PacR (All3953) has previously been identified as a global transcriptional regulator of carbon assimilation in cyanobacteria. In the facultative diazotrophic and filamentous cyanobacterium Anabaena PCC 7120 (Anabaena), inactivation of pacR has been shown to affect cell growth under various conditions. Nitrogen fixation in Anabaena occurs in heterocysts, cells differentiated semiregularly along the filaments following deprivation of combined nitrogen such as nitrate or ammonium. Here, we created a markerless deletion mutant of pacR. In addition to its growth defects observed under different light and nitrogen conditions, the mutant could form a high frequency of heterocysts, including heterocyst doublets, even in the presence of nitrate. Inactivation of pacR led to the upregulation of ntcA, a global regulator of nitrogen metabolism and heterocyst formation, as well as downregulation of genes involved in nitrate uptake and assimilation. These changes led to N-limited cells in the presence of nitrate. PacR also regulates most of the genes encoding bicarbonate transport systems. The promoter regions of ntcA, and several other genes involved in nitrogen or carbon uptake and assimilation, as well as patS and hetN involved in heterocyst patterning can be directly recognized by PacR in vitro. These findings, along with previously reported ChIP-seq data, establish PacR as a crucial transcriptional regulator for balancing carbon and nitrogen metabolism in cyanobacteria.

Coagulase-negative staphylococci (CoNS) are commensal bacteria of the human skin and mucosal membranes. The incidence of nosocomial infections caused by these species is on the rise, leading to a potential increase in antibiotic tolerance and resistance. Phages are emerging as a promising alternative to combat CoNS infections. Scientists are isolating phages infecting CoNS with a particular interest in S. epidermidis. This review compiles and analyses CoNS phages for several parameters including source, geographical location, host species, morphological diversity, and genomic diversity. Additionally, recent studies have highlighted the potential of these phages based on host range, in vitro evaluation of performance and stability, and interaction with biofilms. This comprehensive analysis enables a better understanding of the steps involved in using these phages for therapeutic purposes.

The flagellum is a complex molecular nanomachine crucial for cell motility. Its assembly requires coordinated expression of over 50 flagellar genes, regulated by the transcription activator FleQ. Phylogenomic analyses suggest that many non-flagellated bacterial species have evolved from flagellated ancestors by losing specific flagellar components, though the evolutionary mechanisms driving this process remain unclear. In this study, we examined the evolutionary dynamics of Pseudomonas syringae DC3000 under standard laboratory conditions using quantitative proteomics. We observed a notable reduction in flagellar gene expression following prolonged serial passages. Whole-genome sequencing revealed multiple adaptive mutations in fleQ, dksA, and glnE, all of which are associated with flagellar biosynthesis. Furthermore, our findings demonstrate that nonmotile ΔfleQ cells can hitchhike onto wild-type cells, potentially facilitated by increased production of the surfactant syringafactin. Our study suggests that the high metabolic costs associated with flagella biosynthesis, coupled with advantageous hitchhiking properties, contribute to the degenerative evolution of flagella.

Woronin bodies are unique organelles in Pezizomycotina fungi that allow hyphae compartmentalization and prevent cytoplasmatic bleeding after mechanical injury. Several studies have related the peroxisomal protein HEX1, the major component of Woronin bodies with other biological processes such as hyphal growth, osmotic stress tolerance and pathogenicity. Trichoderma spp. are plant-beneficial multipurpose biological control agents, and proteomic and transcriptomic studies have shown that HEX1 and its corresponding gene are overrepresented when grown in the presence of fungal cell walls and plant polymers. To further investigate the involvement of hex1 in Trichoderma biology, we generated hex1 deletion transformants using the wheat endophytic strain T. simmonsii T137 as host. Results confirmed that hex1 gene is involved in the prevention of cytoplasmatic bleeding, and also has a role in fungal growth and biocontrol potential against phytopathogenic fungi and oomycetes. The involvement of hex1 in the fungal response to osmotic and oxidative stresses is conditioned by the type of stress and by the nutrient richness of the culture medium. The hex1 deletion also affected the interaction with wheat, but did not affect the plant protective effect of T137 against water stress. Overall, this study shows the implication of HEX1 in a wide range of biological processes necessary for T. simmonsii to deploy its abilities to be used as an agriculturally beneficial fungus.

Volatile organic compounds (VOCs) produced by microorganisms may have a noteworthy role in the control of plant pathogens. Xanthomonas are a well-studied group of phytobacteria that cause diverse diseases in economically important crops worldwide. Key species that infect sugarcane are X. albilineans (Xab) and X. axonopodis pv. vasculorum (Xav). Here, we investigated VOC-producing bacteria with antagonistic effects against Xab and Xav. We demonstrated that VOCs produced by Pseudomonas sp. V5-S-D11 was able to abolish the growth of these pathogens. A set of 32 VOCs was identified in the volatilome of V5-S-D11, with 10 showing a concentration-dependent inhibitory effect on both phytobacteria. Among them, dimethyl disulfide (DMDS), a volatile sulfur compound, has the potential to be biotechnologically explored in agriculture since it can improve plant growth and induce systemic resistance against plant pathogens. Interestingly, transcriptomic analysis of Xab treated with DMDS revealed several up-regulated metabolic pathways such as a two-component system, flagellar assembly, chemotaxis, and a bacterial secretion system. Although the ethanol (ETOH) used as DMDS solvent did not inhibit Xab growth, it triggered a similar up-regulation of some genes, indicating that this phytopathogen can deal with ETOH better than DMDS. Overall, this study explores the wide role of VOCs in the interactions with bacteria. Moreover, our results indicate that VOCs from Pseudomonas sp. may represent a novel biotechnological strategy to counteract diseases caused by Xanthomonas species and can be further exploited for sustainable approaches in agriculture.

Bacteria and viruses pose significant threats to human health, as drug molecules and therapeutic agents are often hindered by cell membranes and tissue barriers from reaching intracellular targets. Cell-penetrating peptides (CPPs), composed of 5-30 amino acids, function as molecular shuttles that facilitate the translocation of therapeutic agents across biological barriers. Despite their therapeutic potential, CPPs exhibit limitations, such as insufficient cell specificity, low in vivo stability, reduced delivery efficiency, and limited tolerance under serum conditions. However, intelligent design and chemical modifications can enhance their cell penetration, stability, and selectivity. These advancements could significantly improve CPP-based drug delivery strategies, facilitating both infection treatment and immunization against bacterial and viral diseases. This review provides an overview of the applications of CPPs in various infections and immune diseases, summarizing their mechanisms and the challenges encountered during their application.

Aspergillus niger is a powerful and efficient cell factory, with the potential to synthesize valuable products as chassis cells. The use of microbial cell factories to produce monacolin J, a precursor for statin synthesis, as an alternative to chemical synthesis could meet increasing market demand. However, the need for precise large fragment gene editing and the availability of suitable integration loci hinders the application of this strain. Herein, we identified neutral integration sites of A. niger based on the combination of ATAC-seq, H3K4me3 epigenetic datasets. Next, a landing pad system was developed for the one-step integration of the MJ biosynthesis gene cluster (BGC) in A. niger. Furthermore, we optimized the precursor module supply, the auxiliary factor supply module of NADPH, the module for eliminating oxidative stress pressure, and the transporter module to improve the production of MJ. Finally, a multi-copy integration strategy was applied to the rapid integration of MJ BGC, achieving MJ titer up to 1851.52 mg/L at the 500 mL shaker level.

The anti-obesity effects of Lactobacillus paragasseri (L. paragasseri) have been reported, but the exact mechanisms have not been elucidated. There are also no reports on the impact of L. paragasseri on the gut microbiota environment. Recently, the incidence of sarcopenia due to obesity has increased regardless of age, exacerbating metabolic disorders caused by obesity. Therefore, we investigate the beneficial effects of L. paragasseri SBT2055 (LG2055) on obesity along with obese sarcopenia and gut microbiome changes. C57BL/6 J mice were fed a high-fat diet (HFD) and LG2055 (1×10 or 1×10 CFU/mice, low-dose LG2055 (LP) or high-dose LG2055 (HP), respectively was administered orally. LG2055 supplementation significantly reduced white adipose tissues compared to the HFD group and modified plasma lipid profiles to normal levels. The anti-obesity efficacy of LG2055 was due to increased lipid excretion into feces by reducing the mRNA levels of fatty acid binding protein 1 (Fabp1), fatty acid binding protein 2 (Fabp2), fatty acid transport protein 4 (Fatp4), cluster of differentiation 36 (Cd36), and apolipoprotein 48 (ApoB48) in the small intestine. The body fat reduction inhibits ectopic lipid accumulation in the muscles, leading to improvements in muscle mass, grip strength, hind leg thickness, muscle protein levels, and muscle fiber size in both LP and HP groups. LG2055 increased gut microbiota diversity and elevated the levels of Bacteroidota, resulting in a lower Firmicutes/Bacteroidota ratio compared to the HFD group. Changes in the Bacteroidota showed a negative correlation with body fat and plasma free fatty acid (FFA) while exhibiting a positive correlation with lean body mass, grip strength, and hind leg thickness. Our results demonstrated the anti-obesity effects of LG2055 through the white adipose tissue (WAT)-muscle-gut axis, suggesting its potential as an anti-obesity agent.

Strategies aimed at targeting fungal extracellular heat shock protein 90 (eHsp90) using vaccines and antibodies have demonstrated encouraging potential in the prevention and management of invasive fungal diseases (IFDs). However, the precise underlying mechanism by which eHsp90 contributes to the heightened virulence of Candida albicans (C. albicans) remains an enigma, awaiting further elucidation. In our current research, we have found that the 47-kDa fragment of C. albicans Hsp90 (CaHsp90), which serves as the primary antigenic determinant, is not degraded within C. albicans cells. Moreover, we have discovered that extracellular CaHsp90 (eCaHsp90) is derived from the components of lysed C. albicans cells. We also generated recombinant CaHsp90 in Escherichia coli, and found that eCaHsp90 spreads beyond the initial C. albicans colonization site, thereby enhancing the overall virulence of the organism. Our results further clarify that eCaHsp90 activates the nuclear factor kappa-B (NF-κB) signaling pathway and upregulates the expression of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3). This upregulation results in the activation of Gasdermin D (GSDMD) and subsequent macrophage pyroptosis, ultimately increasing the virulence of C. albicans. This study provides valuable insights into the mechanism by which eCaHsp90 contributes to the virulence of C. albicans, offering a pharmacological basis for antifungal strategies targeting fungal eHsp90.

In a molecular-arm-race between viruses and their hosts, viruses have evolved to harness their host's post-translational modifications (PTMs) machinery to gain a competitive edge. These modifications are the most reliable target of plant viruses to overcome the host defence for successful infection. Relatively fewer PTMs i.e., phosphorylation, O-GlcNAcylation, Ubiquitination, and SUMOylation have been studied regulating the potyvirus-plant interaction. Therefore, it is worth drawing attention towards the importance and potential of this undermined but key strategy of potyvirids (members of family Potyviridae) to abduct their host defence line, suggesting to review in detail the existing knowledge of these PTMs and highlight the unexplored modifications that might have played their part in establishing successful infection. The current review provides an understanding of how PTMs execute viral replication and infection dynamics during plant-potyvirid interactions. We highlighted that PTMs linked to CP, NIa-pro, NIb, and VPg are important to specify their host, virulence, overcoming host innate immunity, and most importantly disarming the host of RNA silencing tool of nailing any intruder. The limitations and potential improvements in studying undermined PTMs, including acetylation, glycosylation, methylation, and neddylation, as well as challenges and future perspectives of this inevitable process are mechanistically deciphered in the course of plant-virus interactions. This communication opens new avenues for investigating the fundamental mechanisms of virus infection and the development of new antiviral strategies for sustainable disease managements.

Drought is a significant abiotic stress that adversely affects the physiological and biochemical processes in crops, posing a considerable challenge to agricultural productivity. The present study explored the efficacy of plant-derived biostimulant (PDB) and plant growth-promoting rhizobacteria (PGPR) strains Pseudomonas putida (RA) and Paenibacillus lentimorbus CHM12) in the management of negative impacts of drought stress in Zea mays (maize). Adathoda vasica leaf extracts (ADLE) emerged as the most potent biostimulant of the seven evaluated medicinal plant extracts. The synergetic effect of ADLE and RA enhances plant vegetative growth (root length, shoot length, fresh weight and dry weight) as well as significantly modulates drought-induced oxidative stress, as indicated by higher chlorophyll content and increased sugar and phenolic levels and reduction of proline level. The expression of defence-related (ZmAPX, ZmSOD, and ZmCAT) and transcription factor (ZmNAC, ZmWRKY, and ZmMYB) genes further supported the beneficial effects of this synergism under drought conditions. Furthermore, metabolite profiling through GC-MS analysis showed significant alterations in metabolites such as glucose, galactose, mannose, hexopyranose, linolenic acid, hexadecenoic acid, and butanedioic acid when PDB and PGPR were applied together. Overall, the findings of the present study affirm that the combined application of plant-derived biostimulant ADLE and plant-beneficial rhizobacteria RA can effectively alleviate the adverse effects of drought on maize, providing an eco-friendly and sustainable solution for improving productivity under stress.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects joints and multiple organs and systems, which is long-lasting and challenging to cure and significantly impacting patients' quality of life. Alterations in the composition of intestinal flora in both preclinical and confirmed RA patients indicate that intestinal bacteria play a vital role in RA immune function. However, the mechanism by which the intestinal flora is regulated to improve the condition of RA is not fully understood. This paper reviews the methods of regulating gut microbiota and its metabolites through prebiotics, probiotics, and pharmacological interventions, and discusses their effects on RA. Additionally, it explores the potential predictive role of cellular therapy mechanisms of intestinal flora in treating RA. These findings suggest that restoring the ecological balance of intestinal flora and regulating intestinal barrier function may enhance immune system function, thereby improving rheumatoid arthritis. This offers new insights into its treatment.

Bifidobacterium longum (B. longum) is a species of the core microbiome in the human gut, whose abundance is closely associated with host age and health status. B. longum has been shown to modulate host gut microecology and have the potential to alleviate various diseases. Comprehensive understanding on the colonization mechanism of B. longum and mechanism of the host-B. longum interactions, can provide us possibility to prevent and treat human diseases through B. longum-directed strategies. In this review, we summarized the gut colonization characteristics of B. longum, discussed the diet factors that have ability/potential to enrich indigenous and/or ingested B. longum strains, and reviewed the intervention mechanisms of B. longum in multiple diseases. The key findings are as follows: First, B. longum has specialized colonization mechanisms, like a wide carbohydrate utilization spectrum that allows it to adapt to the host's diet, species-level conserved genes encoding bile salt hydrolase (BSHs), and appropriate bacterial surface structures. Second, dietary intervention (e.g., anthocyanins) could effectively improve the gut colonization of B. longum, demonstrating the feasibility of diet-tuned strain colonization. Finally, we analyzed the skewed abundance of B. longum in different types of diseases and summarized the main mechanisms by which B. longum alleviates digestive (repairing the intestinal mucosal barrier by stimulating Paneth cell activity), immune (up-regulating the regulatory T cell (Treg) populations and maintaining the balance of Th1/Th2), and neurological diseases (regulating the kynurenine pathway and quinolinic acid levels in the brain through the gut-brain axis).

The influence of nitrogen (N) inputs on soil microbial communities and N uptake by plants is well-documented. Seasonal variations further impact these microbial communities and their nutrient-cycling functions, particularly within multiple cropping systems. Nevertheless, the combined effects of N fertilization and growing seasons on soil microbial communities and plant N uptake remain ambiguous, thereby constraining our comprehension of the optimal growing season for maximizing crop production. In this study, we employed N isotope labeling, high-throughput sequencing, and quantitative polymerase chain reaction (qPCR) techniques to investigate the effects of two distinct growing seasons on microbial communities and maize N uptake ratios (NUR). Our results showed that the warm growing season (26.6 °C) increased microbial diversity, reduced network complexity but enhanced stability, decreased microbial associations, and increased modularization compared to the cool growing season (23.1 °C). Additionally, the warm growing season favored oligotrophic species and increased the abundance of microbial guilds and functional genes related to N, phosphorus, and sulfur cycling. Furthermore, alterations in the characteristics of soil microbial keystone taxa were closely linked to variations in maize NUR. Overall, our findings demonstrate significant seasonal variations in soil microbial diversity and functioning, with maize exhibiting higher NUR during the warm growing season of the double cropping system.

Fusarium head blight (FHB) represents a significant threat for wheat production due to the risk for food security and safety. Despite the huge number of biofungicides on the market, only one is actually available at European level to control Fusarium infections on cereals. The present work aimed to assess the possible use of Trichoderma asperellum strain ICC012 and Trichoderma gamsii strain ICC080 to manage FHB on common wheat Triticum aestivum cv Apogee. Initially, the capability of ICC012 and ICC080 to endophytically colonize wheat roots, a prerequisite very often correlated with the induction of resistance in the host plant, was investigated. It resulted in 100 % of roots internally colonized by the two strains, followed by a significant up-regulation of the defense-related genes encoding for pathogenesis-related protein 1 (pr1), superoxide dismutase (sod), polygalacturonase inhibitor protein 2 (pgip2) and phenylalanine ammonia-lyase 1 (pal1). When the expression of the same genes was investigated in spikes treated at the flowering stage with the two strains, applied individually or co-inoculated, a significant up-regulation of only pal1 was registered 24 hours post inoculation (hpi) in spikes treated with ICC080. To check if a systemic defense response was induced, the expression of the same genes was analyzed in leaves collected 7 and 14 days post inoculation (dpi) of roots, resulting in a significant up-regulation of sod at 7 dpi in leaves collected from plants inoculated with ICC012. Even if induction of resistance is probably not the main mode of action of the two strains, ICC012 and ICC080 applied on spikes at anthesis significantly reduced, in greenhouse conditions, the Disease Incidence (DI) caused by the inoculation mix of F. graminearum, F. culmorum, F. langsethiae and F. sporotrichioides, four of the most important FHB casual agents. This reduction in disease symptoms was observed when the two beneficial strains were applied both individually and co-inoculated on the spikes. Finally, ICC012 and ICC080 demonstrated a good competitive ability for substrate possession. The amount of F. graminearum (as DNA and number of perithecia) on wheat straw pieces was significantly reduced after 6 months of incubation in presence of the two beneficial strains, applied individually and co-inoculated. Being cultural debris used to overwinter, this competitive behavior of ICC012 and ICC080 is an important trait to reduce the potential inoculum of the pathogen. The results collected here lay the groundwork for the use of ICC012 and ICC080 in managing FHB on common wheat.

PehR is a transcriptional regulator among the various response regulators found in Ralstonia solanacearum, a bacterium that causes lethal wilt disease in over 450 plant species worldwide, including economically important crops such as tomato, chilli, and brinjal. PehR regulates the production of polygalacturonase, an extracellular enzyme that degrades plant cell walls, playing a significant role in bacterial wilt. Despite its significance, the precise function and regulatory mechanism of PehR in R. solanacearum are yet to be thoroughly investigated. The goal of this research is to better understand the role of PehR in R. solanacearum pathogenicity by identifying the genes and pathways that it regulates. By disrupting the pehR gene, we created the ΔpehR mutant of R. solanacearum F1C1, a strain isolated from Tezpur, Assam, India. Transcriptomic analysis revealed 667 differentially expressed genes (DEGs) in the ΔpehR mutant, with 320 upregulated and 347 downregulated compared to the wild-type F1C1 strain. GO and KEGG analyses indicated the downregulation of genes related to flagellum-dependent cell motility, membrane function, and amino acid degradation pathways in the ΔpehR mutant. EPS estimation, biochemical assays for biofilm production, motility, and enzymatic assays for cellulase and pectinase production were all used in the further characterization process. The ΔpehR mutant showed lower virulence in tomato seedlings compared to the wild-type F1C1 strain. The findings suggest that PehR could be a promising target for bacterial wilt disease control, as well as provide critical information for ensuring crop production safety around the world.

Competition phenomenon is widely presented in nature, however, few reports on the competition phenomenon between bacteria based on the perspective of quorum sensing (QS), especially between Gram-positive bacteria. Here, the Gram-positive bacteria Rhodococcus sp. HD1 and Microbacterium sp. HM-2 were co-cultured, and the epiphysiological indicators, transcriptomics combined with gene engineering technique were applied to clarify the role of QS in the competition between Gram-positive bacteria. The results showed that the morphology of strain HD1 was changed into ellipsoids from long rods, the surface-to-volume ratio increased, and the competition index increased within strains HM-2 and HD1. The biomass of strain HD1(8.06×10 CFU/mL) was decreased significantly (p＜0.05) under co-culture system, compared with mono-culture (5.75×10 CFU/mL), indicating that strain HM-2 had an inhibitory effect on HD1 at 12 h. Transcriptomic analysis revealed that QS-related genes were highly expressed in strain HM-2, and the expression level of the virulence gene TM_0352 was the highest (FPKM: 1774.19). Meanwhile, the ABC transporters-related genes in strain HD1 were significantly increased. Furthermore, QS pathway-related genes in strain HM-2 and ABC transporters-related genes in strain HD1 showed a significant correlation with the gene TM_0352 expression by the Mantel test analysis (p<0.05), surmising that the TM_0352 gene played a dominant role in the co-culture system. Knockout and complementation experiments confirmed that the function of gene TM_0352. The structural equation model showed that the QS up-regulation of strain HM-2 significantly promoted the expression of virulence genes, while strain HD1 promoted ABC transporters to cope with the up-regulation of TM_0352. The up-regulation of TM_0352 promoted the biomass of strain HM-2 and inhibited the biomass of HD1.The above results displayed that the competition phenomenon appeared by QS driving the up-regulation of TM_0352 gene in strain HM-2, which led to the up-regulation of ABC transporters in strain HD1. And these findings provided new insights into the perspective of factors related to competition inhibition between bacteria.

Exosomal microRNAs (miRNAs) in circulation were recognized as potential biomarkers for the diagnosis of multiple diseases. However, its potential as a diagnostic hallmark for tuberculosis (TB) has yet to be explored. Here, we comprehensively analyze miRNA profiles in exosomes derived from the plasma of active TB patients and healthy persons to evaluate its efficacy in TB diagnosis. Small-RNA transcriptomic profiling analysis identified a total of 14 differentially expressed miRNAs (DEmiRNAs), among which the diagnostic potential of exosomal miR-766-3p, miR-376c-3p, miR-1283, and miR-125a-5p was evident from their respective areas under the ROC curve, which were 0.8963, 0.8313, 0.8097, and 0.8050, respectively. The bioinformatics analysis and Luciferase reporter assays confirmed that the 3'-untranslated region of natural resistance-associated macrophage protein 1 (NRAMP1) mRNA was targeted by miR-766-3p. The exosomes could be internalized by the A549 cells in co-culturing experiments. Furthermore, both increased miR-766-3p and decreased NRAMP1 expression were observed in Mtb-infected A549 cells. MiR-766-3p overexpression reduced the NRAMP1 levels, but increased intracellular Mtb, suggesting that miR-766-3p may facilitate Mtb survival by targeting NRAMP1. Moreover, miR-766-3p-transfected cells exhibited increased apoptosis and reduced proliferation following Mtb infection. Taken together, circulating exosomal miR-766-3p, miR-1283, miR-125a-5p, and miR-376c-3p may serve as candidate hallmarks for TB diagnosis where the presence of miR-766-3p seems associated with the vulnerability to Mtb infection in humans and could be a new molecular target for therapeutic intervention of TB.

The yield of natural products from plants is currently insufficient and cannot be considered a sustainable and secure source of supply, especially given the challenges posed by global climate change. Therefore, a biofoundry that can quickly and accurately produce desired materials from microorganisms based on synthetic biology is urgently needed. Moreover, it is important to find new microbial and genetic chassis to meet the rapidly growing global market for high-value-added zeaxanthin. In this study, we aimed to identify the zeaxanthin biosynthetic gene cluster, crtZ-crtB-crtI-crtY, and confirm zeaxanthin production (11,330 μg g dry biomass weight) through genome mining and liquid chromatography/mass spectrometry profiling using the novel zeaxanthin-producing bacteria Sphingomonas sp. strain BN140010 isolated from the subsurface soil of arable land. We report the highest yield among zeaxanthin-producing Sphingomonas strains to date. Moreover, we determined the taxonomic position of BN140010 using a polyphasic approach based on phylogenetic, physiological and chemotaxonomic characteristics, and we proposed Sphingomonas arvum strain BN140010 as a novel strain. Our results provide a zeaxanthin-producing chassis and diverse genetic tools for microbiological zeaxanthin production. Therefore, this research advances our progress towards the goal of lowering the unit cost of zeaxanthin production, making it more accessible for industrial applications.

Diabetes mellitus (DM) is a common metabolic disease and one of the diseases with the highest number of complications at present. As the disease progresses, patients will gradually develop diabetes-related cognitive decline, mild cognitive impairment (MCI) or even dementia. The occurrence of diabetes-combined cognitive impairment undoubtedly imposes a heavy burden on patients and their families. Current research suggests that risk factors such as blood glucose levels, insulin resistance, oxidative stress and neuroinflammation have an important role in the development of diabetic cognitive impairment (DCI). With the development of technology and in-depth research, the relationship between the two-way communication between the gut and the brain has been gradually revealed, and more studies have found that the gut microbiota plays an important role in the development of DCI. This review explores the feasibility of probiotics as a potential strategy to assist in the improvement of DCI and its potential mechanisms from the perspective of the factors affecting DCI.

Metabolites of plant and microbial origin have a great influence on plant-microbe interactions. Members from Bacillus subtilis are known to produce a plethora of metabolites that shape plant responses towards biotic and abiotic stresses. Similarly, endophyte B. subtilis L1-21 efficiently controls the Huanglongbing (HLB) causing pathogen: Candidatus Liberibacter asiaticus (CLas). However, the molecular mechanisms are highly elusive. Herein, our study highlights the critical role of endophyte L1-21 in planta-produced surfactin in its colonization in citrus plants and regulation of plant-microbe interactions by comparing three gene knockout mutants △srfAA-L1-21, △sfp-L1-21, and △pel-L1-21. All three mutants exhibited reduced pathogen control and colonization efficiency compared to wild-type (WT) L1-21, but knockout mutant deficient of surfactin △srfAA-L1-21 was significantly impaired in the abovementioned functions as compared to △sfp-L1-21 and △pel-L1-21. Further, △srfAA-L1-21 could not activate various metabolic pathways in citrus as WT-L1-21. Integrated metabolomic-transcriptomic analysis reveals that important secondary metabolites such as flavonoids, volatile organic compounds, and lignins were highly accumulated in citrus plants treated with WT-L1-21 as compared to △srfAA-L1-21, highlighting the role of surfactin as an elicitor of the defense system in citrus-HLB pathosystem. Interestingly, auxin-related metabolites and transcripts were also downregulated in △srfAA-L1-21 compared to WT-L1-21 showing that surfactin might also influence plant-microbe interactions through metabolic reprogramming. Further, higher enrichment of Bacilli with WT-L1-21 might corresponds to surfactin-mediated regulation of community-related behavior in Bacilli. To the best of our knowledge, this is the first study reporting the role of surfactin from Bacillus endophyte in metabolic reprogramming in citrus-HLB pathosystem and mounting defense response against CLas pathogen.