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IntroductionSevere sepsis is associated with a high mortality rate despite implementation of guideline recommendations. Adjunctive treatment may be efficient and require further investigation. In light of the crucial role of immunologic derangement in severe sepsis, thymosin alpha 1 (Tα1) is considered as a promising beneficial immunomodulatory drug. The trial is to evaluate whether Tα1 improves 28-day all-cause mortality rates and immunofunction in patients with severe sepsis.MethodsWe performed a multicenter randomized controlled trial in six tertiary, teaching hospitals in China between May 12, 2008 and Dec 22, 2010. Eligible patients admitted in ICU with severe sepsis were randomly allocated by a central randomization center to the control group or Tα1 group (1:1 ratio). The primary outcome was death from any cause and was assessed 28 days after enrollment. Secondary outcomes included dynamic changes of Sequential Organ Failure Assessment (SOFA) and monocyte human leukocyte antigen-DR (mHLA-DR) on day 0, 3, 7 in both groups. All analyses were done on an intention-to-treat basis.ResultsA total of 361 patients were allocated to either the control group (n = 180) or Tα1 (n = 181) group. The mortalities from any cause within 28 days in the Tα1 group and control group were 26.0% and 35.0% respectively with a marginal P value (nonstratified analysis, P = 0.062; log rank, P = 0.049); the relative risk of death in the Tα1 group as compared to the control group was 0.74 (95% CI 0.54 to 1.02). Greater improvement of mHLA-DR was observed in the Tα1 group on day 3 (mean difference in mHLA-DR changes between the two groups was 3.9%, 95% CI 0.2 to 7.6%, P = 0.037) and day 7 (mean difference in mHLA-DR changes between the two groups was 5.8%, 95% CI 1.0 to 10.5%, P = 0.017) than in the control group. No serious drug-related adverse event was recorded.ConclusionsThe use of Tα1 therapy in combination with conventional medical therapies may be effective in improving clinical outcomes in a targeted population of severe sepsis.Trial registrationClinicalTrials.gov NCT00711620.

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Emerging evidence highlights the role of gut microbiota in regulating the pathogenesis of coronary heart disease. Here, we performed 16S rRNA gene sequencing and UPLC-Q-TOF/MS-based metabolomics to investigate the gut microbiome and metabolomes of cecal contents in the isoproterenol (ISO)-induced acute myocardial ischemia (AMI) rats. As expected, considerable gut microbiota alterations were observed in the AMI rats compared with the control rats, paralleling with intestinal inflammation and apoptosis. At phylum level, the abundance of Firmicutes was significantly decreased, whereas the abundance of Bacteroidetes and Spirochaetae was strikingly enriched in the AMI group. At genus level, the significant alteration of genera Treponema 2 , Rikenellaceae RC9 gut group , Prevotellaceae UCG-003 , and Bacteroides may contribute to the pathogenesis of AMI. These altered microbiota might influence the intestinal permeability and subsequently impair intestinal barrier and stimulate gut inflammation. Consistently, significantly metabolic differences of cecal contents between the AMI and control groups were revealed, and threonic acid, L-urobilin and L-urobilinogen were considered the most associated cecal metabolites with AMI. These strikingly altered metabolites were mainly related to energy metabolism and oxidative stress which could lead to apoptosis and further affect gut barrier. Ultimately, we revealed the potential link of these altered gut microbiota/metabolomes and intestinal inflammatory factors and apoptotic proteins and further confirmed their intimate connections with intestinal inflammation and gut barrier. Our findings depict uncovered potential relationship among the gut microbiome, cecal metabolomes and AMI.