Crosstalk between gut and brain has long been appreciated in health and disease, and the gut microbiota is a key player in communication between these two distant organs. Yet, the mechanisms through which the microbiota influences development and function of the gut–brain axis remain largely unknown. Barriers present in the gut and brain are specialized cellular interfaces that maintain strict homeostasis of different compartments across this axis. These barriers include the gut epithelial barrier, the blood–brain barrier and the blood–cerebrospinal fluid barrier. Barriers are ideally positioned to receive and communicate gut microbial signals constituting a gateway for gut–microbiota–brain communication. In this Review, we focus on how modulation of these barriers by the gut microbiota can constitute an important channel of communication across the gut–brain axis. Moreover, barrier malfunction upon alterations in gut microbial composition could form the basis of various conditions, including often comorbid neurological and gastrointestinal disorders. Thus, we should focus on unravelling the molecular and cellular basis of this communication and move from simplistic framing as 'leaky gut'. A mechanistic understanding of gut microbiota modulation of barriers, especially during critical windows of development, could be key to understanding the aetiology of gastrointestinal and neurological disorders. The gut microbiota is an important modulator of the gut–brain axis. This Review provides an overview of barrier function across this axis and examines the role of the gut microbiota in communication across and between these specialized gastrointestinal and brain barriers in health and disease. 

Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota-gut-brain axis.

Claudin-5 (CLDN5) is an endothelial tight junction protein essential for blood-brain barrier (BBB) formation. Abnormal CLDN5 expression is common in brain disease, and knockdown of Cldn5 at the BBB has been proposed to facilitate drug delivery to the brain. To study the consequences of CLDN5 loss in the mature brain, we induced mosaic endothelial-specific Cldn5 gene ablation in adult mice (Cldn5iECKO). These mice displayed increased BBB permeability to tracers up to 10 kDa in size from 6 days post induction (dpi) and ensuing lethality from 10 dpi. Single-cell RNA sequencing at 11 dpi revealed profound transcriptomic differences in brain endothelial cells regardless of their Cldn5 status in mosaic mice, suggesting major non-cell-autonomous responses. Reactive microglia and astrocytes suggested rapid cellular responses to BBB leakage. Our study demonstrates a critical role for CLDN5 in the adult BBB and provides molecular insight into the consequences and risks associated with CLDN5 inhibition. 

Mosaic deletion of claudin-5 reveals rapid non-cell-autonomous consequences of blood-brain barrier leakage.

Peripheral giant cell granuloma (PGCG) is a non-neoplastic, tumour-like reactive lesion that exclusively involves the gingiva and/or the alveolar crest. The surgical approach with a scalpel has been the golden standard of treatment for PGCG, but the scientific literature reports a high rate of lesion recurrence. Hence, this unique case report aimed to evaluate the efficacy of λ 10,600 nm high-level laser therapy (HLLT) in eradicating persistent, aggressive, and recurrent PGCG that failed to respond to standard surgical treatment. A fit and healthy thirty-four-year-old Caucasian male presented with a two-month history of recurrent episodes of an oral mucosal lesion involving the buccal and lingual interdental papillae between the lower right second premolar (LR5) and lower right first molar (LR6), which was surgically excised with a scalpel three times previously. A λ 10,600 nm-induced HLLT was chosen as a treatment modality at a lower peak power of 1.62 W, measured with a power metre, emitted in gated emission mode (50% duty cycle), whereby the average output power reaching the target tissue was 0.81 W. The spot size was 0.8 mm. Ninety seconds was the total treatment duration, and the total energy density was 7934.78 J/cm2. Patient self-reporting outcomes revealed minimal to no post-operative complications. Initial healing was observed on the 4th day of the post-laser treatment, and a complete healing occurred at two-weeks post-operatively. The histological analysis revealed PGCG. This unique case report study demonstrated the efficacy of λ 10,600 nm-induced HLLT and its superiority to eradicate persistent aggressive PGCG over the standard surgical approach with minimal to no post-operative complications, accelerating wound healing beyond the physiological healing time associated with no evidence of PGCG recurrence at the six-month follow-up timepoint. Based on the significant findings of this unique study and the results of our previous clinical studies, we can confirm the validity and effectiveness of our standardised λ 10,600 nm laser dosimetry-induced HLLT and treatment protocol in achieving optimal outcomes. Randomised controlled clinical trials with large data comparing λ 10,600 nm with our dosimetry protocol to the standard surgical treatment modality at long follow-up timepoints are warranted.

10,600 nm High Level-Laser Therapy Dosimetry in Management of Unresponsive Persistent Peripheral Giant Cell Granuloma to Standard Surgical Approach: A Case Report with 6-Month Follow-Up.

https://fluidsbarrierscns.biomedcentral.com/counter/pdf/10.1186/s12987-023-00428-1

Genetic disorders and genetic manipulation at the blood-brain barriers

Stroke is a devastating condition that can lead to significant morbidity and mortality. The aftermath of a stroke, particularly hemorrhagic transformation (HT) and brain edema, can significantly impact the prognosis of patients. Early detection and effective management of these complications are crucial for improving outcomes in stroke patients. This review highlights the emerging diagnostic markers and therapeutic targets including claudin, occludin, zonula occluden, s100β, albumin, MMP-9, MMP-2, MMP-12, IL-1β, TNF-α, IL-6, IFN-γ, TGF-β, IL-10, IL-4, IL-13, MCP-1/CCL2, CXCL2, CXCL8, CXCL12, CCL5, CX3CL1, ICAM-1, VCAM-1, P-selectin, E-selectin, PECAM-1/CD31, JAMs, HMGB1, vWF, VEGF, ROS, NAC, and AQP4. The clinical significance and implications of these biomarkers were also discussed.

Emerging diagnostic markers and therapeutic targets in post-stroke hemorrhagic transformation and brain edema

Mammalian Claudin-5 is the main endothelial tight junction component maintaining blood-brain barrier (BBB) permeability, while Claudin-1 and -3 seal the paracellular space of choroid plexus (CP) epithelial cells contributing to the blood-cerebrospinal fluid barrier (BCSFB). In zebrafish, two paralogs of claudin-5a and -5b are expressed while their roles in the formation of BBB and BCSFB are unclear.The expression patterns of Claudin-5a and -5b in zebrafish brains were systematically analyzed by immunofluorescence (IF) assay. The developmental functions of Claudin-5a and -5b were characterized by generating of claudin-5a and -5b mutants respectively. Meanwhile, the cerebral inflammation and cell apoptosis in claudin-5a-/- were assessed by live imaging of transgenic zebrafish, RT-qPCR, IF, and TUNEL assay. The integrity of BBB and BCSFB was evaluated by in vivo angiographic and dye permeation assay. Finally, RT-qPCR, whole-mount RNA in situ hybridization (WISH), and transmission electron microscopy (TEM) analyses were performed to investigate the development of cerebral vessels and choroid plexus.We showed that Claudin-5a and -5b are both expressed in zebrafish cerebrovascular endothelial cells (ECs). In addition, Claudin-5a was strongly expressed in CP epithelial cells. Loss of Claudin-5b showed no effect on zebrafish vasculogenesis or BBB function. In contrast, the knockout of claudin-5a caused a lethal phenotype of severe whole-brain oedema, ventricular dilatation, and cerebral hernia in zebrafish larvae, although the cerebral vasculogenesis and the development of CP were not altered. In claudin-5a-/- , although ultrastructural analysis of CP and cerebral capillary showed intact integrity of epithelial and endothelial tight junctions, permeability assay indicated a disruption of both BBB and BCSFB functions. On the molecular level, it was found that ZO-1 was upregulated in the CP epithelium of claudin-5a-/-, while the notch and shh pathway responsible for CP development was not affected due to loss of Claudin-5a.Our findings verified a non-functional role of zebrafish Claudin-5b in the BBB and identified Claudin-5a as the ortholog of mammalian Claudin-5, contributing to the development and the functional maintenance of both BBB and BCSFB. 

https://fluidsbarrierscns.biomedcentral.com/counter/pdf/10.1186/s12987-022-00337-9

Claudin-5a is essential for the functional formation of both zebrafish blood-brain barrier and blood-cerebrospinal fluid barrier

Background Measuring pain on digital devices using classic unidimensional pain scales such as the visual analog scale (VAS), numerical rating scale (NRS), and faces pain scale (FPS) has been proven to be reliable and valid. Emoji are pictographs designed in colorful form following the Unicode standard. It could be more beneficial to use emoji as faces of FPS on digital devices because emoji can easily fit on most devices and emoji are open-source so no approval would be needed before use. With a concise and user-friendly design, the emoji faces pain scale (Emoji-FPS) might be more generalizable to a wider population and more preferred by digital device users. Objective This study was designed to develop an Emoji-FPS as well as to evaluate its reliability, validity, and preference on mobile devices in adult patients who underwent surgery. Methods A modified Delphi technique with 2 rounds of web-based surveys was applied to obtain panelists’ consensus on the sequence of emoji that can best represent 6 levels of pain. The initial candidate sequences of emoji for the Delphi process were constructed referring to 2 well-validated FPSs (Wong-Baker FACES pain rating scale [Wong-Baker FACES] and faces pain scale-revised [FPS-R]). Then, a prospective cohort of patients scheduled to receive perianal surgery was recruited and asked to complete a web-based questionnaire on a mobile device at 5 time points (before surgery [T1], wake up after surgery [T2], 4 hours after surgery [T3], the second day after surgery [T4], and 15 minutes after T4 [T5]). The 4 well-validated pain scales (NRS, VAS, Wong-Baker FACES, and FPS-R) were used as reference scales. Results After 2 rounds of surveys on 40 Delphi panelists, an Emoji-FPS was finally determined to represent 6 pain levels (0, 2, 4, 6, 8, and 10) from “no hurt” to “hurts worst.” For validation, 300 patients were recruited and 299 were analyzed, the mean age of whom was 38.5 (SD 10.5) years, and 106 (35.5%) were women. For concurrent validity, the Emoji-FPS was highly correlated with 4 reference scales with Spearman correlation coefficient ρ ranging from 0.91 to 0.95. Excellent agreements were observed between 4 versions of Emoji-FPS (iOS, Android, Microsoft, and OpenMoji), with weighted κ coefficients ranging from 0.96 to 0.97. For discriminant validity, patients’ mean preoperative Emoji-FPS score (T1) was significantly higher than their postoperative Emoji-FPS score (T4) with a difference of 1.4 (95% CI 1.3-1.6; P<.001). For test-retest reliability, Emoji-FPS scores measured at T4 and T5 were highly correlated with a ρ of 0.91. The Emoji-FPS was mostly preferred, followed by the Wong-Baker FACES, FPS-R, NRS, and VAS. Conclusions The Emoji-FPS is reliable and valid compared with traditional pain scales in adult surgery patients.

Development of the Emoji Faces Pain Scale and Its Validation on Mobile Devices in Adult Surgery Patients: Longitudinal Observational Study

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Claudin-5a is essential for the functional formation of both zebrafish blood-brain barrier and blood-cerebrospinal fluid barrier

Development of the Emoji Faces Pain Scale and Its Validation on Mobile Devices in Adult Surgery Patients: Longitudinal Observational Study

Claudin-5a is essential for the functional formation of both zebrafish blood-brain barrier and blood-cerebrospinal fluid barrier