廣岡 芳樹

Abstract Background Paraprobiotics, the non-viable microbial cells with health benefits, have gained interest as candidates for preventing food allergies owing to their safety and stability. Heat-killed Lactiplantibacillus plantarum FM8 (FM8) has been reported to induce interleukin (IL)-10 production in dendritic cells in vitro; however, its in vivo efficacy as a standalone intervention remains unexplored. We investigated the preventive effect of heat-killed FM8 in a murine model of ovalbumin (OVA)-induced food allergy. Methods BALB/c mice were assigned to control, OVA-induced allergy, or three FM8 treatment groups receiving FM8 at low (2 × 10⁹ CFU/day), medium (1 × 10¹⁰ CFU/day), or high (5 × 10¹⁰ CFU/day) doses. Food allergy was induced by repeated OVA sensitization and challenge. Allergy symptoms, OVA-specific immunoglobulin E (IgE), and IL-10 levels were measured. Tight junction gene expression, mucin production, gut microbiota composition, and short-chain fatty acids (SCFAs) were also analyzed. Results FM8 supplementation attenuated allergic responses in a dose-dependent manner. Allergy symptom scores were reduced in the High group, and the rectal temperature decline following OVA challenge was ameliorated in both the Med and High groups. The sensitization-induced increase in OVA-specific IgE was also attenuated in these groups. IL-4 expression in Peyer’s patches was reduced, whereas colonic IL-10 expression and serum IL-10 levels were increased in the High group. FM8 supplementation was further associated with increased ileal expression of tight junction-related genes ( Occludin , Claudin-1 and Zo-1 ) and Muc2 , along with a trend toward increased fecal mucin levels; however, no comparable changes in tight junction-related gene expression were observed in the colon. Although taxa with reported SCFA-producing potential were enriched in the High group, cecal acetate and propionate levels remained unchanged, while butyrate levels were decreased. Conclusions FM8 may prevent food allergy by promoting IL-10-associated immunoregulation and enhancing gut barrier-related responses, without a corresponding increase in cecal SCFA concentrations. The contribution of SCFA-related mechanisms remains to be clarified, and further studies are needed to determine clinically feasible dosing and efficacy in humans.

BACKGROUND: With recent advances in chemotherapy for unresectable pancreatic ductal adenocarcinoma (PDAC) with liver metastasis (LM), attempts have been made to resect the primary tumor in patients showing favorable responses to anti-cancer treatment (so-called "conversion surgery"; CS). This study aimed to clarify the outcomes of CS for PDAC with LM in a nationwide multicenter study. METHODS: This retrospective, multicenter study was conducted as a project study of the Japan Pancreas Society and included patients with PDAC with LM at initial diagnosis, diagnosed radiologically or intraoperatively (occult LM), who underwent CS after at least 4 months of chemotherapy between 2010 and 2022. Survival outcomes and prognostic factors were analyzed. RESULTS: 90 patients were enrolled from 31 Japanese institutions. Median duration of preoperative chemotherapy was 10.4 (range, 4.2-58.5) months, and gemcitabine plus nab-paclitaxel was the most common first-line regimen, followed by folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin. Liver metastasectomy was performed in 27 patients (30%). 82 patients (91.1%) initiated adjuvant chemotherapy, and 41 (45.6%) completed it. Overall survival (OS) from initial treatment was 53.1 (95% CI 41.6-65.7) months; OS after CS was 39.7 (95% CI 24.4-55.9) months, and disease-free survival was 14.7 (95% CI 9.3-23.4) months. Preoperative normalization of carbohydrate antigen 19-9 and pathologic negative lymph node metastasis were independent prognostic factors for OS. CONCLUSION: CS may provide a survival benefit for highly selected patients with PDAC and LM, including those with occult lesions, who respond well to multidisciplinary treatment.