BackgroundParkinson's disease is characterized by a high burden of gastrointestinal comorbidities, especially constipation and reduced colonic transit time, and by gut microbiota alterations. The diverse metabolites produced by the microbiota are broadly relevant to host health. How microbiota composition and metabolism relate to gastrointestinal function in Parkinson's disease is largely unknown. The objectives of the current study were to assesses associations between microbiota composition, stool consistency, constipation, and systemic microbial metabolites in Parkinson's disease to better understand how intestinal microbes contribute to gastrointestinal disturbances commonly observed in patients.MethodsThree hundred participants (197 Parkinson's patients and 103 controls) were recruited for this cross‐sectional cohort study. Participants supplied fecal samples for microbiota sequencing (n = 300) and serum for untargeted metabolomics (n = 125). Data were collected on motor and nonmotor Parkinson's symptoms, medications, diet, and demographics.ResultsSignificant microbiota taxonomic differences were observed in Parkinson's patients, even when controlling for gastrointestinal function. Parkinson's microbiota was characterized by reduced carbohydrate fermentation and butyrate synthesis capacity and increased proteolytic fermentation and production of deleterious amino acid metabolites, including p‐cresol and phenylacetylglutamine. Taxonomic shifts and elevated proteolytic metabolites were strongly associated with stool consistency (a proxy for colonic transit time) and constipation among patients.ConclusionsCompositional and metabolic alterations in the Parkinson's microbiota are highly associated with gut function, suggesting plausible mechanistic links between altered bacterial metabolism and reduced gut health in this disease. The systemic detection of elevated deleterious proteolytic microbial metabolites in Parkinson's serum suggests a mechanism whereby microbiota dysbiosis contributes to disease etiology and pathophysiology. © 2020 International Parkinson and Movement Disorder Society

Our expanding knowledge of microbial mechanisms is challenging the notion of "good" versus "bad" microbes and encouraging a better understanding of their roles in various contexts before their widespread therapeutic and clinical application. The intestinal microbe Akkermansia muciniphila, a promising probiotic with an emerging cautionary tale, best highlights this challenge.

Summary The gut microbiota affects many aspects of human health, and research, especially over the past decade, is demonstrating that the brain is no exception. This review summarizes existing human observational studies of the microbiota in brain health and neurological conditions at all ages, as well as animal studies that are advancing the field beyond correlation and into causality. Potential mechanisms by which the brain and the gut microbiota are connected are explored, including inflammation, bacterially‐produced metabolites and neurotransmitters and specific roles for individual microbes. Finally, important challenges and potential mitigation strategies are discussed, as well as ways in which some of these same challenges can be harnessed to advance our understanding of this complex, exciting and rapidly evolving field.

I would like to comment on the recently published article titled "Microbiota Composition and Metabolism Are Associated With Gut Function in Parkinson's Disease" in Movement Disorders. Cirstea et al 1 analyzed the correlation between intestinal symptoms, intestinal flora, and serum metabolomics in patients with Parkinson's disease (PD) based on large samples and came up with novel findings. The researchers evaluated 300 participants in detail, including daily dietary intake and intestinal complications. However, I have some concerns. First, it was declared in the Results section that p-cresol (HMDB0001858) and phenylacetylglutamine (HMDB0006344) were both significantly positively correlated with constipation severity among patients (Fig. 3E). Nevertheless, the result of phenylacetylglutamine cannot be found in Figure 3E, and there are 2 plots of different correlations between p-cresol and constipation severity among patients with PD. Second, as shown in the Discussion section, nearly half of controls (43 of 103) were spouses of the PD patients. In other words, within the cohort composed of pairs of couples, the diet-driven heterogeneity in gut microbiota between the patient and the control might be negligible because couples share more of their gut microbiota than individuals from different households. 2 However, an individual's dietary pattern might be a confounding factor for analysis of gut microbiota for the rest of the 147 patients and the other healthy controls. Notably, several studies 2-4 assessing the relationship between gut microbiota and PD included merely couples-based populations to reduce the interfering effect of different dietary patterns. Therefore, we hope that the authors will make a further subgroup analysis to validate their findings in different patient cohorts. To sum up, the present study is interesting and inspiring research in which more detailed information should be analyzed and available to readers so as to be more helpful in a deep understanding of intestinal symptoms, intestinal flora, and serum metabolomics in PD patients.

Fecal-oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL-BG). The MAL-BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non-neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal-oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL-BG mice. Unexpectedly, these changes occurred independently from significant cytokine-induced inflammation or blood-brain barrier (BBB) disruption, key gut-brain pathways. Metabolomic profiling of the MAL-BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant-associated diet (PAO) mitigated cognitive deficits within the MAL-BG model. These findings provide valued insight into the malnourished gut microbiota-brain axis, highlighting PUFA metabolism as a potential therapeutic target.

Background: Parkinson’s disease (PD) is a multi-system disorder consisting of not only classic motor symptoms but also a variety of non-motor symptoms including gastrointestinal (GI) dysfunction and mood disorders. The gut microbiota has been suggested to play a role in modulating PD motor and non-motor features, although the causality and mechanisms behind these proposed interactions remains largely understudied. Objective: In this study, we aimed to provide in-depth characterization of an established mouse model of PD (transgenic (TG) SNCA A53T) and experimentally address how changes to the gut microbiota impact the PD-like phenotype. Methods: We profiled the PD-like phenotype of transgenic mice through a panel of motor, GI, and behavioral tests. We then investigated how antibiotic treatment or gut microbial community transfer (via cohousing with wild-type mice) impacted the PD-like phenotype. Results: We found that this mouse model demonstrated early (6 weeks of age) motor symptoms when compared to a wild-type control mouse strain. Transgenic mice also exhibited early GI dysfunction, as well as behavioral alterations, including reduced anxiety-like behavior, and increased depression-like and apathy-like behavior. Compared to wild-type mice, the transgenic fecal microbiota was less diverse and compositionally distinct. Interestingly, drastic alterations to the gut microbiota, through antibiotic treatment or cohousing with wild-type mice, had a minimal effect on the motor, GI, and behavioral phenotype of transgenic mice. Conclusion: We concluded that this mouse model effectively recapitulates motor and non-motor features of PD; however, the gut microbiota appears to exhibit a minor impact on the pathophysiology of this PD model.

IntroductionMicronutrients perform a wide range of physiological functions essential for growth and development. However, most people still need to meet the estimated average requirement worldwide. Globally, 2 billion people suffer from micronutrient deficiency, most of which are co-occurring deficiencies in children under age five. Despite decades of research, animal models studying multiple micronutrient deficiencies within the early-life period are lacking, which hinders our complete understanding of the long-term health implications and may contribute to the inefficacy of some nutritional interventions. Evidence supporting the Developmental Origins of Health and Disease (DOHaD) theory demonstrates that early-life nutritional deficiencies carry life-long consequences mediated through various mechanisms such as abnormal metabolic programming, stunting, altered body composition, and the gut microbiome. However, this is largely unexplored in the multiple micronutrient deficient host.Methodswe developed a preclinical model to examine undernutrition’s metabolic and functional impact on the host and gut microbiome early in life. Three-week-old weanling C57BL/6N male mice were fed a low-micronutrient diet deficient in zinc, folate, iron, vitamin A, and vitamin B12 or a control diet for 4-weeks.ResultsOur results showed that early-life multiple micronutrient deficiencies induced stunting, altered body composition, impaired glucose and insulin tolerance, and altered the levels of other micronutrients not depleted in the diet within the host. In addition, functional metagenomics profiling and a carbohydrate fermentation assay showed an increased microbial preference for simple sugars rather than complex ones, suggestive of a less developed microbiome in the low-micronutrient-fed mice. Moreover, we found that a zinc-only deficient diet was not sufficient to induce these phenotypes, further supporting the importance of studying co-occurring deficiencies.DiscussionTogether, these findings highlight a previously unappreciated role of early-life multiple micronutrient deficiencies in shaping the metabolic phenome of the host and gut microbiome through altered glucose energy metabolism, which may have implications for metabolic disease later in life in micronutrient-deficient survivors.