While the role of the gut microbiota is well-established in the pathogenesis of gastrointestinal disorders such as irritable bowel syndrome and ulcerative colitis, an accumulating body of research implicates its involvement in the development of various neurodegenerative diseases.1,2 The strongest evidence thus far pertains to multiple sclerosis (MS), Parkinson disease (PD), and autism spectrum disorder (ASD). Emerging findings also point the potential for altered microbial composition playing a role in the development of Alzheimer disease, stroke, and amyotrophic lateral sclerosis.2
“It is becoming clear that a healthy diverse microbiome is essential for brain health, especially as we age,” said John F Cryan, PhD, professor and chair of the Department of Anatomy and Neuroscience at the University of College Cork in Cork, Ireland, and co-author of a review published in February 2020 in the Lancet Neurology.2
It has been proposed that the microbiota-gut-brain axis represents a bidirectional communication pathway through which the gut microbiota can influence the central nervous system, contributing to neurological and behavioral alterations. For example, increased permeability of the blood-brain barrier may “allow the translocation of immune cells and bacterial components into the brain and influence neuroinflammation,” according to the study authors.2
Dr Cryan and colleagues examined relevant results from clinical and preclinical studies to date, with selected findings highlighted below.
Considering the essential role of the gut microbiota in the “development and maturation of the immune system, it is not surprising that the microbiota is implicated in the pathogenesis of multiple sclerosis,” they wrote.2 In a case-control study published in 2016 in the European Journal of Neurology, researchers examined the gut microbiome composition of 18 patients with early-onset pediatric MS and 17 healthy control children without autoimmune disorders.3
In the patient group, they found that “perturbations in the gut microbiome composition were observed, in parallel with predicted enrichment of metabolic pathways associated with neurodegeneration” compared to the control group. “Findings were suggestive of a pro-inflammatory milieu,” they concluded.
Additional insights have been derived from research based on animal models of MS (experimental autoimmune encephalomyelitis). Studies investigating transplantation of microbiota from MS patients into mice “highlighted the importance of “interleukin IL10producing CD4 T cells in the immunomodulatory effects of the gut microbiota.”2
In research involving germ-free mice, resistance to the development of experimental autoimmune encephalomyelitis was reversed with transplantation of fecal microbiota from normal mice. “Furthermore, the presence of specific Gram-positive segmented filamentous bacteria in the gastrointestinal tract, which activate Th17 cells, significantly affected the severity of experimental autoimmune encephalomyelitis,” Dr Cryan, et al, explained.
Results from other studies of germ-free mice suggest the involvement of gut microbiota in regulating myelin production in the mouse prefrontal cortex and in the regulation of the blood-brain barrier. In the latter investigation, impaired integrity of the blood-brain barrier was reversed by dietary administration of short-chain fatty acids or bacteria that produce them.2
A 2018 pilot study showed that oral administration of a probiotic for 2 months decreased the abundance of taxa that have been linked to dysbiosis in MS, as well as “several KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways associated with altered gut microbiota function in MS patients, such as methane metabolism.”4 Probiotic supplementation also “induced an anti-inflammatory peripheral immune response characterized by decreased frequency of inflammatory monocytes, decreased mean fluorescence intensity (MFI) of CD80 on classical monocytes, as well as decreased human leukocyte antigen (HLA) D related MFI on dendritic cells.”
Larger trials are warranted to investigate the feasibility and efficacy of microbiota-targeted treatment strategies to reduce symptoms and the frequency of relapse in MS.
Autism Spectrum Disorder
It is estimated that non-heritable factors account for more than 50% of the neurobiology of ASD. Significant gastrointestinal symptoms are often present in ASD and represent an underrecognized comorbidity in this population.2 In cross-sectional studies, researchers have observed altered microbial composition in individuals with ASD, and animal studies have helped to elucidate the underlying mechanisms linking microbiota with ASD. In a 2019 study reported in Cell, germ-free mice exhibited hallmark autistic behaviors after undergoing transplantation of gut microbiota from humans with ASD.5
Altered microbial composition has been noted in mice with environmental risk factors for ASD, including maternal exposure to inflammation or valproate during pregnancy. Administration of single bacterial strains was shown to reverse various ASD-related behavioral and gastrointestinal changes in both human and animal studies, and administration of probiotics or prebiotics were found to modulate social behavior in animal models of ASD.2
In a recent small pilot study, children with ASD who underwent microbiota transfer therapy showed significant reductions in gastrointestinal symptoms including abdominal pain, diarrhea, and constipation, as well as improvements in ASD-related behaviors.6 These changes persisted for at least 2 years after the microbial transfer. There is a need for larger studies to further explore the potential for such interventions to modify symptoms of ASD in humans.
Many PD patients experience functional gut symptoms years before the emergence of motor symptoms, and a range of small studies have demonstrated altered microbial composition in PD patients.2 In a 2016 study, transplantation of fecal microbiota from PD patients led to motor deficits and neuroinflammation in mice, and behavioral symptoms were found to improve with antibiotic treatment.7
Researchers have reported the presence of α-synuclein in the mucosal and submucosal nerve fibers and ganglia of individuals with parkinsonian syndrome, and preclinical evidence supports the possibility that α-synuclein could be transported from the gut to the brain via the vagus nerve.2 “The vagus nerve is particularly well placed to be the conduit for signals from the gut to the brain, either through the transport of small or large molecules such as the prion-like translocation of α-synuclein, or neuronally via electrical signaling,” stated Cryan, et al.
Epidemiological studies have demonstrated protective effects of truncal vagotomy against the development of PD, and mouse models have shown that this procedure prevented gut-to-brain transmission of α-synucleinopathy and associated neurodegenerative and behavioral impairments.8-10
In addition, gut microbiota may influence the course of neurological disorders via interaction with medications such as levodopa. In a 2019 study published in Science, for example, the “identiﬁcation of [tyrosine decarboxylase] TyrDC as the predominant mediator of microbiome-associated L-dopa decarboxylation offers a potential biomarker for reduced L-dopa efﬁcacy in certain populations,” the study authors noted.11,12 “This also raises the future possibility of personalized, biomarker-driven speciﬁc TyrDC inhibition as a therapeutic addition to classic AADC inhibitors.”
Using ex-vivo human fecal suspensions from PD patients and healthy controls, the investigators observed substantial variability in L-dopa metabolism between different gut microbiota.11 They also found that abundance of tyrosine decarboxylase (TyrDC) and Enterococcus faecalis distinguished discriminated metabolizing from nonmetabolizing samples, and a linear correlation between TyrDC abundance and E faecalis abundance was noted.
As studies regarding the connection between gut microbiota and neurodegenerative disorders represent a relatively new area of investigation, many research needs remain. Ultimately, the goal is to determine whether “we can translate all of the amazing findings in animal models to the human clinical setting,” said Dr Cryan, who adds that diet is one of the best ways to modify the microbiome. “Although such research is still in the early stages, the good news is that, unlike our genome where we can only ‘blame’ our parents and grandparents, our microbiome is potentially modifiable, and this could give patients agency over some of the factors that influence their brain health.”
3. Tremlett H, Fadrosh DW, Faruqi AA, et al. Gut microbiota in early pediatric multiple sclerosis: a case-control study. Eur J Neurol. 2016;23(8):1308–1321
4. Tankou SK, Regev K, Healy BC, et al. A probiotic modulates the microbiome and immunity in multiple sclerosis. Ann Neurol. 2018;83(6):1147–1161
5. Sharon G, Cruz NJ, Kang DW, et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell. 2019;177: 1600–1618
6. Kang DW, Adams JB, Coleman DM, et al. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Sci Rep. 2019;9(1):5821
7. Svensson E, Horvath-Puho E, Thomsen RW, et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol. 2015; 78:522–529
8. Liu B, Fang F, Pedersen NL, et al. Vagotomy and Parkinson disease a Swedish register-based matched-cohort study. Neurology. 2017; 88(21):1996–2002
9. Kim S, Kwon SH, Kam TI, et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron. 2019;103(4):627-641.e7