Gut Microbiome of Patients Favors Inflammation, Study Suggests

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by Patricia Inácio, PhD |

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People with Parkinson’s disease appear to have a gut microbiome — the population of microorganisms living in the intestines — that is shifted toward a pro-inflammatory state, a small study suggests.

Looking particularly at a pro-inflammatory gut bacterial metabolite called trimethylamine (TMA), its researchers found significantly higher levels in patients than in people without Parkinson’s. Moreover, this increase was independent of disease characteristics, treatment status, and lifestyle factors.

Findings suggest that gut bacterial-derived metabolites — often, small molecules that are byproducts of metabolic reactions within cells — could serve as disease biomarkers and potential treatment targets, the scientists wrote.

The study “Gut microbial metabolites in Parkinson’s disease: Association with lifestyle, disease characteristics, and treatment status” was published in the journal Neurobiology of Disease.

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A growing body of research supports a potential link between the gut microbiome and Parkinson’s disease. Previous studies found patients carry a distinct intestinal bacterial profile compared to age-matched individuals without the disease.

Stool samples from patients transferred to a mouse model of the disease also intensified symptoms associated with Parkinson’s, while no such changes were evident in these mice given stool samples from healthy people.

Such findings suggest that the gut microbiome can influence Parkinson’s progression, but “beg the question of what specific features of the [Parkinson’s]-associated microbiota” are of influence, the researchers wrote.

Scientists at Rush University Medical Center, in Illinois, evaluated the impact of metabolites produced by gut bacteria in Parkinson’s patients. They focused on metabolites known to be implicated in Parkinson’s: trimethylamine-N-oxide (TMAO), a pro-inflammatory metabolite resulting from TMA; short chain fatty acids (SCFA), an anti-inflammatory metabolite; as well as isovaleric acid, lactic acid, and succinic acid.

TMAO is generated from trimethylamine or TMA, a metabolite produced by intestinal bacteria. TMA is released into the blood and reaches the liver, where it is converted into TMAO.

“The hypothesis was that TMAO would be elevated in [Parkinson’s disease] subjects compared to controls,” the researchers wrote. This expectation, they added, was based on evidence showing “that TMAO is a key contributor to many age-associated diseases (atherosclerosis, obesity), including disorders associated with increased risk of PD (insulin resistance/metabolic syndrome, cardiovascular disease).”

In total, they analyzed blood samples from 86 Parkinson’s patients — 22 not on any disease treatment and 64 others treated with levodopa and other relevant medications. Samples were also collected from seven people with multiple system atrophy (MSA), another progressive neurodegenerative disorder. Both diseases are characterized by the buildup of the alpha-synuclein protein in the brain, which is toxic to brain cells.

Blood samples from 24 spouses or partners in a patient’s household, and 20 unrelated people — matched for sex, age, race, and body mass index (BMI, a parameter of body fat) — were also analyzed and served as controls. Others samples were also taken from individuals within these patient and other groups.

Significantly higher blood levels of TMA and TMAO were found in patients than in controls. The increase in TMA, the scientists noted, was not linked with dietary or lifestyle choices or medication use and disease characteristics.

They then assessed how gut bacterial content correlated with TMA levels — the metabolite directly produced by the microbiota. For this, the researchers profiled the species of bacteria in the microbiome using stool and colon tissue samples collected from 32 Parkinson’s patients and 13 controls.

While some initial correlations were found between TMA levels and certain bacteria, these no longer held after correcting for several parameters. Likewise, no differences were seen for various pathways linked with TMA production between Parkinson’s patients and controls.

The researchers then suggested that environmental and lifestyle factors could play a role in the abundance of TMA and TMAO. To control for this, they compared the levels of both metabolites between 19 patients and 19 people in the same household.

Results showed that TMA was significantly higher in Parkinson’s patients compared with their spouse or household partner. TMAO levels also were increased, but significance could not be determined as “a sample size of 39 would be required for this comparison to be appropriately [statistically] powered,” the researchers wrote.

These findings suggest that factors other than environment or lifestyle play a role in these differences.

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When comparing treatment naïve patients and controls to those on Parkinson’s medications, data showed that treated patients had significantly higher TMA levels. Levels of TMAO were significantly increased across all Parkinson’s patients, treated or not, compared with controls.

In addition to TMA, bacteria produce numerous other metabolites that can influence the body.

Researchers found that treated Parkinson’s patients had lower lactic acid levels than those who were treatment naïve, suggesting that “low lactic acid levels may be a feature associated with treated [Parkinson’s] subjects,” the team wrote.

Higher succinic acid levels associated with lesser Parkinson’s severity, as assessed by the sum of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).

MSA patients had significantly higher levels of acetic acid and significantly lower levels of butyric acid than did treated Parkinson’s patients, prompting the team to suggest that “bacterial metabolites may be biomarkers that differentiate [Parkinson’s] and MSA.”

Importantly, the analysis found that a pro-inflammatory profile shift in bacterial metabolites in Parkinson’s patients, irrespective of treatment, compared with controls.

As such,“bacterial-derived metabolites could be utilized as a biomarker of disease and … modifications of the microbiota (and the production of microbiota-derived metabolites) could be a viable treatment approach” for Parkinson’s, the researchers wrote.

“Additional studies to understand the potential of TMAO and other bacterial metabolites to serve as a biomarker or therapeutic targets are warranted,” they concluded.

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