Supplementation with short-chain fatty acids and a prebiotic improves clinical outcome in Parkinson’s disease: a randomized double-blind prospective study

Scientific Reports · 2025-12-05 · 7 citations

BACKGROUND: Parkinson's disease is associated with a dysbiotic, proinflammatory gut microbiome, disruptions to intestinal barrier functions, and immunological imbalance. Microbiota-produced short-chain fatty acids, such as propionic and butyric acid promote gut barrier integrity and immune regulation, but their impact on Parkinson's disease pathology remains mostly unknown. METHODS: In a randomized double-blind prospective study, 72 people with Parkinson's disease received propionic and butyric acid and/or the prebiotic fiber 2'-fucosyllactose supplementation over 6 months in combination with existing Parkinson's disease-specific therapy. Patients underwent complete neurological assessment and provided blood and stool samples before as well as 3 and 6 months after supplementation. RESULTS: We observed a robust improvement in motor symptoms, with all intervention groups achieving clinically meaningful reductions. These motor benefits were paralleled by clinically relevant reductions in levodopa medication. In contrast, effects on nonmotor symptoms were more heterogeneous. Notably, the interventions also modulated peripheral immune responses and enhanced mitochondrial respiration in immunocytes. Postintervention microbiota remodeled inflammatory and barrier-related gene sets in gut organ cultures and improved in vitro barrier functions. Treatment response was associated with microbiome composition, distinct patterns of colonic transcription and permeability ex vivo. Multiobjective analysis revealed immune parameters associated with an optimal response to supplementation. CONCLUSION: Short-chain fatty acids ameliorate clinical symptoms in Parkinson's disease patients and modulate intestinal and peripheral immunity. REGISTRATION: This clinical trial was retrospectively registered with the German Clinical Trials Register (DRKS), registration number DRKS00027061 on 11/19/2021.

Gut microbiome remodeling provides protection from an environmental toxin

iScience · 2025-03-12 · 3 citations

carrying a neomycin-modifying enzyme. Enrichment was facilitated by altered bacterial competition in the gut, as well as by KGB-1/JNK-dependent behavioral changes. While microbiome remodeling conferred toxin resistance, it was associated with reduced infection resistance and metabolic changes. These findings suggest that microbiome adaptation can help animals cope with stressors but may have long-term consequences that add to effects of direct intoxication.

Beyond translation initiation: dual regulatory interactions with phosphorylated and non-phosphorylated LeishIF4E1

bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-17

Abstract Translation initiation in eukaryotes begins with the assembly of the cap-binding eIF4F complex at the 5’ ends of mRNAs, through eIF4E. Among the six orthologs of eIF4E in Leishmania , LeishIF4E1 is intriguing, as it does not bind any Leishmania eIF4G. It is expressed in both life-forms, maintaining efficient cap-binding activity for translation initiation, unlike other LeishIF4Es. We identified two novel phosphorylation sites specifically S108, and S112, along with S203, which is conserved with the mammalian phosphorylation site. A non-phosphorylatable, tagged, mutant of LeishIF4E1 created by substituting the phosphorylated serine residues with alanine [S(108,112,203)A] was generated. The phosphorylation status did not affect the binding of LeishIF4E1 to translation initiation factors. However, the phosphorylated LeishIF4E1 interacted with proteins involved in DNA and chromatin structure, while non-phosphorylated LeishIF4E1 interacted with proteins that assist cells under stress and unfavorable conditions, particularly in gluconeogenesis. This suggests secondary regulatory roles for LeishIF4E1. RNA sequencing of the LeishIF4E1-associated transcripts revealed a tenfold reduction in transcripts binding to non-phosphorylated LeishIF4E1. GO enrichment analysis indicated distinct phosphorylation-dependent transcript specificities for each form. This study highlights the critical role of LeishIF4E1 phosphorylation in modulating the selectivity of protein interactome and transcript associations, extending the role of LeishIF4E1 beyond its well-established function in translation initiation. Author Summary Leishmania are digenetic parasites that transition from sand fly vector to mammalian hosts, undergoing a developmental program of gene expression regulated at the level of translation. Protein synthesis is initiated by the assembly of multi-subunit complexes at the mRNA 5’ cap structure and is recruited onto the ribosomes. There are six cap-binding proteins in Leishmania denoted LeishIF4Es1-6, and five LeishIF4G candidates. Among these, the function of LeishIF4E1 is intriguing, as it does not bind any LeishIF4G paralogs, and it is highly expressed in both parasite life forms. We examined how LeishIF4E1 phosphorylation modulates its interaction with proteins and transcripts, given that eIF4E phosphorylation in higher eukaryotes is known to regulate gene expression during malignancy. We identified three phosphorylation sites (S108, S112 and S203) and mutated them to A residues [S(108,112,203)A]. The mutated genes were transfected back into parasites for expression. Using pull-down assays, we identified the interacting proteins and associated transcripts for both the phosphorylated and non-phosphorylated LeishIF4E1 forms. The phosphorylated LeishIF4E1 pulled down proteins involved in DNA and chromatin structure, while the non-phosphorylated LeishIF4E1 interacted with proteins known to assist cells during stress and unfavorable conditions, especially gluconeogenesis. The transcript specificities differed markedly in the number of transcripts bound to both forms, shedding light on the importance of LeishIF4E1 phosphorylation. Furthermore, the phosphorylated form bound more transcripts encoding enzymes related to protein phosphorylation. We also showed that phosphorylation of LeishIF4E1 did not influence the cap-binding ability, as both the forms bind the m 7 GTP cap with parallel efficiencies. Our data suggest that the different cap-binding proteins in Leishmania are responsible for different processes and have a transcript-specific effect on gene expression.

An Enterobacteriaceae Bloom in Aging Animals is Restrained by the Gut Microbiome

2024-03-15 · 4 citations

bloom was facilitated by a decline in Sma/BMP immune signaling in aging animals and demonstrated its potential for exacerbating infection susceptibility. However, such detrimental effects were context-dependent, mitigated by competition with commensal communities, highlighting the latter as determinants of healthy versus unhealthy aging, depending on their ability to restrain opportunistic pathobionts.

Emergence of dauer larvae in <i>Caenorhabditis elegans</i> disrupts continuity of host-microbiome interactions

FEMS Microbiology Ecology · 2024-11-08 · 3 citations

Nematodes are common in most terrestrial environments, where populations are often known to undergo cycles of boom and bust. Useful in such scenarios, nematodes present developmental programs of diapause, giving rise to stress-resistant larvae and enabling dispersal in search of new resources. Best studied in Caenorhabditis elegans, stress resistant dauer larvae emerge under adverse conditions, primarily starvation, and migrate to new niches where they can resume development and reproduce. Caenorhabditis elegans is a bacterivore but has been shown to harbor a persistent and characteristic gut microbiome. While much is known about the gut microbiome of reproducing C. elegans, what dauers harbor is yet unknown. This is of interest, as dauers are those that would enable transmission of microbes between nematode generations and geographical sites, maintaining continuity of host-microbe interactions. Using culture-dependent as well as sequencing-based approaches, we examined the gut microbiomes of dauers emerging following population growth on ten different natural-like microbially diverse environments as well as on two defined communities of known gut commensals and found that dauers were largely devoid of gut bacteria. These results suggest that host gut-microbiome interactions in C. elegans are not continuous across successive generations and may reduce the likelihood of long-term worm-microbe coevolution.

Perception of Temperature Even in the Absence of Actual Change is Sufficient to Drive Transgenerational Epigenetic Inheritance

bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-05 · 7 citations

Can processes occurring in one individuals nervous system influence the physiology of the descendants? Here we explored the provocative hypothesis that parents sensation or perception of environmental cues can influence their offspring, extending across many subsequent generations. We show that in Caenorhabditis elegans, temperature perception on its own can induce transgenerational changes in RNAi factors, small RNAs, and the genes that they regulate. Moreover, we identified secreted factors that enable a pair of thermosensory neurons (AFD) to communicate with the germline and trace the path of the epigenetic signal. We further modeled the process mathematically and validated the new predictions generated by the model experimentally. Hence, our results demonstrate that sensory perception is sufficient to trigger small RNA-mediated heritable gene expression memory.

The West African lungfish secretes a living cocoon during aestivation with uncertain antimicrobial function

bioRxiv (Cold Spring Harbor Laboratory) · 2024-07-10

Abstract One of the most exceptional adaptations to extreme drought is found in the sister group to tetrapods, the lungfishes (Dipnoi), which can aestivate inside a mucus cocoon for multiple years at reduced metabolic rates with complete cessation of ingestion and excretion. However, the function of the cocoon tissue is not fully understood. Here we developed a new more natural laboratory protocol for inducing aestivation in the West African lungfish, Protopterus annectens, and investigated the structure and function of the cocoon. We used electron microscopy and imaging of live tissue-stains to confirm that the inner and outer layers of the paper-thin cocoon are composed primarily of living cells. However, we also repeatedly observed extensive bacterial and fungal growth covering the cocoon and found no evidence of anti-microbial activity in vitro against E. coli for the cocoon tissue in this species. This classroom discovery-based research, performed during a course-based undergraduate research experience course (CURE), provides a robust laboratory protocol for investigating aestivation and calls into the question the function of this bizarre vertebrate adaptation.

On the role of social media platforms in the creator economy

International Journal of Research in Marketing · 2024-07-15 · 42 citations

Despite their transformative importance, the perspective and role of social media platforms in the creator economy remains understudied. In this research, we examine the role of platforms in the creator economy using a review approach that leverages insights from both a rich account of the literature on platforms and in-depth interviews with several stakeholders in the creator economy. We develop a framework of the key actors and interactions in the creator economy and the central position of platforms as the underlying ecosystem that supports these elements. In doing so, our frameworks illuminates the focal roles that platforms play in the creator economy: connecting key actors, supporting content creation and management, and facilitating monetization. We use the insights gleaned from the literature and our interviews to overview (1) what we know about each of these roles platforms play, (2) what we do not know, and (3) how each of these roles may look in the future. In doing so, our research proposes directions for future research on the role of platforms in the creator economy.

Changes in Electrocardiogram During Romidepsin Therapy: A Case Report.

PubMed · 2023-05-01 · 1 citations

Identification of intestinal mediators of <i>Caenorhabditis elegans</i> DBL-1/BMP immune signaling shaping gut microbiome composition

bioRxiv (Cold Spring Harbor Laboratory) · 2023-10-27

ABSTRACT The composition of the gut microbiome is determined by a complex interplay of diet, host genetics, microbe-microbe competition, abiotic factors, and stochasticity. Previous studies have demonstrated the importance of host genetics in community assembly of the Caenorhabditis elegans gut microbiome and identified a pivotal role for DBL-1/BMP immune signaling in determining the abundance of gut Enterobacteriaceae , in particular of the genus Enterobacter . However, the effects of DBL-1 signaling on gut bacteria were found to depend on its activation in extra-intestinal tissues, suggesting that yet unidentified intestinal factors must mediate these effects. In the present study, we used RNA-seq gene expression analysis of wildtype, dbl-1 and sma-3 mutants, and dbl-1 over-expressors to identify genes regulated by DBL-1/BMP signaling that take part in interactions with gut commensals. Following confirmation of several putative targets by qRT-PCR, we carried out colonization experiments with respective mutants raised on monocultures as well as on defined bacterial communities. These experiments identified five intestinal DBL-1/BMP targets, predicted to be secreted, that showed increased Enterobacteriaceae abundance compared to wildtype. The extent of increases was for the most part lower than those seen in DBL-1 pathway mutants, suggesting that identified mediators are components of a DBL-1-regulated antibacterial cocktail, which may additively contribute to shaping of gut microbiome composition. IMPORTANCE Compared to the roles of diet, environmental availability, or lifestyle in determining gut microbiome composition, that of genetic factors is the least understood and often underestimated. The identification of intestinal mediators acting downstream of DBL-1/BMP signaling to control enteric bacteria, describes a cocktail of effectors with distinct molecular functions, thus offering a glimpse into the genetic logic of microbiome control as well as a list of targets for future exploration of this logic.