastrointestinal symptoms and constipation is the most complained. Those symptoms stem from the degeneration of vagus nerve-innervated mesenteric plexus. According to the well-known Braak stage which showed the caudal rostral spreading of Lewy body, medullary vagal nucleus is the first area with the involvement of PD-pathology. In fact, abnormal mesenteric α-synuclein accumulation herald the vagal pathological change. The hypothesis that α-synuclein is originated from intestine is supported by an animal study. Mice with mutated α-synuclein over-expressing had abundant PD-pathology in the midbrain. However, elimination of gut microbiota attenuated the pathology. This study hint that gut microbiota is essential for the aggregation of α-synuclein and the therapeutic potential of modulation gut microbiota for the neuroprotection of PD.

Distinct gut microbiota in PwPs compared with healthy people were demonstrated by several studies: higher level of Akkermansia muciniphila, Bifidobacterium, Methanobrevibacter smithii and Enterobacteriaceae whereas lower level of Prevotellacea, Faecalibacterium prausnitzii and Lactobacilli/Enterococci. Although the causal relationship between PD with the alteration of specific species of bacteria is unknown, some of the bacterial species play role in the aforementioned PD pathogenesis. For instance, Prevotella helps in breaking down complex carbohydrates to produce anti-oxidative, anti-inflammatory SCFAs and neuro-beneficial thiamine and folate and reduce the amount of Prevotella may be harmful for the dopaminergic neurons and augmentation the disease progression.