March 23, 2023 | A research team from the Nagoya University Graduate School of Medicine (NUSM), Japan, discovered three gut bacteria types that may lead to predicting and treating dementia with Lewy bodies (DLB): Collinsella, Ruminococcus torques, and Bifidobacterium.
A common form of dementia, DLB is characterized by significant cognitive decline, impaired movement, confusion, autonomic dysfunctions, and visual hallucinations. The disease is primarily attributed to the formation of Lewy bodies, which are abnormal clusters of alpha-synuclein protein fibrils that disrupt signal propagation between brain cells.
Lewy bodies are associated with various neurodegenerative diseases, including Parkinson’s (PD) and idiopathic rapid eye movement sleep behavior disorder (iRBD) (Parkinsonism & Related Disorders, DOI: 10.1016/S1353-8020(13)70017-8).
Since DLB and PD dementia (PDD) maintain similar cognitive profiles, pathologists must look for alternative means of distinguishing between them. Moreover, as many patients develop neurodegenerative diseases in tandem, physicians hope to predict which patients will establish neurological comorbidities and treat them proactively.
“If a patient with Parkinson’s disease develops dementia in one year after the onset of motor symptoms, they are diagnosed with DLB,” explained Kinji Ohno, professor of neurogenetics at NUSM, in a press release. “However, we cannot currently predict whether a patient with Parkinson’s disease will become a DLB patient. The gut microbiome will help to identify such patients.”
Because Lewy bodies are found in the brain, intestines, and various other portions of the body, scientists wondered if gut microbiota—and their metabolites—play a role in LB formation. Published in npj Parkinson’s Disease (DOI: 10.1038/s41531-022-00428-2), the NUSM team not only distinguished three potential bacterial types to serve as biomarkers for DLB, but their research may open the door to a new wave of neurodegenerative disease therapy.
In their lab, the team evaluated the gut microbiota and fecal bile acids of 278 patients with alpha-synucleinopathies—neurodegeneration due to alpha-synuclein protein accumulation. The patient group consisted of 28 subjects with DLB, 193 with PD, 31 with PDD, and 26 with iRBD.
The team included iRBD in the study as more than 90% of these patients develop DLB, PD, or PDD within 10 or more years. The sample size was also compared to 147 control patient profiles showing no neurological dysfunction.
Using a series of differential abundance, statistical, correlation, and permutational multivariate analyses, the team examined each group's taxonomic differences and overall gut microbiota composition across 18 genera and five families.
Against the control group, patients with DLB showed a significant decrease in seven genera: Agathobacter, Lachnospiraceae ND3007 group, Butyricicoccus, Coprococcus, Faecalibacterium, Fusicatenibacter, and Haemophilus. Of these bacteria, all but Haemophilus produce short-chain fatty acids (SCFAs), molecules that increase regulatory T-cell function and reduce inflammation. Therefore, a decrease in these microbes would likely facilitate disease progression.
PD patients also showed a similar reduction of SCFA-associated microbes. “Decreases in SCFA-producing bacteria have been repeatedly reported in Parkinson's disease, Alzheimer's disease, and ALS,” explained Ohno. “This suggests that it is a common feature of neurodegenerative diseases.”
Compared to one another, DLB displayed a significant increase in Ruminococcus torques, Bifidobacterium, and Collinsella over PD and a higher concentration of Collinsella over PDD. Ruminococcus torques and Collinsella increase gut permeability, giving pesticides and herbicides from the diet access to underlying gut neurons to cause inflammation, oxidative stress, and LB formation.
When the team quantified the fecal bile acids for each diagnostic group, they discovered that the high Ruminococcus torques and Collinsella associated with DLB also increased ursodeoxycholic acid (UDCA), a microbe-produced secondary bile acid. UDCA decreases inflammation in the substantia nigra, a portion of the brain that controls movement. The team believes this may explain why BLD patients experience some symptoms later than those with PD, thereby providing another differentiating factor.
PD and DLB Treatment Options
If certain diseases demonstrate a substantial decrease in bacterial concentrations over others, the NUSM team proposed that administering microbes to restore equilibrium may be a therapeutic option. For example, PD patients show a decrease in Collinsella and Ruminococcus torques concentrations compared to other groups. Therefore, increasing those microbes back to a healthy baseline—as opposed to the abnormally high concentration seen in DLB—may be beneficial. “In terms of treatment, the administration of Ruminococcus torques and Collinsella in patients with Parkinson’s is expected to delay neuroinflammation in the substantia nigra,” said Ohno.
The team also observed increased Bifidobacterium in PD patients but quickly determined that PD drugs—catechol-o-methyl-transferase (COMT) inhibitors—caused the increase. Interestingly, patients with PDD demonstrated significantly lower Bifidobacterium concentrations than PD patients, even when both parties were prescribed the same PD drugs. DLB patients also displayed a similar decrease in Bifidobacterium, indicating that this phenomenon may only occur in dementia cases.
“Therapeutic intervention to increase Bifidobacterium may delay the onset and progression of DLB and reduce cognitive dysfunction,” said Ohno. Bifidobacterium administration has already been proven to increase neurogenesis in the central and peripheral nervous systems of Alzheimer’s patients (Beneficial Microbes, DOI: 10.3920/BM2018.0170), suggesting that it could also halt the progression of DLB and PDD.
“Our findings can be used for both diagnosis and treatment,” added Ohno. “The presence of intestinal bacteria unique to DLB may explain why some patients develop Parkinson’s disease, and others develop DLB first. Normalizing the abnormal bacteria shared between DLB and Parkinson's disease may delay the development of both diseases. Improving the gut microbiota is a steppingstone in the treatment of dementia. Our findings may pave the way for the discovery of new and completely different therapeutics.”
The team acknowledges that with just 28 patients, the sample size for DLB warrants more studies with a larger pool. They also aim to conduct a longitudinal study to determine if the associated microbes are causing DLB or if their changes in concentration are merely symptoms. Moving forward, the team seeks to hone their diagnostic skills and design a more exacting therapeutic strategy to predict and treat alpha-synucleinopathies based on an individual’s cognitive and microbiotic profiles.