Intestinal inflammation and malignancy represent two critical pathological states in the gut that severely impair patients’ quality of life. Understanding their molecular mechanisms holds significant therapeutic implications. Lactate plays a key role in cellular signaling and immune regulation. Lactylation, a modification mediated by lactate, plays a key role in epigenetic regulation. Targeting lactate metabolism and lactylation has emerged as a promising intervention strategy for intestinal diseases. This review summarizes the basic framework of the lactate metabolic system and the biological functions of lactate and lactylation, with a focus on the core mechanisms of lactylation in intestinal inflammation and malignancy. Lactylation exerts a context-dependent “paradoxical modulation” role. In intestinal inflammation, as exemplified by inflammatory bowel disease, lactylation drives macrophage phenotypic conversion, mediates gut microbiota-host interactions, regulates fibrosis progression, and modulates intestinal inflammation and tissue repair. Colorectal cancer, a major form of intestinal malignancy, is promoted by lactylation through mechanisms including immunosuppression, malignant proliferation, drug resistance, and tumor metastasis. Finally, we discuss the basis of the paradoxical modulation role of lactylation and explore the therapeutic potential of targeting lactate metabolism and lactylation as novel treatment strategies. In summary, this review highlights lactylation as a central player in intestinal diseases, providing insights into the pathomechanisms of intestinal inflammation and colorectal cancer. Lactate metabolism and lactylation hold significant potential as therapeutic targets for intestinal inflammation and malignancy, providing a promising path for precise intervention strategies in intestinal diseases.

Insufficient maturation of oligodendrocyte progenitor cells (OPCs) contributes to the failure of endogenous remyelination in multiple sclerosis (MS). It remains unclear whether dysregulated oligodendroglial microRNAs (miRNAs) impede remyelination in chronic MS lesions. In this study, we demonstrated that miR-126a-3p was enriched in oligodendroglia from chronic inactive MS plaques and chronic lesions in mice with experimental autoimmune encephalomyelitis (EAE). Functional analyses revealed that miR-126a-3p inhibited OPC differentiation in vitro and that the specific deletion of miR-126a-3p in oligodendroglia accelerated the remyelination process in the EAE and lysolecithin-induced demyelination models. Mechanistically, miR-126a-3p exerted an inhibitory effect on OPC differentiation and remyelination by directly targeting peroxin-5 (Pex5) transcripts. A screening of a US Food and Drug Administration-approved drug library based on Pex5 levels led to the identification of ganciclovir, an antiviral agent, as a potent proremyelinating agent after in vivo demyelinating events. These results identify the aberrant miR-126a-3p-Pex5 axis in oligodendroglia as a potential therapeutic target to facilitate remyelination in chronic MS lesions.

The impact of gut microbiota on disease pathogenesis and progression is receiving increasing attention, particularly in the field of digestive system disorders. Previous reviews have predominantly focused on the composition and function of bacteria and their metabolites. However, host physiological activities rely on a series of interconnected hierarchical processes, including gene expression, signal transduction, and ultimately, physiological responses. Within this framework, cellular metabolic activities provide an essential foundation for cellular functions. In this study, we focused on host intracellular metabolic reprogramming rather than extracellular metabolite profiles-specifically, how microbial signals rewire host cellular energy pathways, such as the balance between oxidative phosphorylation and glycolysis. We systematically explain how dysregulation of the microbiota–host metabolism axis contributes to the pathophysiology of various digestive system disorders. We also outline current prevention and treatment strategies targeting this axis, including probiotics, dietary adjustments, fecal microbiota transplantation (FMT), traditional Chinese medicine, and emerging biotherapies. In addition, we explore future research directions and potential applications in this field. Standardizing interventions such as FMT and validating their efficacy through large‑scale cohort studies remain immediate priorities in clinical practice.

Gut microbiota dysbiosis and metabolic disturbances are implicated in inflammatory bowel disease (IBD). Current probiotic therapies are limited by poor bioavailability and inadequate colonic colonization. Here, we identified Agathobacter rectalis from IBD patient feces and demonstrated that it alleviated dextran sulfate sodium-induced colitis in mice by reshaping the gut microbiota and bile acid pool. To overcome these delivery barriers, we developed a single-cell encapsulation system using aloe vera gel, a natural acid-resistant and anti-inflammatory hydrogel, and designated it A. rectalis@Aloe to enhance probiotic bioavailability and targeted colonic retention. Comprehensive characterization confirmed that encapsulation significantly improved bacterial viability in simulated gastric fluid and enhanced colonic colonization. In murine colitis models, A. rectalis@Aloe synergistically suppressed inflammation, reinforced barrier function, modulated gut microbiota, and increased short-chain fatty acid production. Mechanistically, it inhibited cytokine–cytokine receptor interactions and the PI3K-Akt pathway. By synergistically enhancing gastric acid survival, mucosal colonization, and multi-pathway anti-inflammatory effects, this single-cell aloe gel encapsulation strategy offers a clinically promising and readily translatable platform for live biotherapeutics targeting the gut microbiota–metabolite axis in IBD.

Inflammatory bowel disease (IBD) is a group of chronic gastrointestinal inflammatory disorders, primarily including ulcerative colitis (UC) and Crohn's disease (CD). Reactive oxygen species (ROS) play a pivotal role in the pathogenesis of these diseases. Current treatments for IBD including aminosalicylates, corticosteroids, and immunosuppressive agents aim to alleviate symptoms or delay disease progression. However, long-term use of these drugs may lead to certain toxic side effects, negatively affecting the patient's quality of life. Recent studies have highlighted the potential of various phytochemicals in modulating oxidative stress, inhibiting inflammatory responses, and protecting the intestinal barrier function. These phytochemicals alleviate oxidative stress in the gut by reducing ROS levels, suppressing the production of pro-inflammatory cytokines, and enhancing the integrity of the intestinal barrier, thus improving IBD symptoms. This review summarizes the phytochemicals known to effectively alleviate gut oxidative stress and improve IBD, discusses their mechanisms of action, and emphasizes the promising future applications in the treatment of IBD.

Irritable bowel syndrome (IBS) is a prevalent stress-associated disorder characterised by gut barrier dysfunction and gut-brain axis disturbances. However, the interplay between host metabolites and gut microbes in IBS pathogenesis remains incompletely understood. Here, through integrated microbiome and metabolome profiling of faecal sample from seafarers before and after long-term voyages, we identify a reciprocal interaction between the essential amino acid l-lysine and the gut bacterium Holdemanella biformis (H. biformis). l-lysine was depleted in individuals with voyage-induced IBS, whereas H. biformis abundance increased concurrently. In a mouse model of diarrhoea-predominant IBS, l-lysine supplementation restored intestinal barrier integrity, reduced visceral hypersensitivity, and alleviated anxiety-like behaviours through modulation of tryptophan metabolism. In contrast, oral administration of H. biformis improved tight junction protein expression but paradoxically worsened anxiety-like phenotypes. In vitro, both l-lysine and H. biformis supernatant promoted epithelial wound healing and ZO-1 expression. Mechanistically, H. biformis degrades l-lysine via lysine degradation pathway, while l-lysine suppresses H. biformis growth possibly by downregulating pathways involved in carbohydrate and energy metabolism. These findings reveal a stress-sensitive, bidirectional metabolic loop in between l-lysine and H. biformis, with complementary but opposing effects on gut and neurological function. Targeting this axis may offer new strategies for IBS and other gut-brain axis disorders.

IntroductionCuring is a critical process that determines the sensory quality of cigars. The impact of oxygen on cigar curing and the mechanisms by which it regulates microbial changes affecting cigar quality are not well understood.MethodsIn this study, we selected handmade cigars from the same batch and conducted curing experiments in environments with varying oxygen concentrations (equivalent to 0.1%, 6–12, and 15% of atmospheric oxygen concentration). We collected samples over 60 days and analyzed the distribution of microbial communities using high-throughput sequencing. Combined with the analysis of total sugars, proteins, flavor substances, and other chemical compounds, we elucidated how different oxygen concentrations affect the cigar curing process, influence microbial community succession, and ultimately impact cigar quality.ResultsOur results revealed significant differences in bacterial community composition under different oxygen conditions. Under aerobic conditions, Cyanobacteria were the dominant bacteria, while under oxygen-limited conditions, Staphylococcus and Corynebacterium predominated. As oxygen concentration decreased, so did the richness and diversity of the bacterial community. Conversely, oxygen concentration had a lesser impact on fungi; Aspergillus was the dominant genus in all samples. We also found that Enterococcus showed a positive correlation with aspartic acid, alanine, and 4-aminobutyric acid and a negative correlation with cysteine. Cigars cured at 15% oxygen concentration for 60 days exhibited optimal quality, particularly in terms of flavor richness and sweetness.DiscussionThese findings suggest that oxygen concentration can alter cigar quality by regulating aerobic and anaerobic microbial community succession. The relationship between specific microbial communities and flavor compounds also provides a theoretical reference for developing artificial control technologies in the cigar curing process.

BACKGROUND:Previous studies have indicated bidirectional associations between urate levels and inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). However, it remains unclear whether the observations are causal because of confounding factors.AIM:To investigate the causal associations between urate levels and IBD using bidirectional Mendelian randomization (MR).METHODS:Independent genetic variants for urate levels and IBD were selected as instrumental variables from published genome-wide association studies (GWASs). Summary statistics for instrument-outcome associations were retrieved from three separate databases for IBD (the UK Biobank, the FinnGen database and a large GWAS meta-analysis) and one for urate levels (a large GWAS meta-analysis). MR analyses included the inverse-variance-weighted method, weighted-median estimator, MR-Egger and sensitivity analyses (MR-PRESSO). A meta-analysis was also conducted to merge the data from separate outcome databases using a fixed-effects model.RESULTS:Genetically higher serum urate levels were strongly associated with an increased risk of UC [odds ratio (OR): 1.95, 95% confidence interval (CI): 1.86-2.05] after outlier correction, and the ORs (95%CIs) for IBD and CD were 0.94 (95%CI: 0.86-1.03) and 0.91 (95%CI: 0.80-1.04), respectively. Animal studies have confirmed the positive association between urate levels and UC. Moreover, genetically predicted IBD was inversely related to urate levels (OR: 0.97, 95%CI: 0.94-0.99). However, no association was observed between genetically influenced UC or CD and urate levels.CONCLUSION:Urate levels might be risk factors for UC, whereas genetically predicted IBD was inversely associated with urate levels. These findings provide essential new insight for treating and preventing IBD.

Objective: Previous studies have suggested that irritable bowel syndrome (IBS) is strongly associated with psychiatric disorders. However, it is unclear whether this association is causal, concomitant, or accidental. Thus, we performed Mendelian randomization (MR) analysis to evaluate the causal effects of several psychiatric disorders on IBS. Methods: Summary data of genome-wide association studies (GWASs) were obtained mainly from the Psychiatric Genomics Consortium (PGC) on individuals of European ancestry and from a recent GWAS on IBS. We used three MR methods, the inverse-variance weighting (IVW), weighted median (WM), and MR-Egger regression (MREgger). In addition, two other indicators, namely, the MR-IVW Cochran's Q statistic and MR-Egger intercept, were used to assess heterogeneity and detect directional horizontal pleiotropy, respectively. Results: Heritability was high for bipolar disorder (81.18 %, 95 % CI = 73.18-148.18 %), schizophrenia (33.88 %, 95 % CI = 33.57-38.19 %), and panic disorder (30.66 %, 95 % CI = 20.74-40.58 %). For other disorders, there was a low liability-scale SNP heritability for major depressive disorder (MDD) (0.67 %, 95 % CI = 0.61-0.73 %), anxiety disorder (7.63 %, 95 % CI = 1.67-13.59 %), PTSD (0.96 %, 95 % CI = 0.12-1.8 %), and IBS (2.44 %, 95 % CI = 2.13-2.75 %). We also observed that schizophrenia had a significant causal effect on IBS according to MR-IVW. Notably, the individual causal estimates of genetic instruments for MDD and schizophrenia were heterogeneous, but no pleiotropic effects were observed. Conclusions: Our analyses revealed the causal effects of MDD and schizophrenia on IBS, a matter that has been subject to debate for decades, and also showed that IBS had causal effects on MDD.

A significant distinction between cigar production and tobacco lies in the necessary aging process, where intricate microbial growth, metabolic activities, enzymatic catalysis, and chemical reactions interact. Despite its crucial role in determining the final quality of cigars, our comprehension of the underlying chemical and biological mechanisms within this process remains insufficient. Biomass and alkaloids are the primary constituents that influence the flavor of cigars. Consequently, investigating the entire aging process could begin by exploring the involvement of microbes and enzymes in their biodegradation. In this study, handmade cigars were aged under different conditions. Metagenomic sequencing was employed to identify the microbes and enzymes responsible for the degradation of biomass and alkaloids derived from tobacco leaves. The results revealed that various environmental factors, including temperature, humidity, duration time, and turning frequency, yielded varying contents of total sugar and alkaloids in the cigars. Significant correlations were observed between microbial communities and starch, reducing sugars, total sugars, and alkaloids. Key species involved in the breakdown of biomass constituents, such as starch (Bacillus pumilus, Pseudomonas sp. 286, and Aspergillus cristatus), reducing sugars and total sugars (Aspergillus cristatus and Nitrolancea hollandica), were identified. Furthermore, Corynespora cassiicola and Pseudomonas fulva were found to potentially contribute to the degradation of alkaloid compounds, specifically nornicotine and neonicotinoid. Our work contributes to a deeper understanding of the microbial roles in the aging of cigars. Moreover, the selection of specific microbial strains or starter cultures can be employed to control and manipulate the aging process, thereby further refining the flavor development in cigar products.

Background and objectives: Functional bowel disorders (FBDs) afflict millions of people worldwide. The pathogenesis of FBDs remains unclear and there are no effective treatments currently available. The intestinal microbiota is deemed a critical etiological factor in FBDs, and microbiota-targeted treatment strategies have promising therapeutic value. However, no comprehensive scientometric analyses related to FBDs and the intestinal microbiota have been performed. This study aimed to employ scientometrics to thoroughly analyze the knowledge base and the viable frontier between the intestinal microbiota and FBDs research fields. Methods: Scientometrics was used to analyze the global research trends and hotspots in the overlapping fields of FBDs and the intestinal microbiota. The Web of Science database was selected as the research tool, and documents written in English and published from database inception to June 26th, 2023, were investigated. Results: There was a growth in publications from 2007 to 2022, with a total of 2,924 articles identified. China (n = 685, 23.43%) made the greatest contribution, followed by the United States (n = 672, 22.98%) and United Kingdom (n = 276, 9.44%). Co-citation analysis of references reflected the knowledge base in the past 16 years, including updating the understanding of FBDs, unveiling the relationship between the intestinal microbiota and FBDs, and preliminary research on the effects of microbiotatargeted treatment on FBDs. Conclusions: By utilizing scientometrics, we identified three main research frontiers including microbiome-metabolites-mechanisms in FBDs, microbiota-related biomarkers for FBDs, and mechanism of microbiota-targeted treatments towards FBDs for precise medicine. These findings could provide valuable guidance for future research.

结直肠癌是全球较常见的恶性肿瘤之一，是现阶段我国消化系统发病率排名第一的恶性肿瘤，也是影响国民健康的重要公共卫生问题。早筛、早诊和早治能够有效改善结直肠肿瘤的预后。结肠镜是结直肠疾病最为准确的诊断、筛查和随访手段，但结肠镜检查的效果取决于其质控。本文主要从结直肠癌发病率、癌变途径、危险因素、诊断筛查方式和结肠镜检查质控标准等方面对该领域相关成果进行综述。

Bacillus licheniformis and its related strains have found extensive applications in diverse industries, agriculture, and medicine. However, the current breeding methods for this strain primarily rely on natural screening and traditional mutagenesis. The limited availability of efficient genetic engineering tools, particularly recombination techniques, has hindered further advancements in its applications. In this study, we conducted a comprehensive investigation to identify and characterize a recombinase, RecT, derived from a Bacillus phage. Remarkably, the recombinase exhibited a 10 5 -fold enhancement in the recombination efficiency of the strain. To facilitate genome editing, we developed a system based on the conditional expression of RecT using a rhamnose-inducible promoter (P rha ). The efficacy of this system was evaluated by deleting the amyL gene, which encodes an α-amylase. Our findings revealed that the induction time and concentration of rhamnose, along with the generation time of the strain, significantly influenced the editing efficiency. Optimal conditions for genome editing were determined as follows: the wild-type strain was initially transformed with the genome editing plasmid, followed by cultivation and induction with 1.5% rhamnose for 8 h. Subsequently, the strain was further cultured for an additional 24 h, equivalent to approximately three generations. Consequently, the recombination efficiency reached an impressive 16.67%. This study represents a significant advancement in enhancing the recombination efficiency of B. licheniformis through the utilization of a RecT-based recombination system. Moreover, it provides a highly effective genome editing tool for genetic engineering applications in this strain.

Increasing attention is being paid to the unique roles gut microbes play in both physiological and pathological processes. Crohn’s disease (CD) is a chronic, relapsing, inflammatory disease of the gastrointestinal tract with unknown etiology. Currently, gastrointestinal infection has been proposed as one initiating factor of CD. Yersinia enterocolitica , a zoonotic pathogen that exists widely in nature, is one of the most common bacteria causing acute infectious gastroenteritis, which displays clinical manifestations similar to CD. However, the specific role of Y. enterocolitica in CD is controversial. In this Review, we discuss the current knowledge on how Y. enterocolitica and derived microbial compounds may link to the pathogenesis of CD. We highlight examples of Y. enterocolitica -targeted interventions in the diagnosis and treatment of CD, and provide perspectives for future basic and translational investigations on this topic.

Background Probiotics have been deemed multipotent and unprecedentedly applied in the health field recently. However, there are challenges in promoting credible and reliable resources while avoiding misinformation regarding probiotics for the public. Methods This study analysed 400 eligible probiotic-related videos selected from YouTube, and the three most popular video-sharing platforms (Bilibili, Weibo and TikTok) in China. Video retrieval was performed on September 5 th , 2022. GQS and tailored DISCERN tool assess each video’s quality, usage, and reliability. A comparative analysis of videos from different sources was carried out. Results The identity distribution of probiotic video-producers was predominantly experts ( n = 202, 50.50%), followed by amateurs ( n = 161, 40.25%) and health-related institutions ( n = 37, 9.25%). The videos’ content category mainly discussed the function of probiotics ( n = 120, 30%), the way to choose suitable products ( n = 81, 20.25%), and the methods for taking probiotics ( n = 71, 17.75%).The overall quality of videos was moderate (3/5 point) assessed by GQS, while the usage (1/6 point) and reliability (2/5 point) detailing probiotics assessed by tailored DISCERN tool were poor. The attitude of probiotic video-producers was primarily positive ( n = 323, 80.75%), followed by neutral ( n = 52, 13.00%) and negative ( n = 25, 6.25%) ( P < 0.001). Conclusions The current study showed that videos on social media platforms publicise important information including the concepts, usage, and precautions of probiotics to the public. But the overall quality of uploaded videos about probiotics was unsatisfactory. More efforts are needed to improve the higher-quality content of probiotic-related online videos and better propagate probiotic knowledge to the public in the future.

Gut bacteria facilitate nutrient metabolism and generate small molecules that form part of the broader “metabolome”. It is unclear whether these metabolites are disturbed in chronic pancreatitis (CP). This study aimed to evaluate the gut microbial–host cometabolites and their relationship in patients with CP. Fecal samples were collected from 40 patients with CP and 38 healthy family members. Each sample was examined with 16S rRNA gene profiling and gas chromatography time-of-flight mass spectrometry to estimate the relative abundances of specific bacterial taxa between the two groups and to profile any changes in the metabolome, respectively. Correlation analysis was used to evaluate the differences in metabolites and gut microbiota between the two groups. The abundance of Actinobacteria was lower at the phylum level, and that of Bifidobacterium was lower at the genus level in the CP group. Eighteen metabolites had significantly different abundances and the concentrations of 13 metabolites were significantly different between the two groups. Oxoadipic acid and citric acid levels were positively correlated with Bifidobacterium abundance ( r  = 0.306 and 0.330, respectively, both P  < 0.05), while the 3-methylindole concentration was negatively correlated with Bifidobacterium abundance ( r  = −0.252, P  = 0.026) in CP. Gut microbiome and host microbiome metabolic products might be altered in patients with CP. Evaluating gastrointestinal metabolite levels may further enhance our understanding of the pathogenesis and/or progression of CP.

Peptidylarginine deiminases (PADs) are the only enzyme class known to deiminate arginine residues into citrulline in proteins, a process known as citrullination. This is an important post-translational modification that functions in several physiological and pathological processes. Neutrophil extracellular traps (NETs) are generated by NETosis, a novel cell death in neutrophils and a double-edged sword in inflammation. Excessive activation of PADs and NETs is critically implicated in their transformation from a physiological to a pathological state. Herein, we review the physiological and pathological functions of PADs and NETs, in particular, the involvement of PAD2 and PAD4 in the digestive system, from inflammatory to oncological diseases, along with related therapeutic prospects.

Background Dietary management is considered a potential adjunctive treatment for inflammatory bowel disease (IBD). Short-video sharing platforms have enabled patients to obtain dietary advice more conveniently. However, accessing useful resources while avoiding misinformation is not an easy task for most patients. Objective This study aimed to evaluate the quality of the information in IBD diet–related videos on Chinese short-video sharing platforms. Methods We collected and extracted information from a total of 125 video samples related to the IBD diet on the 3 Chinese short-video sharing platforms with the most users: TikTok, Bilibili, and Kwai. Two independent physicians evaluated each video in terms of content comprehensiveness, quality (rated by Global Quality Score), and reliability (rated by a modified DISCERN tool). Finally, comparative analyses of the videos from different sources were conducted. Results The videos were classified into 6 groups based on the identity of the uploaders, which included 3 kinds of medical professionals (ie, gastroenterologists, nongastroenterologists, and clinical nutritionists) and 3 types of non–medical professionals (ie, nonprofit organizations, individual science communicators, and IBD patients). The overall quality of the videos was poor. Further group comparisons demonstrated that videos from medical professionals were more instructive in terms of content comprehensiveness, quality, and reliability than those from non–medical professionals. Moreover, IBD diet–related recommendations from clinical nutritionists and gastroenterologists were of better quality than those from nongastroenterologists, while recommendations from nonprofit organizations did not seem to be superior to other groups of uploaders. Conclusions The overall quality of the information in IBD diet-related videos is unsatisfactory and varies significantly depending on the source. Videos from medical professionals, especially clinical nutritionists and gastroenterologists, may provide dietary guidance with higher quality for IBD patients.

Objectives: Gut bacteria facilitate nutrient metabolism and generate small molecules that form part of the broader "metabolome ". It is unclear whether these metabolites are disturbed in chronic pancreatitis (CP). This study aimed to evaluate the gut microbial-host cometabolites and their relationship in patients with CP.Methods: Fecal samples were collected from 40 patients with CP and 38 healthy family members. Each sample was examined with 16S rRNA gene profiling and gas chromatography time-of-flight mass spectrometry to estimate the relative abundances of specific bacterial taxa between the two groups and to profile any changes in the metabolome, respectively. Correlation analysis was used to evaluate the differences in metabolites and gut microbiota between the two groups.Results: The abundance of Actinobacteria was lower at the phylum level, and that of Bifidobacterium was lower at the genus level in the CP group. Eighteen metabolites had significantly different abundances and the concentrations of 13 metabolites were significantly different between the two groups. Oxoadipic acid and citric acid levels were positively correlated with Bifidobacterium abundance (r = 0.306 and 0.330, respectively, both P < 0.05), while the 3-methylindole concentration was negatively correlated with Bifidobacterium abundance (r = -0.252, P = 0.026) in CP.Conclusions: Gut microbiome and host microbiome metabolic products might be altered in patients with CP. Evaluating gastrointestinal metabolite levels may further enhance our understanding of the pathogenesis and/or progression of CP.

Blood-brain barrier (BBB) impairment is an early prevalent feature of multiple sclerosis (MS), and remains vital for MS progression. Microglial activation precedes BBB disruption and cellular infiltrates in the brain of MS patients. However, little is known about the function of microglia in BBB impairment. Here, microglia acts as an important modulator of BBB integrity in inflammatory demyelination. Microglial depletion profoundly ameliorates BBB impairment in experimental autoimmune encephalomyelitis (EAE). Specifically, miR-126a-5p in microglia is positively correlated with BBB integrity in four types of MS plaques. Mechanistically, microglial deletion of miR-126a-5p exacerbates BBB leakage and EAE severity. The protective effect of miR-126a-5p is mimicked and restored by specific inhibition of MMP9 in microglia. Importantly, Auranofin, an FDA-approved drug, is identified to protect BBB integrity and mitigate EAE progression via a microglial miR-126a-5p dependent mechanism. Taken together, microglia can be manipulated to protect BBB integrity and ameliorate inflammatory demyelination. Targeting microglia to regulate BBB permeability merits consideration in therapeutic interventions in MS.