The clinical spectra of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) intersect to form a scantily defined overlap syndrome, termed pre-IBD. We show that increased Enterobacteriaceae and reduced Clostridia abundance distinguish the fecal microbiota of pre-IBD patients from IBS patients. A history of antibiotics in individuals consuming a high-fat diet was associated with the greatest risk for pre-IBD. Exposing mice to these risk factors resulted in conditions resembling pre-IBD and impaired mitochondrial bioenergetics in the colonic epithelium, which triggered dysbiosis. Restoring mitochondrial bioenergetics in the colonic epithelium with 5-amino salicylic acid, a PPAR-g (peroxisome proliferator-activated receptor gamma) agonist that stimulates mitochondrial activity, ameliorated pre-IBD symptoms. As with patients, mice with pre-IBD exhibited notable expansions of Enterobacteriaceae that exacerbated low-grade mucosal inflammation, suggesting that remediating dysbiosis can alleviate inflammation. Thus, environmental risk factors cooperate to impair epithelial mitochondrial bioenergetics, thereby triggering microbiota disruptions that exacerbate inflammation and distinguish pre-IBD from IBS.

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Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown. Here, we investigated whether colitis alters the colonic microbiota to enhance its cancer-inducing activity. Colitis increased epithelial oxygenation in the colon of mice and drove an expansion of Escherichia coli within the gut-associated microbial community through aerobic respiration. An aerobic expansion of colibactin-producing E. coli was required for the cancer-inducing activity of this pathobiont in a mouse model of colitis-associated colorectal cancer formation. We conclude that increased epithelial oxygenation in the colon is associated with an expansion of a prooncogenic driver species, thereby increasing the cancer-inducing activity of the microbiota. IMPORTANCE One of the environmental factors important for colorectal cancer formation is the gut microbiota, but the habitat filters that control its cancer-inducing activity remain unknown. Here, we show that chemically induced colitis elevates epithelial oxygenation in the colon, thereby driving an expansion of colibactin-producing Escherichia coli, a prooncogenic driver species. These data suggest that elevated epithelial oxygenation is a potential risk factor for colorectal cancer formation because the consequent changes in the gut habitat escalate the cancer-inducing activity of the microbiota.

5-Aminosalicylic acid (5-ASA), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is a widely used first-line medication for the treatment of ulcerative colitis, but its anti-inflammatory mechanism is not fully resolved. Here, we show that 5-ASA ameliorates colitis in dextran sulfate sodium (DSS)-treated mice by activating PPAR-γ signaling in the intestinal epithelium. DSS-induced colitis was associated with a loss of epithelial hypoxia and a respiration-dependent luminal expansion of Escherichia coli, which could be ameliorated by treatment with 5-ASA. However, 5-ASA was no longer able to reduce inflammation, restore epithelial hypoxia, or blunt an expansion of E. coli in DSS-treated mice that lacked Pparg expression specifically in the intestinal epithelium. These data suggest that the anti-inflammatory activity of 5-ASA requires activation of epithelial PPAR-γ signaling, thus pointing to the intestinal epithelium as a potential target for therapeutic intervention in ulcerative colitis. IMPORTANCE An expansion of Enterobacterales in the fecal microbiota is a microbial signature of dysbiosis that is linked to many noncommunicable diseases, including ulcerative colitis. Here, we used Escherichia coli, a representative of the Enterobacterales, to show that its dysbiotic expansion during colitis can be remediated by modulating host epithelial metabolism. Dextran sulfate sodium (DSS)-induced colitis reduced mitochondrial activity in the colonic epithelium, thereby increasing the amount of oxygen available to fuel an E. coli expansion through aerobic respiration. Activation of epithelial peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling with 5-aminosalicylic acid (5-ASA) was sufficient to restore mitochondrial activity and blunt a dysbiotic E. coli expansion. These data identify the host’s epithelial metabolism as a potential treatment target to remediate microbial signatures of dysbiosis, such as a dysbiotic E. coli expansion in the fecal microbiota.

BackgroundAtopic dermatitis (AD) is characterized by pruritic and eczematous skin lesions, which often cause depressive symptoms, anxiety, stress, sleep disturbances, social withdrawal, and stigmatization.MethodsIn total, 23,442 subjects (434 AD patients and 23,008 control subjects) aged 19 years or older and without a history of major medical illness or depressive disorders were selected from The Fifth Korea National Health and Nutrition Examination Survey 2007-2012. Following the initial selection, 2,170 age- and sex-matched control subjects were selected using 1:5 propensity score matching. Multiple logistic regression analysis was performed to identify the presence of depressive symptoms of at least 2 weeks in duration.ResultsThe demographic, socioeconomic, and clinical characteristics of AD patients and control subjects were presented and compared, and some variables differed significantly between groups. Presence of depressive symptoms was set as dependent variable, and multiple logistic regression analysis was performed as follows: (1) unadjusted; (2) with alcohol use, exercise status, smoking status, and body mass index (BMI) adjusted for; and (3) with alcohol use, exercise status, smoking status, marital status, occupation, BMI, total caloric intake, history of hypertension, and history of diabetes mellitus adjusted for. Depressive symptoms were significantly higher (odds ratios, 1.46, 1.40, and 1.36; 95% confidence intervals, 1.09-1.95, 1.0.4-1.88, and 1.01-1.85, respectively) in AD patients relative to those of matched controls.ConclusionAD and clinical depression interact closely, and causal relationships between the two conditions have frequently been observed. Physicians should consider mental health interventions cautiously. It is particularly important that primary care physicians provide comprehensive, continuous long-term care.

BackgroundCarcinoembryonic antigen (CEA) is a tumor marker overexpressed in adenocarcinoma that has proinflammatory properties. Recent studies have reported that CEA is positively associated with carotid atherosclerosis and metabolic syndrome. Because visceral obesity is a known risk factor for cardiometabolic diseases, CEA may also be associated with visceral adiposity. Therefore, we investigated the relationship between serum CEA concentration and visceral obesity in female Korean nonsmokers.MethodsA total of 270 Korean female nonsmokers were enrolled during their routine health check-ups. Biomarkers of metabolic risk factors were assessed along with body composition by computed tomography. Serum CEA levels were measured by using a chemiluminescence immunoassay analyzer.ResultsSerum CEA levels correlated with visceral fat area, fasting glucose, and triglyceride levels after adjusting for age and BMI. The mean visceral fat area increased significantly with the increasing CEA tirtiles. In a step-wise multiple regression analysis, age (β = 0.26, p<0.01) and visceral fat area (β = 0.19, p = 0.03) were identified as explanatory variables for serum CEA level.ConclusionsThis study suggested that CEA may be a mediator that links metabolic disturbance and tumorigenesis in visceral obesity. Further studies are required to better understand the clinical and pathophysiological significance of our findings.

BackgroundMetabolic syndrome (MS) is known to increase the risk of various cardiometabolic diseases and in-sulin resistance (IR) has known to have central role in the development of MS. Many surrogate indices of IR have been proposed and the detection of MS might be a suitable model for assessing the accuracy of surrogate indices. The aims of our study are to invest the most appropriate index by assessment of the diagnostic capacity of IR among each surrogate index and identifying cut-off values for discriminating uncomplicated MS in Korean adults.MethodsA cross-sectional study was performed, assessing 294 Korean adults, 85 of whom were diagnosed with uncomplicated MS. The sensitivities and specificities of five surrogate IR indices were compared to discriminate MS from healthy subjects; these included fasting serum insulin, homeostasis model assessment–insulin resistance index, quantitative insulin sensitivity check index, McAuley index, and Disse index. Correlations between each index value were assessed using Pearson's and Spearman's correlation methods.ResultsThe McAuley index showed the highest area under the curve (0.85), specificity (86.12%), accuracy (82.31%), positive predictive value (68.13%), and negative predictive value (88.67%) to distinguish MS, with a cut-off point of 5.3 defined. Correlation coefficients of the five indices showed that the McAuley index had the strongest correlation with IR.ConclusionThe McAuley index showed the best accuracy in the detection of MS as a surrogate marker of IR. To establish more effective and accurate standards of measuring IR, comprehensive and multi-scaled studies are required.

BackgroundObesity is a known risk factor for colorectal cancer (CRC), and emerging data suggest that this association is mediated by visceral fat rather than total body fat. However, there is a lack of studies evaluating the association between visceral fat area and the prevalence of CRC.MethodsTo investigate the relationship between visceral adiposity and prevalence of CRC, data of 497 women diagnosed with CRC and 318 apparently healthy women were analysed and data of well-balanced 191 pairs of women with CRC and healthy women matched based on propensity scores were additionally analysed. Diagnosis of CRC was confirmed by colonoscopy and histology. Metabolic parameters were assessed, along with body composition, using computed tomography.ResultsThe median visceral fat area was significantly higher in the CRC group compared with the control group before and after matching. The prevalence of CRC increased significantly with increasing visceral fat tertiles after matching (p for trend <0.01). A multivariate analysis showed that mean visceral fat area of individuals in the 67th percentile or greater group was associated with an increased prevalence of CRC (adjusted odds ratio: 1.80; 95% confidence interval: 1.12–2.91 before matching and adjusted odds ratio: 2.96; 95% confidence interval: 1.38–6.33) compared with that of individuals in the 33th percentile or lower group.ConclusionThus, we conclude that visceral fat area is positively associated with the prevalence of CRC. Although we could not determine the causality, visceral adiposity may be associated with the risk of CRC. Further prospective studies are required to determine the benefits of controlling visceral obesity for reducing CRC risk.