The Gut-Brain Axis – Opportunities for a Novel Approach Against Neurodegeneration

Editors

Małgorzata Kujawska

Poznan University of Medical Sciences

Grzegorz Kreiner

Maj Institute of Pharmacology, Polish Academy of Sciences

Impact

Behavioral motor testing data in young and old sham-operated Fischer 344 rats at 3 months post sham surgery. The larger standard deviation in older control rats across all three tests indicate a higher n-value is required to detect small differences in motor dysfunction in old rats. Furthermore, standard deviation increased over time, also in rats that were operated at 3 months old.

Systematic Review

28 July 2022

Impact of aging on animal models of Parkinson's disease

Ida Hyllen Klæstrup

, 5 more and

Nathalie Van Den Berge

Aging is the biggest risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. Several animal models have been developed to explore the pathophysiology underlying neurodegeneration and the initiation and spread of alpha-synuclein-related PD pathology, and to investigate biomarkers and therapeutic strategies. However, bench-to-bedside translation of preclinical findings remains suboptimal and successful disease-modifying treatments remain to be discovered. Despite aging being the main risk factor for developing idiopathic PD, most studies employ young animals in their experimental set-up, hereby ignoring age-related cellular and molecular mechanisms at play. Consequently, studies in young animals may not be an accurate reflection of human PD, limiting translational outcomes. Recently, it has been shown that aged animals in PD research demonstrate a higher susceptibility to developing pathology and neurodegeneration, and present with a more disseminated and accelerated disease course, compared to young animals. Here we review recent advances in the investigation of the role of aging in preclinical PD research, including challenges related to aged animal models that are limiting widespread use. Overall, current findings indicate that the use of aged animals may be required to account for age-related interactions in PD pathophysiology. Thus, although the use of older animals has disadvantages, a model that better represents clinical disease within the elderly would be more beneficial in the long run, as it will increase translational value and minimize the risk of therapies failing during clinical studies. Furthermore, we provide recommendations to manage the challenges related to aged animal models.

6,795 views

24 citations

Original Research

27 July 2022

Differences in gut microbiota correlate with symptoms and regional brain volumes in patients with late-life depression

Chia-Fen Tsai

, 7 more and

Ching-Liang Lu

Depression is associated with gut dysbiosis that disrupts a gut-brain bidirectional axis. Gray matter volume changes in cortical and subcortical structures, including prefrontal regions and the hippocampus, have also been noted in depressive disorders. However, the link between gut microbiota and brain structures in depressed patients remains elusive. Neuropsychiatric measures, stool samples, and structural brain images were collected from 36 patients with late-life depression (LLD) and 17 healthy controls. 16S ribosomal RNA (rRNA) gene sequencing was used to profile stool microbial communities for quantitation of microbial composition, abundance, and diversity. T1-weighted brain images were assessed with voxel-based morphometry to detect alterations in gray matter volume between groups. Correlation analysis was performed to identify the possible association between depressive symptoms, brain structures and gut microbiota. We found a significant difference in the gut microbial composition between patients with late-life depression (LLD) and healthy controls. The genera Enterobacter and Burkholderia were positively correlated with depressive symptoms and negatively correlated with brain structural signatures in regions associated with memory, somatosensory integration, and emotional processing/cognition/regulation. Our study purports the microbiota-gut-brain axis as a potential mechanism mediating the symptomatology of LLD patients, which may facilitate the development of therapeutic strategies targeting gut microbes in the treatment of elderly depressed patients.

4,938 views

22 citations

Gut microbiota signatures of healthy aging in different regions. (A,B) principal-coordinate analysis (PCoA) based on the Bray-Curtis distance derived from the relative abundance of the species (A) and KEGG orthologous (KOs) (B) were plotted for the gut microbiota composition and function at the species and KOs level. (C) Differences of KOs in the methanogenesis and acetate, butyrate, and lactate biosynthesis pathways. HL, Chinese long-living group; HE, Chinese elderly group; HY, Chinese young group; LSI, Sardinia (Italian) long-living group; ESI, Sardinia (Italian) elderly group; YSI, Sardinia (Italian) young group; LEI, Emilia Romagna (Italian) elderly group; EEI, Emilia Romagna (Italian); YEI, Emilia Romagna (Italian) young group.

Original Research

07 July 2022

Gut Microbiota Composition and Metabolic Potential of Long-Living People in China

Siyuan Zhang

, 6 more and

Ying Li

3,987 views

6 citations

Differentially abundant taxa between faster and slower progressing Parkinson’s disease (PD) patients. ALDEx2 model-informed volcano plots identifying longitudinal gut microbiome (GM) differences between faster progressing (n = 34) and slower progressing (n = 40) PD patients over the three (t = 0, 6, 12 months) intervals. Comparing these two PD sub-cohorts revealed no statistically significant difference in GM composition across genus, family and order levels, persisting over the study duration. However, discrete microbiota differences were observed for each taxonomic level across each of the time intervals individually (p < 0.01 genus, <0.01 family, 0.02 order). Barnesiella appeared to be underrepresented in faster progressing PD patients at two-time intervals, t = 0 and t = 12 months. This was accompanied by an underrepresentation of Barnesiellaceae in faster progressing PD patients at the t = 0 interval.

Original Research

17 May 2022

The Gut Microbiome in Parkinson’s Disease: A Longitudinal Study of the Impacts on Disease Progression and the Use of Device-Assisted Therapies

Michal Lubomski

, 5 more and

Carolyn M. Sue

Background: Altered gut microbiome (GM) composition has been established in Parkinson’s disease (PD). However, few studies have longitudinally investigated the GM in PD, or the impact of device-assisted therapies.

Objectives: To investigate the temporal stability of GM profiles from PD patients on standard therapies and those initiating device-assisted therapies (DAT) and define multivariate models of disease and progression.

Methods: We evaluated validated clinical questionnaires and stool samples from 74 PD patients and 74 household controls (HCs) at 0, 6, and 12 months. Faster or slower disease progression was defined from levodopa equivalence dose and motor severity measures. 19 PD patients initiating Deep Brain Stimulation or Levodopa-Carbidopa Intestinal Gel were separately evaluated at 0, 6, and 12 months post-therapy initiation.

Results: Persistent underrepresentation of short-chain fatty-acid-producing bacteria, Butyricicoccus, Fusicatenibacter, Lachnospiraceae ND3007 group, and Erysipelotrichaceae UCG-003, were apparent in PD patients relative to controls. A sustained effect of DAT initiation on GM associations with PD was not observed. PD progression analysis indicated that the genus Barnesiella was underrepresented in faster progressing PD patients at t = 0 and t = 12 months. Two-stage predictive modeling, integrating microbiota abundances and nutritional profiles, improved predictive capacity (change in Area Under the Curve from 0.58 to 0.64) when assessed at Amplicon Sequence Variant taxonomic resolution.

Conclusion: We present longitudinal GM studies in PD patients, showing persistently altered GM profiles suggestive of a reduced butyrogenic production potential. DATs exerted variable GM influences across the short and longer-term. We found that specific GM profiles combined with dietary factors improved prediction of disease progression in PD patients.

7,793 views

33 citations

(A) Keplan Meier plot of the cumulative incidence of developing future dementia in people between 40–49 years old. (B) Keplan Meier plot of the cumulative incidence of developing future dementia in people between 50–59 years old. (C) Keplan Meier plot of the cumulative incidence of developing future dementia in people between 60–69 years old. (D) Keplan Meier plot of the cumulative incidence of developing future dementia in people >70 years old.

Original Research

04 April 2022

Higher Dementia Risk in People With Gastroesophageal Reflux Disease: A Real-World Evidence

Shuo-Yan Gau

, 3 more and

James Cheng-Chung Wei

Background: Whether or not patients with gastroesophageal reflux disease (GERD) have a higher risk of developing subsequent dementia remains unknown, and no observational evidence from population-based data is available. This study was to determine whether patients with GERD have a higher future risk of developing dementia.

Methods: For the period 2000–2012, datasets from the Longitudinal Health Insurance Database (LHID, subset of National Health Insurance Research Database in Taiwan) were analyzed. Definition of GERD was based on ICD-9-CM codes 530.11 and 530.81 and prescriptions for PPIs. After matching gender, age, index year, and comorbidities, each GERD patient was matched with four control patients without GERD. Future risk of dementia was evaluated, and sensitivity analysis of subgroups was conducted to clarify the potential association.

Results: In the present study, 13,570 patients were included in the GERD cohort and 54,280 patients were included in the control cohort. Patients with GERD showed higher risk developing dementia than control group, with an aHR of 1.34 (95% C.I., 1.07, 1.67). In GERD patients between above 70 years old, the risk of developing dementia was higher than that of the control groups (aHR = 1.34; 95% C.I., 1.01, 1.77).

Conclusion: Patients with GERD showed higher incidence of dementia, and elder patients had the highest risk of developing dementia. Clinicians should be concern of the association between GERD and dementia and should develop strategies to prevent dementia while managing patients with GERD.

5,026 views

19 citations

Predictive modeling to identify Parkinson’s disease (PD) was optimized by a two-stage model that incorporates nutritional and microbiome data. (A) Predictive Random Forest modeling was undertaken to identify the utility of the gut microbiome as a potential signature for PD. Comparisons at five taxonomic levels; phylum, order, family, genus and ASV, were used to predict PD, with greatest predictive capacity provided at the genus level on receiver operating characteristic curve (ROC), with an area under the curve (AUC) of 0.71. (B) An optimized two-stage predictive Random Forest model analysis was subsequently undertaken that considered dietary intake as an influence on the gut microbiome. Comparing the utility of the one-stage microbiome model (AUC = 0.71) with the two stage model, a slightly improved predictability was achieved. when incorporating dietary macronutrient data. Specifically, the incorporation of carbohydrate contribution to total energy in the model improved the prediction (AUC = 0.74), whereas incorporation of fiber, fat or protein macronutrient data alone into the model did not improve the predictive potential to identify PD. Accompanying sensitivity and specificity analyses are presented in the tables.

Original Research

11 May 2022

Nutritional Intake and Gut Microbiome Composition Predict Parkinson’s Disease

Michal Lubomski

, 5 more and

Carolyn M. Sue

4,081 views

14 citations

Review

22 December 2021

Gut-Brain Axis: Possible Role of Gut Microbiota in Perioperative Neurocognitive Disorders

Xiao-qing Wang

, 3 more and

Hang Zhao

Aging is becoming a severe social phenomenon globally, and the improvements in health care and increased health awareness among the elderly have led to a dramatic increase in the number of surgical procedures. Because of the degenerative changes in the brain structure and function in the elderly, the incidence of perioperative neurocognitive disorders (PND) is much higher in elderly patients than in young people following anesthesia/surgery. PND is attracting more and more attention, though the exact mechanisms remain unknown. A growing body of evidence has shown that the gut microbiota is likely involved. Recent studies have indicated that the gut microbiota may affect postoperative cognitive function via the gut-brain axis. Nonetheless, understanding of the mechanistic associations between the gut microbiota and the brain during PND progression remains very limited. In this review, we begin by providing an overview of the latest progress concerning the gut-brain axis and PND, and then we summarize the influence of perioperative factors on the gut microbiota. Next, we review the literature on the relationship between gut microbiota and PND and discuss how gut microbiota affects cognitive function during the perioperative period. Finally, we explore effective early interventions for PND to provide new ideas for related clinical research.

6,800 views

14 citations

Review

23 December 2021

Mitochondria-Microbiota Interaction in Neurodegeneration

Peter Kramer

8,265 views

8 citations

Original Research

05 October 2021

Activation of Microbiota Sensing – Free Fatty Acid Receptor 2 Signaling Ameliorates Amyloid-β Induced Neurotoxicity by Modulating Proteolysis-Senescence Axis

Atefeh Razazan

, 5 more and

Hariom Yadav

Multiple emerging evidence indicates that the gut microbiota contributes to the pathology of Alzheimer’s disease (AD)—a debilitating public health problem in older adults. However, strategies to beneficially modulate gut microbiota and its sensing signaling pathways remain largely unknown. Here, we screened, validated, and established the agonists of free fatty acid receptor 2 (FFAR2) signaling, which senses beneficial signals from short chain fatty acids (SCFAs) produced by microbiota. The abundance of SCFAs, is often low in the gut of older adults with AD. We demonstrated that inhibition of FFAR2 signaling increases amyloid-beta (Aβ) stimulated neuronal toxicity. Thus, we screened FFAR2 agonists using an in-silico library of more than 144,000 natural compounds and selected 15 of them based on binding with FFAR2-agonist active sites. Fenchol (a natural compound commonly present in basil) was recognized as a potential FFAR2 stimulator in neuronal cells and demonstrated protective effects against Aβ-stimulated neurodegeneration in an FFAR2-dependent manner. In addition, Fenchol reduced AD-like phenotypes, such as Aβ-accumulation, and impaired chemotaxis behavior in Caenorhabditis (C.) elegans and mice models, by increasing Aβ-clearance via the promotion of proteolysis and reduced senescence in neuronal cells. These results suggest that the inhibition of FFAR2 signaling promotes Aβ-induced neurodegeneration, while the activation of FFAR2 by Fenchol ameliorates these abnormalities by promoting proteolytic Aβ-clearance and reducing cellular senescence. Thus, stimulation of FFAR2 signaling by Fenchol as a natural compound can be a therapeutic approach to ameliorate AD pathology.

12,790 views

18 citations

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