The relationship between the gut, inflammation and the nervous system is only beginning to be explored. Speaking at the Teva Central Nervous System Weekend (TCW 19), Dr Hugo Morales-Briceno, consultant neurologist at the neurology department and movement disorder unit at Westmead Hospital, Sydney, discussed what we know right now about the interactions between the gut and the brain when it comes to Parkinson’s disease (PD) and multiple sclerosis (MS). “There’s a lot we are learning about how these systems are connected, but now we’re at the point where we need to do some trials to look at the effect of modifying the microbiome on disease outcomes,” began Dr Morales-Briceno.

Deciphering the language between the gut and brain

“There is evidence of a communication and transport system between the gut and the brain which may play a role in Parkinson’s disease (PD) and multiple sclerosis (MS),”¹ summarised Dr Morales-Briceno. He explained to delegates the current understanding of the system that integrates neural, hormonal and immunological signalling between the gut and the brain.² It also provides the intestinal microbiota and its metabolites with a potential route through which to access the brain.² The communication is bidirectional and involves the central, autonomic and enteric nervous systems.² Of note, he explained how “the enteric nervous system receives modulatory input from the brain and provides information to the brain via ascending neural circuits; yet it can also operate independently of the brain.”²

Gut microbiota evolves over a lifetime

Dr Morales-Briceno gave an overview of what is known about the role and composition of a gut microbiome. “Humans co-exist in a mutualistic relationship with intestinal microbiota.³ In the lower gastrointestinal tract alone there are almost 100 trillion microorganisms, the composition of which evolves over a lifetime.³ Most of an infant’s microbiome is acquired during birth and is influenced by diet, geography and exposure to antibiotics.³ By age 3, the microbiome closely resembles that of an adult, which is more than 90% composed of Firmicutes and Bacteroidetes,”³ he pointed out.

Does the gut microbiome influence disease or is it the other way around?

“Identifying possible mechanisms linking the gut microbiota with the brain is one thing; establishing that those mechanisms are responsible for the observed effects is another,”¹ explained Dr Morales-Briceno. “In PD there is evidence the microbiome can promote disease progression in genetically susceptible individuals. In MS, changes in the composition of the microbiota may be related to autoimmunity and the pathology of disease.” Dr Morales-Briceno presented animal data that demonstrated that in the absence of pathogenic agents, the gut microbiota can trigger immune processes, leading to a relapsing-remitting autoimmune disease driven by myelin-specific CD4+ T-cells.4 “The precise mechanism remains unclear, but there is evidence that gut-derived CD4+ T-cells can shape the gut-systemic axis. We know that under normal conditions, gut-derived CD4+ T-cells can recirculate into the peripheral blood and in the central nervous system (CNS) generally create an anti-inflammatory environment. However, in models of MS the frequency of gut-derived CD4+ T-cells in the peripheral circulation is reduced and biased toward a Th17 phenotype. Secondly, tryptophan – which is mainly produced by gut bacteria – may play a role through its interaction with aryl hydrocarbon receptor (AHR). Reductions in tryptophan have been observed in MS,”^{5 -8} he explained.

Dr Morales-Briceno summarised the evidence for alterations in gut microbiota in MS. “Epidemiological studies show striking similarities and some differences in overall findings. Bacteroidetes and Firmicutes, which have anti-inflammatory products are decreased in MS.⁹ In contrast, Methanobrevibacter and Akkermansia are increased, and interestingly increments of exhaled methane has been shown in MS patients.”⁹

Can we alter disease through administration of probiotics?

“While a change in microbiota can be observed with probiotic administration in healthy controls and those with MS,⁹ there are no studies as yet that prove a disease-modifying effect in MS,” acknowledged Dr Morales-Briceno. “What is interesting is that disease-modifying treatments themselves have shown an effect on the composition of gut microbiota in MS, yet the impact of this remains unknown.”¹⁰

Does PD start in the gut?

“When it comes to PD, there is more and more interest in exploring the contribution of the gut to disease pathogenesis,” explained Dr Morales-Briceno. “Toxic aggregation of misfolded a-synuclein within Lewy bodies is a key pathological process.¹¹ One hypothesis is that the initial formation of a-synuclein aggregates occurs outside the brain, which could in part be caused by exterior insults such as toxins or microorganisms.¹² There are studies supporting this hypothesis that show 56% of PD subjects had a-synuclein deposits in gastrointestinal tissue in PD before developing symptoms, compared with 26% of matched control tissues.¹³ A recent study in rapid eye movement sleep behaviour disorder (RBD), a prodromal phenotype of PD also showed that a-synuclein initially targets peripheral autonomic nerves before involvement of the dopamine system.”

Dr Morales-Briceno explained how the vagal nerve is thought to be the major highway for centripetal spreading of a-synuclein pathology. He presented evidence that supports this notion where truncal vagotomy was associated with a reduced risk of PD.¹⁴ However, he was quick to caution that the jury is still out as to whether PD starts in the gut or not. “There’s multiple arguments for and against PD starting in the gut.¹⁵ Large, reproducible studies need to be undertaken to be sure. But what is interesting is that gut microbiota may be a modifier of disease severity.¹⁶ Dysbiosis of the gut microbiota has been identified in PD patients,¹⁷ what’s more is that dysbiosis may occur early, as there are similarities in microbiota composition between prodromal (RBD) and PD patients compared with healthy controls.¹⁸ The changes in microbiota composition may have implications for levodopa/carbidopa treatment. Recently, using a mouse model, one study has demonstrated that bacterial enzymes can convert levodopa into dopamine – which is problematic in the peripheral circulation.¹⁹

Following our gut in Parkinson’s disease and multiple sclerosis

How to modulate or prevent disease progression through the manipulation of gut microbiota are questions for future clinical trials, emphasised Dr Morales-Briceno. “For PD, we need to look at the effect of modifying the microbiome on motor fluctuations and absorption of medication. In MS, trials are already underway to look at whether altering the microbiome can stop or reduce the number of lesions, along with the effect of disease-modifying therapies.”

This article was sponsored by TEVA, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of TEVA.

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