Listeria monocytogenes is a major foodborne pathogen, capable of proliferating under refrigeration. Antimicrobial blue light (aBL) has emerged as a promising non-thermal decontamination strategy, yet its comprehensive mechanisms and compatibility with complex food systems remain incompletely characterized. Here, we demonstrate that aBL induces substantial killing of L. monocytogenes in a dose- and wavelength-dependent manner, and we identified the optimal combination of 420 nm and a fluence of 108 J/cm2, which achieved a maximum reduction of 3.8 log₁₀ CFU/mL (compared with 3–4 log reductions at other settings). Mechanistically, aBL suppresses free cells and biofilms by promoting ROS and autolysis, respectively. Transcriptomic profiling reveals significant upregulation of spxA, kat, and recA (log₂(fold change) > 1, padj <0.001), indicating strong activation of oxidative stress defense and DNA repair pathways. Subsequently, the food safety applicability of aBL was validated among liquid, solid, and packaged food formats, with 420 nm consistently eliciting superior efficacy while preserving sensory qualities of food products. Notably, in surimi, hardness, chewiness and cohesiveness were significantly enhanced, whereas springiness and adhesiveness remained unchanged. Importantly, aBL retained its bactericidal activity under refrigerated conditions, underscoring its practical value for cold-chain food storage. These findings establish aBL as a promising, scalable intervention strategy for L. monocytogenes decontamination across multiple food storage scenarios.

Probiotics, as ratified by the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus that endorsed and refined the original FAO/WHO definition, are “live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host” [...]

As a prevalent neurodevelopmental disease, whether ASD (autism spectrum disorder) can be ameliorated by the early use of a single microbe remains unknown. Here we used a lactobacillus strain, Lacticaseibacillus rhamnosus GR-1 (LGR-1), for prenatal intervention in autism-like mice with either environmental or idiopathic origins by exclusively administering to the pregnant dams at a dose of 109/mouse/day, followed by offspring behavioral assessment with 3-chamber trial and marble burying test. The results revealed that LGR-1 prevented the occurrence of autism-like symptoms, as evidenced by the improved behaviors and restored E/I (excitatory-inhibitory) balance in the prefrontal cortex of male pups. In parallel, the offspring microbiome was reshaped by LGR-1 treatment, probably mediated by the vertical transmission of maternal microbiome, with its roles further unraveled by fecal microbiota transplant and cross-fostering experiments. In addition to gut commensals, the LGR-1-shaping vaginal microbiota also contributed to the establishment of “beneficial” microbiome. Regarding key taxa in offspring, Akkermansia muciniphila was influenced by LGR-1 and exerted impact on behaviors via pathways related to IL-17-producing lymphocytes. Our findings demonstrate that prenatal microbial administration protects offspring against autism-like behavioral phenotypes through microbiome transmission, highlighting a potential microbe-based therapeutic avenue to mitigate ASD risk.

Gut microbiome has a considerable impact on the central nervous system via the "gut-brain axis." Neuroepigenome emerges as the interface between environment and genes, potentially help conveying the signals derived from the microbiome to the brain tissue. While only a limited number of studies have implicated epigenetic roles in the gut-brain axis, this review explores how gut microbiome might impact various brain-based epigenetic mechanisms, including DNA methylation, histone modification, ncRNA and RNA methylation, notably in the context of the specific neural complications. Among the epigenetic mechanisms, histone acetylation was most well-studied with respect to its relationships with gut microbiome, exerting a dynamic influence on gene expression in the brain. Furthermore, the pathways connecting gut bacteria to neuroepigenome were summarized, highlighting the roles of metabolites such as butyrate, propionate, acetate, lactate, and folate. Of particular interest, the roles of butyrate are emphasized due to their outstanding inhibitory activity towards histone deacetylases (HDACs), among other mechanisms. It is worth noting that some indirect gut-brain pathways may also be associated with the interplay between microbiome and neuroepigenome, while IL-6 has been found to effectively transmit microbe-derived signals to histone methylation in brains. Finally, we recapitulate the future perspectives critical to understanding this gut-brain crosstalk, such as clarifying the cause-and-effect relationship, bacterial cross-feeding within the gut, and the mechanisms underlying the site-specific histone modification in the brain. Together, this review attempts to consolidate our current knowledge about the "microbiome-neuroepigenome interplay" and propose a conceptual pathway to decipher the gut-brain axis in various neurological conditions.

There is robust evidence that environmental risk factors impact cognitive performance. However, the effect of the environmental risk factor lead (Pb) on susceptibility to non-spatial memory deficits is unknown. Here, it is demonstrated that Pb exposure increases the susceptibility to these deficits, with the impairment of CA1 excitatory neurons as the underlying cause. Furthermore, Pb exposure increased HDAC2 levels in CA1 excitatory neurons, a crucial epigenetic factor for reprogramming synaptic plasticity and memory formation. These non-spatial memory deficit effects could be rescued via Hdac2-cKO in CA1 excitatory neurons. Additionally, Hdac2-cKO reversed reductions in miniature excitatory postsynaptic currents (mEPSC), Ca2+ signaling, and spine density caused by Pb in CA1 excitatory neurons. In terms of the mechanistic insight, Hdac2-cKO reversed the downregulation of TRPC6, LRP2, VGLUT1, NMDAR1, NMDAR2B, AMPAR2, and PSD95 in CA1 excitatory neurons. In conclusion, Pb induces non-spatial memory deficits and synaptic plasticity impairments by increasing HDAC2 epigenetic reprogramming in hippocampal CA1 excitatory neurons, providing a new reference for the prevention and treatment of memory deficits induced by environmental cues.

Royal jelly (RJ), a nutrient-rich secretion fed exclusively to queen honeybees, exhibits diverse biological activities. Due to limited insights into its effects on central nervous system (CNS)-related functions and pathologies, this review attempts to recapitalize the recent advances of neuroregulatory function of RJ in mammals and humans. Another central aim of this review is to summarize the known mechanisms underlying the neuroregulatory effect of RJ. RJ components were first discussed concerning their link to neuroprotection, with a focus on the queen bee acid (QBA, 10-HDA, trans-10‑hydroxy-2-decenoic acid), MRJPs (major royal jelly proteins), and microbiota. The neuroregulatory implications of RJ are then categorized into three domains: fundamental CNS functions, including learning and memory, in vitro neuronal cell activity and social behavior; neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), anxiety and depression; neurotoxic events. In terms of mechanistic insights, RJ modulates neuroinflammation, a pivotal driver of neurological disorders, and acts as an HDAC (histone deacetylase) inhibitor among other epigenetic regulators, influencing gene expression in the CNS. Emerging evidence also implicates the microbiota-gut-brain (MGB) axis, where RJ alters gut microbiota composition, subsequently impacting brain function. Finally, we outline critical research directions, including clinical significance, comparisons with other honeybee products, epigenetic mechanisms, and RJ's untapped role in reshaping social behaviors. This review aims to consolidate our knowledge on the neuroregulatory effects of RJ, underscoring its therapeutic potential for neurological conditions in both nutritional and pharmaceutical contexts.

Royal jelly (RJ) has long been considered a crucial dietary component in dictating caste differentiation in honeybees. As a nutritional additive, royal jelly imparts a broad range of benefits to mammals and humans; however, its precise impact on the social hierarchy of these advanced animals is not yet fully understood. This study aims to determine whether the benefits of royal jelly can be transferred to rats to alter their social ranks and uncover the underlying mechanisms. A submissive model was established by inducing dysbiosis in rats, via the persistent exposure of vancomycin. Royal jelly at a dose of 2.5 g/kg was daily administered to the subject rats during postnatal weeks (PNW) 6 and 7. At the end of the intervention, animals were subjected to agonistic, water and tube competition tests, in order to assess their dominance status. As revealed by the results, the RJ treatment significantly improved the social rank of the dysbiotic rats, demonstrating that RJ can elicit positive effect on the social behaviors (caused by dysbiosis) of rats. All behavioral paradigms yielded consistent results, with no notable differences in body weight or anxiety levels. Regarding gut microbiome, vancomycin exposure caused the dysbiosis of the subject rats, which was partially reversed by treatment with royal jelly. Specifically, the intestinal presence of Proteobacteria was profoundly attenuated by the RJ supplementation, resulting in a comparable level with the intact/dominant rats. At the genus level, both Escherichia and Clostridium displayed similar dynamics in relation to Proteobacteria, implying their involvement with the RJ-mediated dominance switching. Transcriptomic analysis in the medial prefrontal context showed that the expression of a broad range of genes was influenced by RJ intake, embodying various pathways related to neuronal transmission such as neuroactive ligan-receptor interaction, the synaptic vesicle cycle, etc. By virtue of correlation analysis, Escherichia, Akkermansia and Clostridium were strongly associated with a set of gene modules around gastrin releasing peptide (Grp) and signaling pathways around Rps6ka3, establishing an intrinsic gut-brain communication. Furthermore, the infection trials of Escherichia significantly degraded the social ranks of the RJ-remedied rats in tube tests, while a series of cerebral genes like Grpr and Grpel1, as well as prefrontal spine density, were concordantly altered, underscoring the critical role of the gut-brain link in deciding the outcomes of the dyadic contests. In summary, this is an intriguing example of how royal jelly can influence the social ranks of mammals, emphasizing the importance of microbe-host interaction in mediating this species-spanning function of royal jelly in shaping social hierarchy.

Antimicrobial blue light (aBL) is utilized as a new approach to inhibit the growth of Staphylococcus aureus (S. aureus). Mediated by the endogenous chromophore, aBL possesses the similar photokilling property with aPDI (antimicrobial photodynamic inactivation), however, their mechanistic discrepancies in triggering the death of staphylococcal cells are not yet understood. Here, we describe the use of a 460-nm-LED to curb the viability of S. aureus. According to the results, the bacterial survival was sharply decreased when blue light was applied, reaching a maximum of 4.11 ± 0.04 log10 units. Moreover, the membrane integrity was damaged by aBL, causing the leakage of intracellular DNA. Transcriptomic analysis indicates the divergent gene expression upon either aBL or aPDI, with pathways such as transport, DNA repair, expression regulation and porphyrin massively affected by aBL. Among the commonly regulated genes, LrgA was underpinned on account of its involvement with biofilm formation and protein transport. By comparing the wildtype with the LrgA-overexpressing (LrgA+) strain, the survival rate, membrane penetration, surface structure and biofilm formation were, to a varying degree, improved for LrgA+, which may suggest that LrgA plays essential roles in modulating the responsiveness of S. aureus. Besides, LrgA may function through regulating the expression of autolysis-related systems. Finally, LrgA overexpression did not attenuate but aggravate the impairment induced by aPDI, showcasing a distinct responsive strategy from aBL. Taken together, this study unveils a unique molecular alteration for the aBL-mediated inactivation, providing the basis of utilizing blue light to reduce the harm brought by S. aureus.

Lead (Pb) is a pervasive heavy metal with multi-organ toxicity. However, the molecular mechanisms of Pb-induced neurotoxicity are not fully understood. The dynamics of N6-methylademine (m6A) is an emerging regulatory mechanism for gene expression, which is closely related to nervous system diseases. To elucidate the association between m6A modification and Pb-mediated neurotoxicity, primary hippocampal neurons exposed to 5 μM Pb for 48 h were used as the paradigm neurotoxic model in this study. According to the results, Pb exposure reprogrammed the transcription spectrum. Simultaneously, Pb exposure remodeled the transcriptome-wide distribution of m6A while disrupting the overall level of m6A in cellular transcripts. United analysis of MeRIP-Seq and RNA-Seq was applied to further identify the core genes whose expression levels are regulated by m6A in the process of lead-induced nerve injury. GO and KEGG analysis unveiled that the modified transcripts were overrepresented by the PI3K-AKT pathway. Mechanically, we elucidated the regulatory role of the methyltransferase like3 (METTL3) in the process of lead-induced neurotoxicity and the downregulation of the PI3K-AKT pathway. In conclusion, our novel findings shed new light on the functional roles of m6A modification in the expressional alternations of downstream transcripts caused by lead, providing an innovative molecular basis to explain Pb neurotoxicity.

Background: The aim of this study is to interrogate the prophylactic effect of probiotic on the lead-induced spatial memory impairment, as well as the underlying mechanisms based on gut microbiota.Methods: Rats were exposed postnatally to 100 ppm of lead acetate during lactation (from postnatal day 1 to 21), to establish the memory deficits model. A probiotic bacterium, namely Lacticaseibacillus rhamnosus, was administered by drinking into pregnant rats with a dosage of 109 CFU/rat/day till birth. At postnatal week 8 (PNW8), the rats were subjected to Morris water maze and Y-maze test, with fecal samples collected for 16S rRNA sequencing. Besides, the inhibitory effect of Lb. rhamnosus on Escherichia coli was carried out in bacterial co-culture.Results: Female rats prenatally exposed to probiotic improved their performances in the behavioral test, indicating that probiotic could protect rats from memory deficits caused by postnatal lead exposure. This bioremediation activity varies depending on the intervention paradigm used. As revealed by microbiome analysis, although administered in a distinct period from lead exposure, Lb. rhamnosus further changed the microbial structure disrupted by lead exposure, suggesting an effective transgenerational intervention. Of note, gut microbiota, represented by Bacteroidota, varied greatly depending on the intervention paradigm as well as the developmental stage. The concerted alterations were revealed between some keystone taxa and behavioral abnormality, including lactobacillus and E. coli. To this end, an in vitro co-culture was created to demonstrate that Lb. rhamnosus could inhibit the growth of E. coli with direct contact, which is dependent on the growth condition under study. In addition, in vivo infection of E. coli O157 aggravated memory dysfunction, which could also be rescued by probiotic colonization.Conclusions: Early probiotic intervention could prevent organisms from lead-induced memory decline in later life through reprogramming gut microbiota and inhibiting E. coli, providing a promising approach to ameliorate the cognitive damage with environmental origins.

Cronobacter sakazakii is an opportunistic foodborne pathogen primarily found in powdered infant formula (PIF). To date, it remains challenging to control the growth of this ubiquitous bacterium. Herein, antimicrobial photodynamic inactivation (aPDI) was first employed to inactivate C. sakazakii. Through 460 nm light irradiation coupled with hypocrellin B, the survival rate of C. sakazakii was diminished by 3~4 log. The photokilling effect was mediated by the attenuated membrane integrity, as evidenced by PI staining. Besides, scanning electron microscopy showed the deformed and aggregated cell cluster, and intracellular ROS was augmented by 2~3 folds when light doses increase. In addition to planktonic cells, the biofilm formation of C. sakazakii was also affected, showing an OD590nm decline from 0.85 to 0.25. In terms of molecular aspects, a two-component system called CpxRA, along with their target genes, was deregulated during illumination. Using the knock-out strain of ΔCpxA, the bacterial viability was reduced by 2 log under aPDI, a wider gap than the wildtype strain. Based on the promoted expression of CpxR and OmpC, aPDI is likely to play its part through attenuating the function of CpxRA-OmpC pathway. Finally, the aPDI system was applied to PIF, and C. sakazakii was inactivated under various desiccated or heated storage conditions. Collectively, aPDI serves as an alternative approach to decontaminate C. sakazakii, providing a new strategy to reduce the health risks caused by this prevalent foodborne pathogen.

Lead (Pb) exposure during early life has been associated with an increased risk of neurodevelopmental disorders, including learning and memory deficits. The intestinal flora, via the microbiome–gut–brain axis, could play a significant role in the nervous system. However, the effects of probiotics on ameliorating Pb-induced learning and memory deficits are still unclear. In this study, we showed that adolescent Pb exposure (150 ppm) for 2 months impaired spatial learning and memory ability, accompanied by the decreasing diversity of gut microbiota, and the decreasing abundance of Lactobacillus at the genus level. Surprisingly, administration of the Lactobacillus rhamnosus GR-1 (1010 organisms/rat/day), not L. rhamnosus LGG or Lactobacillus reuteri RC-14, reversed learning and memory deficits induced by Pb exposure. Meanwhile, administration of the L. rhamnosus GR-1 increased the diversity of the gut microbiota composition and partially normalized the genus level of Lactobacillus, Parabacteroides, Enterococcus, and Akkermansia in Pb-exposed rats. Notably, supplementation of L. rhamnosus GR-1 decreased the gut permeability of Pb-exposed rats, reduced proinflammatory cytokines [interleukin-1β (IL-1β) and IL-6] expression, and promoted anti-inflammatory cytokines [granulocyte colony-stimulating factor (G-CSF)] expression. Interestingly, neural cell treatment with G-CSF rescued Pb-induced neurotoxicity. In general, L. rhamnosus GR-1 supplementation recovered the Pb-induced loss of intestinal bacteria (Lactobacillus), which may have reversed the damage to learning and memory ability. Collectively, our findings demonstrate an unexpectedly pivotal role of L. rhamnosus GR-1 in Pb-induced cognitive deficits and identify a potential probiotic therapy for cognitive dysfunction during early life.

Social dominance is a ubiquitous phenomenon among social animals, including humans. To date, individual attributes leading to dominance (after a contest) remain largely elusive. Here, we report that socially dominant rats can be distinguished from subordinates based on their intestinal microbiota. When dysbiosis is induced, rats are predisposed to a subordinate state, while dysbiotic rats reclaim social dominance following microbiota transplantation. Winning hosts are characterized by core microbes, a majority of which are associated with butyrate production, and the sole colonization of Clostridium butyricum is sufficient to restore dominance. Regarding molecular aspects, a histone deacetylase, HDAC2, is responsive to microbial status and mediates competition outcome; however, this occurs only in a restricted population of cells in the medial prefrontal cortex (mPFC). Furthermore, HDAC2 acts by modulating synaptic activity in mPFC. Together, these findings uncover a link between commensals and host dominance, providing insight into the gut-brain mechanisms underlying dominance determination.

Staphylococcus aureus (S. aureus) is a foodborne pathogen that endangers human health worldwide. Antimicrobial photodynamic inactivation (aPDI), mediated by titanium dioxide nanoparticles (TiO2NP), was recently used to control the growth of S. aureus, however, UV illumination had to be offered to initiate the photodynamic reaction. To overcome this drawback, a dual-photon system was established here based on TiO2NP and hypocrellin B (HB), a natural pigment with photocatalyst activity. Irradiated at the visible light (9 J/cm2) at the wavelength of 460 nm, the joint use of both photosensitizers (PS) caused a substantial decline of staphylococcal survival, reaching a maximum decrease of 4 ∼ 5 logs. When 10 nM HB and 100 µM TiO2NP were applied, a synergistic photokilling effect was achieved, only in the mixed phase of anatase/rutile, Degussa P25. Regarding the antimicrobial mechanisms, it was found that the membrane integrity of S. aureus was heavily disrupted, surface morphology was altered, intracellular substances like potassium and DNA were leaked, and biofilm formation was significantly circumvented due to the excitation of sensitized PS. In terms of antioxidant responsiveness of S. aureus, qPCR results showed that a series of genes encoding the membrane-associated cell death effectors were deregulated. Among them, LrgA was recognized as a key responsive element, due that the mutant strain harboring a constitutively-expressed LrgA strengthened the bactericidal effect of aPDI. Finally, the dual-photon strategy lowered the microbial contamination in the tested apple with its quality maintained, under the condition of visible light. Taken together, a new dual-photon system based on TiO2NP and HB was constructed and validated in photokilling S. aureus, providing a well-adapted technique to maintain food safety.

A dual modification of waxy maize starch was applied by sodium dodecyl sulfate (SDS) and multiple freezing/ thawing (1, 5 and 10 cycles) treatments for porous starch preparation. The combined treatment made the edges and corners of starch granules disappeared while large holes were observed on the starch surface. It was accompanied with a significant increase in swelling power and solubility, which resulted in lower gelatinization temperatures and enthalpy. X-ray diffraction analysis showed that the relative crystallinity was decreased from 49.62% to 45.23% after 10 freezing/thawing (F/T) cycles, which was further lowered down to 40.79% as the combined treatment applied. The peak, breakdown and setback viscosities were increased by 335, 230 and 84.4 cp, respectively. These results suggested that removal of starch granule-surface protein by SDS provided the frozen starch granules with open structure, resulting in high water absorption and more ice pressure. These changes effectively produced homogeneous porosity than the isolated treatments, exhibiting a potential application of waxy maize starch.

Glucocorticoids (GCs) are widely used in tumor therapy to reduce tumor growth, inflammation, edema, and other side effects. Controversially, GCs may also cause the progression of highly aggressive pancreatic ductal adenocarcinoma (PDAC). Because microRNA (miR) and autophagy signaling support the invasive growth of PDAC, we asked whether these mechanisms may be targeted by GCs. Six established human PDAC cell lines, tissue from patients who received GC medication ( n = 35) prior to surgery, or not ( n = 35), and tumor xenografts were examined by RT‒qPCR, transmission electron microscopy (TEM), monodansylcadaverine (MDC) staining, immunohistochemistry, in situ hybridization, gene array and Kaplan‒Meier analysis with bioinformatics, and MTT, western blot, colony, spheroid, migration, and invasion assays. We found that various GCs, including dexamethasone (DEX), induced typical features of macroautophagy with the appearance of autolysosomes, enhanced LC3-II, decreased SQSTM1/p62 expression and induced epithelial-mesenchymal transition (EMT) and gemcitabine resistance. The GC receptor (GR) antagonist mifepristone (RU486) counteracted DEX-induced autophagy features, suggesting that the GC-GR complex is involved in the induction of autophagy. The autophagy-related miR-378i and miR-378a-3p were selected as the top upregulated candidates, and their high expression in PDAC patient tissue correlated with low survival. siRNA-mediated downregulation of miR-378 inhibited DEX-induced autophagy, and tumor progression. Bioinformatics confirmed the contribution of miR-378 to the regulation of signaling networks involved in GC-induced autophagy and tumor progression. The construction of a molecular docking model revealed stable binding of miR-378 to the DEX-GR complex, suggesting direct regulation. These substantial, novel, in-depth data reveal that GCs favor autophagy-mediated cancer progression by inducing miR-378 and GR binding and implicate GR and miR-378 as new therapeutic targets.

The contamination of infant milk and powder with Enterobacter sakazakii poses a risk to human health and frequently caused recalls of affected products. This study aims to explore the inactivation mechanism of E. sakazakii induced by high hydrostatic pressure (HHP), which, unlike conventional heat treatment, is a nonthermal technique for pasteurization and sterilization of dairy food without deleterious effects. The mortality of E. sakazakii under minimum reaction conditions (50 MPa) was 1.42%, which was increased to 33.12% under significant reaction conditions (400 MPa). Scanning electron microscopy (SEM) and fluorescent staining results showed that 400 MPa led to a loss of physical integrity of cell membranes as manifested by more intracellular leakage of nucleic acid, intracellular protein and K + . Real-time quantitative PCR (RT-qPCR) analysis presents a downregulation of three functional genes ( glpK, pbpC , and ompR ), which were involved in cell membrane formation, indicating a lower level of glycerol utilization, outer membrane protein assembly, and environmental tolerance. In addition, the exposure of E. sakazakii to HHP modified oxidative stress, as reflected by the high activity of catalase and super oxide dismutase. The HHP treatment lowered down the gene expression of flagellar proteins ( fliC, flgI, fliH , and flgK ) and inhibited biofilm formation. These results determined the association of genotype to phenotype in E. sakazakii induced by HHP, which was used for the control of food-borne pathogens.

SummaryAntimicrobial photodynamic inactivation (aPDI) serves as a new approach to control the growth of foodborne bacteria. It remains elusive if the photodynamic efficacy of hypocrellin B (HB) can be potentiated by joint action with curcumin. In this study, we measured the survival rate of Staphylococcus aureus strains under the varying photodynamic conditions. According to our data, a maximum of 5–6 log10 decrease of bacterial survival can be achieved under the tested conditions (500 nM, 9 J cm‒2). Regarding the bactericidal mechanisms, HB‐based aPDI disrupted the membrane integrity of staphylococcal cells, probably owing to the stimulated reactive oxygen species (ROS). In addition, aPDI disrupted the enzymatic activities of bacterial antioxidant proteins and caused the leakage of multiple intracellular substances. The HB‐mediated photodynamic efficacy was potentiated by the addition of curcumin with a sublethal dose. This dual‐photon synergy arose from unique aPDI conditions (100 nM each and 9 J cm‒2). The synergistic action might be accounted for by the increased type I/type II ratio of ROS, as evidenced by the effect of different quenchers. Finally, the joint use of photosensitizers reduced the microbial contamination of the tested apple while maintaining its quality. In summary, photodynamic inactivation based on dual photons showed synergistic activity in controlling the growth of Staphylococcal aureus, which provided a novel approach to maintain food safety.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Eigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, is known to exert a beneficial effect on PD patients. Although some mechanisms were suggested to underlie this intervention, it remains unknown if the EGCG-mediated protection was achieved by remodeling gut microbiota. In the present study, 0.1 mM or 0.5 mM EGCG was administered to the Drosophila melanogaster with PINK1 (PTEN induced putative kinase 1) mutations, a prototype PD model, and their behavioral performances, as well as neuronal/mitochondrial morphology (only for 0.5 mM EGCG treatment) were determined. According to the results, the mutant PINK1B9 flies exhibited dopaminergic, survival, and behavioral deficits, which were rescued by EGCG supplementation. Meanwhile, EGCG resulted in profound changes in gut microbial compositions in PINK1B9 flies, restoring the abundance of a set of bacteria. Notably, EGCG protection was blunted when gut microbiota was disrupted by antibiotics. We further isolated four bacterial strains from fly guts and the supplementation of individual Lactobacillus plantarum or Acetobacter pomorum strain exacerbated the neuronal and behavioral dysfunction of PD flies, which could not be rescued by EGCG. Transcriptomic analysis identified TotM as the central gene responding to EGCG or microbial manipulations. Genetic ablation of TotM blocked the recovery activity of EGCG, suggesting that EGCG-mediated protection warrants TotM. Apart from familial form, EGCG was also potent in improving sporadic PD symptoms induced by rotenone treatment, wherein gut microbiota shared regulatory roles. Together, our results suggest the relevance of the gut microbiota-TotM pathway in EGCG-mediated neuroprotection, providing insight into indirect mechanisms underlying nutritional intervention of Parkinson's disease.

Chronic lead exposure is associated with the development of neurodegenerative diseases, characterized by the long-term memory decline. However, whether this pathogenesis could be prevented through adjusting gut microbiota is not yet understood. To address the issue, pregnant rats and their female offspring were treated with lead (125 ppm) or separately the extra probiotics (1010 organisms/rat/day) till adulthood. For results, memory dysfunction was alleviated by the treatment of multispecies probiotics. Meanwhile, the gut microbiota composition was partially normalized against lead-exposed rats, which in turn mediated the memory repairment via fecal transplantation trials. In the molecular aspect, the decreased H3K27me3 (trimethylation of histone H3 Lys 27) in the adult hippocampus was restored with probiotic intervention, an epigenetic event mediated by EZH2 (enhancer of zeste homolog 2) at early developmental stage. In a neural cellular model, EZH2 overexpression showed the similar rescue effect with probiotics, whereas its blockade led to the neural re-damages. Regarding the gut-brain inflammatory mediators, the disrupted IL-6 (interleukin 6) expression was resumed by probiotic treatment. Intraperitoneal injection of tocilizumab, an IL-6 receptor antagonist, upregulated the hippocampal EZH2 level and consequently alleviated the memory injuries. In conclusion, reshaping gut microbiota could mitigate memory dysfunction caused by chronic lead exposure, wherein the inflammation-hippocampal epigenetic pathway of IL-6-EZH2-H3K27me3, was first proposed to mediate the studied gut-brain communication. These findings provided insight with epigenetic mechanisms underlying a unique gut-brain interaction, shedding light on the safe and non-invasive treatment of neurodegenerative disorders with environmental etiology.