Excessive Mitochondrial Fission Suppresses Mucosal Repair by Impairing Butyrate Metabolism in Colonocytes.

BACKGROUND: Mucosal healing is one of the principal therapeutic targets for ulcerative colitis (UC). Mitochondria are dynamic organelles that undergo constant fusion and fission; however, the process that is most conducive to mucosal healing remains unclear. This study investigated the role of mitochondrial fission in mucosal healing in UC patients. METHODS: Quantitative polymerase chain reaction, Western blotting, and immunostaining were used to detect mitochondrial fission in UC patients and a dextran sulfate sodium-induced colitis model. Colonic organoids were used to investigate the role of mitochondrial fission in butyrate metabolism. Enzyme activity assays were performed to identify the key proteins involved in this mechanism. RESULTS: It was found that inhibition of mitochondrial fission promoted mucosal healing in mice and that there was an increase in mitochondrial fission in colonic epithelial cells of UC patients. Excessive fission inhibits stem cell proliferation by impairing butyrate metabolism in colonic organoids. The mitochondrial fission antagonist P110 failed to promote mucosal healing in antibiotic-treated mice, and the addition of exogenous butyrate reversed this effect. Increased butyrate exposure in the colonic stem cell niche has also been observed in UC patients. Mechanistically, enzyme activity assays on colonic organoids revealed that excessive fission inhibits mitochondrial acetoacetyl-CoA thiolase activity via reactive oxygen species. CONCLUSIONS: Collectively, these data indicate that excessive mitochondrial fission suppresses mucosal repair by inhibiting butyrate metabolism and provides a potential target for mucosal healing in patients with ulcerative colitis.

A novel flexible auxiliary single-arm transluminal endoscopic robot facilitates endoscopic submucosal dissection of gastric lesions (with video).

BACKGROUND: Using conventional endoscope to perform endoscopic submucosal dissection (ESD) is difficult because of the one-handed operation and blind dissection caused by gravity. Poor visualization of the submucosal plane causes ESD to be associated with a high risk of bleeding and perforation. This study aimed to develop a novel ESD-assistive robot system and to evaluate its efficacy. METHODS: A novel flexible auxiliary single-arm transluminal endoscopic robot (FASTER) was developed. A total of 36 artificial lesions in ex vivo porcine stomachs were removed using the FASTER-assisted ESD method (n = 18) and the conventional ESD method (n = 18). Lesions were 2 cm or 4 cm in diameter, located on the anterior and posterior walls of the antrum. Primary outcome measurements were dissection time and dissection speed. RESULTS: The dissection time in FASTER-assisted ESD was significantly shorter than that in conventional ESD (7 min vs 13 min, p = 0.012), mainly because of the faster dissection speed (148.6 vs 97.0 mm2/min, p = 0.002). The total procedure time in FASTER-assisted ESD was shorter than that in conventional ESD, but the difference was not significant (16 min vs 24 min, p = 0.252). Complete en bloc resection was achieved in all lesions. No perforations were detected. The FASTER exhibited the ability of regrasp, multidirectional traction, and proper tension control during ESD. CONCLUSION: FASTER significantly increased the dissection speed by providing proper traction and achieving good submucosal vision. This new device is expected to facilitate ESD in clinical practice.

Simplified robot-assisted endoscopic submucosal dissection for esophageal and gastric lesions: a randomized controlled porcine study (with videos).

BACKGROUND AND AIMS: Effective countertraction is a main challenging issue in endoscopic submucosal dissection (ESD). Several countertraction methods have been developed to address this issue. The aim of this study was to compare the efficacy of ESD using a novel simplified robot, the flexible auxiliary single-arm transluminal endoscopic robot (FASTER), with a traditional technique. METHODS: This was a prospective, randomized animal study. Forty-eight ESDs in 6 pigs were carried out at 8 different locations (gastric antrum, gastric body, lower esophagus, and middle esophagus) by the conventional method (n = 24) and by the FASTER-assisted method (n = 24). The primary outcomes were total procedure time, dissection time, and rate of direct-vision dissection. Secondary endpoints were completeness of en-bloc resection and adverse event rate. RESULTS: The total procedure time was significantly shorter in FASTER-assisted ESD than in conventional ESD (18.8 vs 32.8 minutes; P < .001). In contrast to the median direct-vision dissection rate of 73% with conventional ESD, the FASTER-assisted group had a significantly higher rate of 96% (P < .001). The number of sites of muscular damage was significantly lower using the FASTER-assisted method than the conventional method (6 vs 21, respectively; P = .018). This improvement was more apparent in esophageal lesions compared with gastric lesions. CONCLUSIONS: This study demonstrated that using a simplified robot during ESD is technically feasible and enables the endoscopist to dynamically use countertraction. This device could significantly reduce procedure time compared with conventional ESD techniques.

Probiotic Interventions Alleviate Food Allergy Symptoms Correlated With Cesarean Section: A Murine Model.

Delivery by cesarean section (CS) is linked to an increased incidence of food allergies in children and affects early gut microbiota colonization. Furthermore, emerging evidence has connected disordered intestinal microbiota to food allergies. Here, we investigated the impact of CS on a rat model for food allergy to ovalbumin (OVA). Rats delivered by CS were found to be more responsive to OVA sensitization than vaginally born ones, displaying a greater reduction in rectal temperature upon challenge, worse diarrhea, and higher levels of OVA-specific antibodies and histamine. 16S rRNA sequencing of feces revealed reduced levels of Lactobacillus and Bifidobacterium in the CS rats. Preventative supplementation with a probiotic combination containing Lactobacillus and Bifidobacterium could protect CS rats against an allergic response to OVA, indicating that the microbiota dysbiosis contributes to CS-related response. Additionally, probiotic intervention early in life might help to rebuild aberrant Th2 responses and tight junction proteins, both of which have been linked to CS-related high allergic reactions. Taken together, this study shows that disordered intestinal microbiota plays an essential role in the pathogenesis of food allergy mediated by CS. More importantly, interventions that modulate the microbiota composition in early life are therapeutically relevant for CS-related food allergies.

Complete genome sequencing of Peyer's patches-derived Lactobacillus taiwanensis CLG01, a potential probiotic with antibacterial and immunomodulatory activity.

BACKGROUND: The genus Lactobacillus is an important component of the gastrointestinal tract of human and animals and commonly considered as probiotic. L. taiwanensis has long been proposed to be a probiotic whereas understanding on this species is still in its infancy. Genomic information of L. taiwanensis is fairly limited. Extensive characterization of its beneficial traits is needed. RESULTS: A new strain CLG01 of L. taiwanensis was isolated from mouse Peyer's patches. We established its probiotic profile through in vitro experiments. Complete genome of this strain was also sequenced and analyzed. L. taiwanensis CLG01 showed robust tolerance to acid and a degree of tolerance to bile salt with a promising antibacterial activity against a broad spectrum of pathogenic bacteria. In vitro treatment of mouse RAW 264.7 macrophage cells with heat-killed bacteria and bacterial supernatant of L. taiwanensis CLG01 resulted in enhancement of immune responses and upregulated expression of TNF-α and IL-6. The strain CLG01 also increased the IL-10 production of macrophages when co-treated with lipopolysaccharide (LPS). Complete genome of L. taiwanensis CLG01 contained a 1.89 Mb chromosome and two plasmids. Further genomic analysis revealed the presence of genes related to its resistance to different stresses and the beneficial effects mentioned above. Moreover, biosynthetic gene clusters (BGCs) encoding antimicrobial peptides, like bacteriocin, linear azol(in)e-containing peptide (LAP) and lanthipeptide, were also identified in the genome of L. taiwanensis CLG01. CONCLUSIONS: L. taiwanensis CLG01, isolated from mouse Peyer's patches, is the first L. taiwanensis strain with both phenotypes and genotypes systematically studied. These preliminary data confirmed the role of L. taiwanensis CLG01 as a potential probiotic candidate with antibacterial and immunomodulatory activity, which provide insight for further investigation to this species.