The intestinal microenvironment in sepsis

Fay, Katherine; Ford, Mandy L.; Coopersmith, Craig M.

doi:10.1016/j.bbadis.2017.03.005

Cited by 133 publications

(107 citation statements)

References 109 publications

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“…Whereas the most common microbe makes up 25% of the microbiome in healthy patients, a massive diversity crash causes results in the most common microbe making up 95% of the microbiome in ICU patients [215]. These changes appear to result from both the underlying disorder (sepsis) and its treatment (antibiotics), which by definition alter the microbiome [216][217][218][219][220][221][222]. Further, microbes alter their virulence in response to both the internal host environment (availability of phosphate) and treatments in critically ill patients (opiates) [223][224][225].…”

Section: Basic/translational Science What Mechanisms Underlie Sepsis-mentioning

confidence: 99%

Surviving sepsis campaign: research priorities for sepsis and septic shock

et al. 2018

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Objective: To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock.Design: A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations.Methods: Each committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 -supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science. Results:The Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction?Conclusions: While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.

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Section: Basic/translational Science What Mechanisms Underlie Sepsis-mentioning

confidence: 99%

Surviving sepsis campaign: research priorities for sepsis and septic shock

et al. 2018

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“…The gut has long been hypothesized to be the "motor" of multiple organ dysfunction (5)(6)(7)(8)(9)(10)(11). Gut epithelial integrity is altered in sepsis, with increased apoptosis, decreased villus length and…”

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confidence: 99%

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

Lorentz

Liang

Meng

et al. 2017

Mol Med

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Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the perijunctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK -/-and wild-type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK -/-mice (95% versus 24%, p < 0.0001). Intestinal permeability increased in septic WT mice compared with unmanipulated mice. In contrast, permeability in septic MLCK -/-mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK -/-mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8 and 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion, as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK -/-mice; however, survival was similar between septic MLCK -/-mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

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“…The gastrointestinal (GI) tract has long been hypothesized to play an integral role in the pathophysiology of sepsis, by both driving and perpetuating multiple organ dysfunction 8,9 . The original concept of gut-derived sepsis proposed that the altered inflammatory milieu induced by overwhelming infection leads to intestinal hyperpermeability, allowing luminal contents, including intact microbes, and microbial products, to escape their natural environment where they can cause either local or distant injury 1,5,6,10 .…”

Section: The World Healthmentioning

confidence: 99%

“…Sepsis continues to be the leading cause of mortality in the intensive care unit 1,2 . There were more than 1 million sepsis-related deaths in 2015 in China 3 .…”

Section: Introductionmentioning

confidence: 99%

Fecal microbiota transplantation reconstructs the gut microbiota of septic mice and protects the intestinal mucosal barrier

Gai

Wang

et al. 2020

Preprint

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The gastrointestinal (GI) tract has long been hypothesized to play an integral role in the pathophysiology of sepsis, and gut microbiota (GM) dysbiosis may be the key factor. Previous studies has confirmed that microbiome is markedly altered in critical illness. We aimed to confirm the existence of gut microbiota imbalance in the early stage of sepsis, observe the effect of fecal microbiota transplantation (FMT) on sepsis, and explore whether FMT can reconstruct the GM of septic mice and restore its protective function on the intestinal mucosal barrier. Through the study of flora, mucus layer, tight junction, immune barrier, and short-chain fatty acid changes in septic mice and fecal microbiota transplanted mice , we found that GM imbalance exists early in sepsis. FMT can improve morbidity and effectively reduce mortality in septic mice. After the fecal bacteria were transplanted, the abundance and diversity of the gut flora were restored, and the microbial characteristics of the donors changed. FMT can effectively reduce epithelial cell apoptosis, improve the composition of the mucus layer, upregulate the expression of tight junction proteins, and reduce intestinal permeability and the inflammatory response, thus protecting the intestinal barrier function. After FMT, Lachnospiraceae contributes the most to intestinal protection through enhancement of the L-lysine fermentation pathway, resulting in the production of acetate and butanoate, and may be the key bacteria for short-chain fatty acid metabolism and FMT success.

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The intestinal microenvironment in sepsis

Cited by 133 publications

References 109 publications

Surviving sepsis campaign: research priorities for sepsis and septic shock

Surviving sepsis campaign: research priorities for sepsis and septic shock

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

Fecal microbiota transplantation reconstructs the gut microbiota of septic mice and protects the intestinal mucosal barrier

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