Gut Inflammation Linked to Brain Disease Onset in Preclinical Study

Gut inflammation could play a critical role in the onset and progression of Parkinson’s disease, a preclinical study shows.

Specifically, this type of inflammation triggered the accumulation of alpha-synuclein protein clumps in the nerves lining the colon of a mouse model of Parkinson’s, say scientists from Van Andel Institute in Michigan and Roche Pharma Research in Switzerland. Eventually, disease-causing alpha-synuclein occurred in the brain, leading to the loss of cells that produce dopamine, the underlying cause of Parkinson’s symptoms. 

“It was striking to see protein aggregation pathology [disease] in the brain that mirrored pathology in the colon brought on by inflammation,” Emmanuel Quansah, PhD, the study’s co-author said in a press release. “A particularly intriguing observation was the loss of dopamine-producing nerve cells — which play a major role in Parkinson’s onset — in our models that had gut inflammation a year-and-a-half earlier.”

The study, “Specific immune modulation of experimental colitis drives enteric alpha-synuclein accumulation and triggers age-related Parkinson-like brain pathology,” was published in the journal Free Neuropathology. 

Inflammatory bowel disease (IBD) is a risk factor for Parkinson’s disease, and this risk is lower in IBD patients treated with medications that reduce bowel inflammation. These findings suggest that gut inflammation may be involved in the onset of Parkinson’s. 

“There is increasing evidence that changes in the gut can affect a variety of neurological and psychiatric brain disorders,” said Patrik Brundin, MD, PhD, the institute’s deputy chief scientific officer and study lead. “Parkinson’s is a complex disease with a wide range of factors that work in concert to spark its onset and progression. We need to understand the gut’s likely influence on Parkinson’s development better.”

Studies suggest gut inflammation can trigger the misfolding and clumping (aggregation) of the protein alpha-synuclein in the walls of the colon as well as in local immune cells. Aggregation of alpha-synuclein also causes the loss of brain cells that produce the chemical messenger dopamine, which leads to the hallmark symptoms of Parkinson’s. 

How misfolded alpha-synuclein in the gut and the brain are connected is unclear. It is thought that either inflammatory molecules travel through the bloodstream from the gut to the brain, causing disease, or alpha-synuclein aggregates move to the brain via the vagus nerve — one of the longest nerves in the body, which is part of the enteric nervous system (ENS) that governs the function of the digestive tract. 

The researchers wondered if different types and severity of intestinal inflammation could trigger alpha-synuclein accumulation in the ENS, then cause the subsequent development of alpha-synuclein brain disease.

The team studied a special breed of mice that produced a mutant form of human alpha-synuclein. An examination of these mice revealed clumps of human alpha-synuclein in the nerves connected to the muscles in the gut and the submucosal region, the layer below the gut lining (mucosa). This accumulation was age-dependent, as it increased in mice from three months to 12 months of age. 

An IBD model was established by giving the mice dextran sulfate sodium (DSS) in their drinking water in acute dosing (two doses for five days followed by two days of water) or chronic dosing (two doses alternating with water for 28 days). 

The results showed the induction of IBD exacerbated the clumping of alpha-synuclein in the nerve cells of the submucosal region. In addition, DSS given to healthy mice also caused the aggregation of mouse alpha-synuclein in the gut. 

To investigate an alternative inflammatory model that induced different types of immune stimulation, mice were injected with the molecule LPS, a well-established experimental immune trigger, into the abdominal (peritoneal) cavity. 

Although both DSS and LPS caused immune cells to move into the submucosa of the colon, only the DSS administration led to the marked destruction of the mucosa and the accumulation of alpha-synuclein. No change in alpha-synuclein was seen in nerves connected to gut muscles.

LPS caused an increase in the levels of the anti-inflammatory, immune signaling protein interleukin-10 (IL-10), whereas DSS strongly increased IL-6 and IL-1-beta, both associated with inflammation, but not IL-10.

“Together these results indicate that, in our model, colonic inflammation induced by peroral [by mouth] DSS but not intraperitoneal LPS increases the accumulation of [alpha-synuclein] in the colon,” the researchers wrote. 

Next, the alpha-synuclein mice were bred with mice that lacked the receptor CX3CR1 — which plays an essential role in maintaining the function of immune macrophage cells of the gut wall. 

The number of immune cells moving into the mucosa and submucosa after DSS exposure was not different between mutant mice with and without CX3CR1. In contrast, a significantly higher level of alpha-synuclein accumulated in the submucosa in mice lacking CX3CR1, which “provide a potential association between [macrophage] signaling and [alpha-synuclein] accumulation in ENS in this experimental IBD model,” the team added. 

Consistently, treatment with IL-10, an important regulator of macrophages, reduced DSS-induced gut inflammation and the accumulation of alpha-synuclein in the submucosa. 

To better mimic the chronic nature of IBD, mutant mice were given DSS over four weeks with increasing doses, then allowed to recover with water for two months and analyzed at six months. As expected, after two months of recovery, the DSS inflammation had returned to normal. 

However, the nerves in the submucosal layer contained nearly twice as much alpha-synuclein aggregates than mice not exposed to DSS, which was also exacerbated in mutant mice lacking CX3CR1, suggesting that “accumulation of [alpha-synuclein] is not a transient effect or response,” the scientists wrote. 

Finally, to assess the link between IBD and alpha-synuclein brain disease, 3-month-old mutant mice were given increasing doses of DSS or normal drinking water for 23 days. At nine months of age, both groups had very low levels of disease-causing alpha-synuclein in the brain.

At 21 months, although the water-treated mice showed some alpha-synuclein clumping in the brain, the mice exposed to DSS showed a marked increase in disease-causing alpha-synuclein throughout various brain regions, included the cells that produce dopamine. This was also accompanied by a significant loss of tyrosine hydroxylase, the enzyme the generates the dopamine precursor. 

“Our data suggest that specific types and severity of intestinal inflammation, mediated by [macrophage] signaling, could play a critical role in the initiation and progression of [Parkinson’s disease],” the authors concluded. 

“Our results in mice, together with the genetic and epidemiological data by others in humans, make a strong case for further exploring systemic immune pathways for future therapies and biomarkers for Parkinson’s,” said Markus Britschgi, PhD, study corresponding author and scientist at Roche. 

Brundin added: “This study provides novel insights, and this new knowledge can facilitate the development of improved treatment approaches.”