Antibiotic-induced microbiome depletion improves LPS-induced acute lung injury via gut-lung axis.

AIMS: Acute lung injury (ALI) is an acute inflammatory disorder. However, the precise mechanisms underlying the pathology of ALI remain elusive. An increasing evidence suggests the role of the gut-microbiota axis in the pathology of lung injury. This study aimed to investigate whether antibiotic-induced microbiome depletion could affect ALI in mice after lipopolysaccharide (LPS) administration. MAIN METHODS: The effects of antibiotic cocktail (ABX) on ALI in the mice after intratracheally administration of LPS (5 mg/kg) were examined. Furthermore, 16s rRNA analysis and measurement of short-chain fatty acids in feces samples and metabolomics analysis of blood samples were performed. KEY FINDINGS: LPS significantly increased the interleukin-6 (IL-6) levels in the bronchoalveolar lavage fluid (BALF) of water-treated mice. Interestingly, an ABX significantly attenuated the LPS-induced increase in IL-6 in BALF and lung injury scores. Furthermore, ABX and/or LPS treatment markedly altered the α- and ß-diversity of the gut microbiota. There were significant differences in the α- and ß-diversity of the water + LPS group and ABX + LPS group. LEfSe analysis identified Enterococusfaecalis, Clostriumtertium, and Bacteroidescaecimyris as potential microbial markers for ABX + LPS group. Untargeted metabolomics analysis identified several plasma metabolites responsible for discriminating water + LPS group from ABX + LPS group. There were correlations between the relative abundance of the microbiome and plasma metabolites. Integrative network analysis showed correlations between IL-6 levels in BALF and several gut microbes (or plasma metabolites). SIGNIFICANCE: These data suggest that ABX-induced microbiome depletion could protect against LPS-induced ALI via the gut-microbiota-lung axis.

Effects of splenectomy on skin inflammation and psoriasis-like phenotype of imiquimod-treated mice.

Imiquimod (IMQ) is widely used as animal model of psoriasis, a chronic inflammatory skin disorder. Although topical application of IMQ to back skin causes splenomegaly in mice, how the spleen affects the psoriasis-like phenotype of IMQ-treated mice remains unclear. In this study, we analyzed the cellular composition of spleen and measured metabolites in blood of IMQ-treated mice. We also investigated whether splenectomy influences the degree of skin inflammation and pathology in IMQ-treated mice. Flow cytometry showed that the numbers of CD11b+Ly6c+ neutrophils, Ter119+ proerythroblasts, B220+ B cells, F4/80+ macrophages, and CD11c+ dendritic cells in the spleen were significantly higher in IMQ-treated mice compared to control mice. An untargeted metabolomics analysis of blood identified 14 metabolites, including taurine and 2,6-dihydroxybenzoic acid, whose levels distinguished the two groups. The composition of cells in the spleen and blood metabolites positively correlated with the weight of the spleen. However, splenectomy did not affect IMQ-induced psoriasis-like phenotypes compared with sham-operated mice, although splenectomy increased the expression of interleukin-17A mRNA in the skin of IMQ-treated mice. These data suggest that the spleen does not play a direct role in the development of psoriasis-like phenotype on skin of IMQ-treated mice, though IMQ causes splenomegaly.

Effects of spleen nerve denervation on depression-like phenotype, systemic inflammation, and abnormal composition of gut microbiota in mice after administration of lipopolysaccharide: A role of brain-spleen axis.

BACKGROUND: Accumulating evidence suggests the role of brain-spleen axis as well as brain-gut-microbiota axis in inflammation-related depression. The spleen mediates anti-inflammatory effects of the vagus nerve which plays a role in depression. However, the role of spleen nerve in inflammation-related depression remains unclear. METHODS: The effects of the splenic nerve denervation (SND) in the depression-like phenotype, systemic inflammation, and abnormal composition of gut microbiota in adult mice after administration of lipopolysaccharide (LPS) were examined. RESULTS: LPS (0.5 mg/kg) caused depression-like phenotype, systemic inflammation, splenomegaly, increased expression of Iba1 (ionized calcium-binding adapter molecule 1) and decreased expression of postsynaptic density protein-95 (PSD-95) in the hippocampus in the sham-operated mice. In contrast, LPS did not produce depression-like phenotype, and abnormal expressions of Iba1 and PSD-95 in the hippocampus in the SND-operated mice. Furthermore, SND significantly blocked LPS-induced increased plasma levels of pro-inflammatory cytokine interleukin-6 although SND did not affect LPS-induced splenomegaly and increased plasma levels of tumor necrosis factor-α in mice. There were significant changes in several microbiota among the four groups. Interestingly, there were correlations between the relative abundance of several microbiota and Iba1 (or PSD-95) expression in the hippocampus. In addition, expression of Iba1 in the hippocampus was correlated with the relative abundance of several microbiota. LIMITATIONS: Detailed mechanisms are unclear. CONCLUSIONS: These results suggest that the splenic nerve plays a role in inflammation-related depression, microglial activation in the hippocampus, and that gut microbiota may regulate microglial function in the brain via gut-microbiota-brain axis.

Abnormal composition of microbiota in the gut and skin of imiquimod-treated mice.

Psoriasis is a chronic, inflammatory skin disease. Although the precise etiology of psoriasis remains unclear, gut-microbiota axis might play a role in the pathogenesis of the disease. Here we investigated whether the composition of microbiota in the intestine and skin is altered in the imiquimod (IMQ)-treated mouse model of psoriasis. Topical application of IMQ to back skin caused significant changes in the composition of microbiota in the intestine and skin of IMQ-treated mice compared to control mice. The LEfSe algorithm identified the species Staphylococcus lentus as potential skin microbial marker for IMQ group. Furthermore, there were correlations for several microbes between the intestine and skin, suggesting a role of skin-gut-microbiota in IMQ-treated mice. Levels of succinic acid and lactic acid in feces from IMQ-treated mice were significantly higher than control mice. Moreover, the predictive functional analysis of the microbiota in the intestine and skin showed that IMQ caused alterations in several KEGG pathways. In conclusion, the current data indicated that topical application with IMQ to skin alters the composition of the microbiota in the gut and skin of host. It is likely that skin-gut microbiota axis plays a role in pathogenesis of psoriasis.

Dextran sulfate sodium-induced inflammation and colitis in mice are ameliorated by (R)-ketamine, but not (S)-ketamine: A role of TrkB signaling.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that causes long-lasting inflammation and colitis in the gastrointestinal tract. Depression is a common symptom in patients with UC. (R)-ketamine is a new safer antidepressant than (R,S)-ketamine and (S)-ketamine. Here, we examined the effects of two ketamine enantiomers on the dextran sulfate sodium (DSS)-induced colitis model of UC. Ingestion of 3% DSS in drinking water for 14 days increased the scores of Disease Activity Index (DAI) in mice. Repeated administration of (R)-ketamine (10 mg/kg/day, 14 days or last 7 days), but not (S)-ketamine (10 mg/kg/day, 14 days or last 7 days), significantly ameliorated the increased DAI score and increased blood levels of interleukin-6 (IL-6) in DSS-treated mice. In addition, (R)-ketamine, but not (S)-ketamine, attenuated the reduced colonic length in DSS-treated mice. Furthermore, DSS-induced increased DAI score and blood IL-6 levels were significantly ameliorated after subsequent repeated administration of (R)-ketamine (10 mg/kg/day for last 7 days), but not 5-aminosalicyclic acid (50 mg/kg/day for last 7 days). Moreover, the pretreatment with a tropomyosin-receptor-kinase B (TrkB) antagonist ANA-12 (0.5 mg/kg) significantly blocked the beneficial effects of (R)-ketamine in DSS-induced UC model. The study shows that (R)-ketamine can produce beneficial effects in DSS-induced colitis model through TrkB stimulation. Therefore, (R)-ketamine may be a novel therapeutic drug for inflammatory bowel diseases such as UC.

Topical steroid application can induce branched/reticular vessels in Bowen disease on the upper trunk.

We aimed to elucidate the dermoscopic vasculature of patients with Bowen Disease (BD) that was misdiagnosed as chronic eczema and had branched and/or reticular vessels after topical steroid application. The medical records of 19 patients with BD on the upper trunk were retrospectively reviewed for steroid use history, vascular structure observed in dermoscopy, and corresponding histological findings. Four patients treated with strong topical steroids showed remarkable branched and/or reticular vessels on dermoscopy. Histopathology showed partial epidermal atrophy with irregular thin elongation of the rete ridges, atypical keratinocyte proliferation in the epidermis, and vasodilation in the superficial dermis. We considered that vasodilation and partial epidermal atrophy may be induced by topical steroid application in BD-affected areas. In cases of suspected BD with reddish-brown plaque showing branched and/or reticulated vessels in dermoscopy, confirming a history of topical steroid use is helpful.

Case of fertility treatment-induced Stevens-Johnson syndrome with a severe ocular complication.

Pharmacological regimens with multiple medications are being used in fertility treatments. Herein, we report a case of a 40-year-old Japanese woman who developed Stevens-Johnson syndrome (SJS) with a severe ocular complication during fertility treatment. Despite early multimodal interventions, including methylprednisolone pulse therapy and plasma exchange, her ocular complications persisted for more than a year. The four drugs administered in this case (cabergoline, medroxyprogesterone acetate, clomiphene, and intravenous human chorionic gonadotropin) have never been reported to induce SJS. Based on this case, we suggest that obstetricians, gynecologists, and dermatologists should be aware of fertility treatment-induced severe drug eruptions.