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Several lines of evidence have suggested a role of gut microbiota in the etiology of nonalcoholic steatohepatitis (NASH). NASH subjects reportedly showed a prolonged orocecal transit time coexistent with small intestinal bacterial overgrowth. We considered the possibility that enhanced gastrointestinal motility would influence gut microbiota and thus investigated the effects of the gastroprokinetic agent mosapride citrate (MC) on gut microbiota and the development of NASH using a methionine-choline deficient (MCD) diet-fed rodent model. Mice were divided into three groups, given the normal chow diet (NCD), the MCD diet, or the MCD diet containing 10 mg·kg(-1)·day(-1) of MC (MCD plus MC) for 6 wk. NASH development was evaluated based on hepatic histochemical findings, serum parameters and various mRNA and/or protein expression levels. MC treatment suppressed MCD diet-induced NASH development, with reduced serum lipopolysaccharide and increased plasma glucagon-like peptide-1 (GLP-1) concentrations. Calculation of the relative abundance of each strain based on gut microbiota analyses indicated lactic acid bacteria specifically, such as Bifidobacterium and Lactobacillus, in feces to be decreased in the MCD, compared with the NCD group. Interestingly, the reduction in lactic acid bacteria in the MCD diet group was reversed in the MCD plus MC group. In addition, colon inflammation observed in the MCD diet group was reduced in the MCD plus MC group. Therefore, MC showed a protective effect against MCD diet-induced NASH development in our rodent model, with possible involvements of increased fecal lactic acid bacteria, protection against colon inflammation and elevated plasma GLP-1., (Copyright © 2015 the American Physiological Society.)

Gut microbiota alterations are associated with various disorders. In this study, gut microbiota changes were investigated in a methionine-choline-deficient (MCD) diet-induced nonalcoholic steatohepatitis (NASH) rodent model, and the effects of administering Lactobacillus casei strain Shirota (LcS) on the development of NASH were also investigated. Mice were divided into three groups, given the normal chow diet (NCD), MCD diet, or the MCD diet plus daily oral administration of LcS for 6 wk. Gut microbiota analyses for the three groups revealed that lactic acid bacteria such as Bifidobacterium and Lactobacillus in feces were markedly reduced by the MCD diet. Interestingly, oral administration of LcS to MCD diet-fed mice increased not only the L. casei subgroup but also other lactic acid bacteria. Subsequently, NASH development was evaluated based on hepatic histochemical findings, serum parameters, and various mRNA and/or protein expression levels. LcS intervention markedly suppressed MCD-diet-induced NASH development, with reduced serum lipopolysaccharide concentrations, suppression of inflammation and fibrosis in the liver, and reduced colon inflammation. Therefore, reduced populations of lactic acid bacteria in the colon may be involved in the pathogenesis of MCD diet-induced NASH, suggesting normalization of gut microbiota to be effective for treating NASH.

A 60-year-old man presented with anal pain. He was diagnosed as having perianal abscess and carcinoma associated with anal fistula. We performed chemoradiotherapy (radiation, total 50.4 Gy; capecitabine 2,000 mg/m2) followed by chemotherapy( XELOX, 2 courses: capecitabine 2,000 mg/m2, oxaliplatin 130 mg/m2). After chemoradiotherapy, the tumor significantly reduced in size. Laparoscopic abdominoperineal resection of the rectum, extended resection of the perianal region, and reconstruction of the perianal skin defect using a rectus abdominis musculocutaneous flap were performed. Histopathologically, the tumor was classified as tub2, pMP, ly0, v0, pN0 (0/3), pStage I, and the therapeutic efficacy was classified as Grade 2. Chemoradiation appears to be effective for the treatment of carcinomas associated with anal fistula.

Chemoradiotherapy before surgical treatment of locally advanced lower rectal cancer is currently uncommon in Japan. We have treated 5 patients with T3 and/or N1 and 2 patients with rectal cancer using chemoradiotherapy including capecitabine and oxaliplatin( XELOX). The treatment consisted of concomitant administration of radiotherapy( 45 Gy/25 Fr), capecitabine (2,000 mg/m2/day; 2 weeks followed by 1 week off), and XELOX (2 courses). Surgery was performed 1 month after the final dose of chemotherapy was administered. The adverse events of Grade greater than 2 observed were radiation dermatitis (n=3), peripheral neuropathy (n=1), and rash (n=1). Either laparoscopic abdominoperineal resection( n=4) or open low anterior resection( n=1) was performed for surgical treatment. Histopathological regression grading revealed Grade 1a (n=1) and Grade 2 (n=4). The combined therapy resulted in downstaging in all patients. Preoperative chemoradiotherapy followed by XELOX might be effective for the treatment of locally advanced lower rectal cancer.

Glucose transporter 1 (GLUT1) is widely distributed throughout various tissues and contributes to insulin-independent basal glucose uptake. Using a split-ubiquitin membrane yeast two-hybrid system, we newly identified 4F2 heavy chain (4F2hc) as a membrane protein interacting with GLUT1. Though 4F2hc reportedly forms heterodimeric complexes between amino acid transporters, such as LAT1 and LAT2, and regulates amino acid uptake, we investigated the effects of 4F2hc on GLUT1 expression and the associated glucose uptake. First, FLAG-tagged 4F2hc and hemagglutinin-tagged GLUT1 were overexpressed in human embryonic kidney 293 cells and their association was confirmed by coimmunoprecipitation. The green fluorescent protein-tagged 4F2hc and DsRed-tagged GLUT1 showed significant, but incomplete, colocalization at the plasma membrane. In addition, an endogenous association between GLUT1 and 4F2hc was demonstrated using mouse brain tissue and HeLa cells. Interestingly, overexpression of 4F2hc increased the amount of GLUT1 protein in HeLa and HepG2 cells with increased glucose uptake. In contrast, small interfering RNA (siRNA)-mediated 4F2hc gene suppression markedly reduced GLUT1 protein in both cell types, with reduced glucose uptake. While GLUT1 mRNA levels were not affected by overexpression or gene silencing of 4F2hc, GLUT1 degradation after the addition of cycloheximide was significantly suppressed by 4F2hc overexpression and increased by 4F2hc siRNA treatment. Taken together, these observations indicate that 4F2hc is likely to be involved in GLUT1 stabilization and to contribute to the regulation of not only amino acid but also glucose metabolism.