Redefining the gut as the motor of critical illness

Mittal, Rohit; Coopersmith, Craig M.

doi:10.1016/j.molmed.2013.08.004

Cited by 271 publications

(211 citation statements)

References 96 publications

(114 reference statements)

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“…Our studies with mice that do not express TSLPR in IECs (Vill-Cre 1 ; Tslpr fl/fl mice) indicate that TSLP-TSLPR interactions indeed contribute to reduced morbidity and inflammation after moderate CLP. These observations seem to support the hypothesis that a loss of balance between the gut's epithelium, the immune system, and the endogenous microflora can lead to multiple organ dysfunction during sepsis (43). Studies are underway to dissect the mechanisms behind these modulatory effects of TSLP on IECs in sepsis.…”

Section: Discussionsupporting

confidence: 58%

Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis

Piliponsky

Lahiri

Truong

et al. 2016

Am J Respir Cell Mol Biol

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The mechanisms that contribute to homeostasis of the immune system in sepsis are largely unknown. One study suggests a potential detrimental role for thymic stromal lymphopoietin (TSLP) in sepsis; however, the immune-regulatory effects of TSLP on myeloid cells within the intestinal microenvironment suggest the contrary. Our objective was to clarify TSLP's role in sepsis. Cecal ligation and puncture was performed in mice with total or myeloid-specific deficiency in the TSLP receptor (TSLPR). Survival was monitored closely, peritoneal fluids and plasma were analyzed for markers of inflammation, and myeloid cell numbers and their ability to produce inflammatory mediators was determined. The interaction of TSLP with TSLPR in myeloid cells contributed to mouse survival after septic peritonitis. Mice with TSLPR deficiency in myeloid cells displayed excessive local and systemic inflammation levels (e.g., increased inflammatory cell and cytokine levels) relative to control mice. Moreover, hepatic injury was exacerbated in mice with TSLPR deficiency in their myeloid cells. However, the enhanced inflammatory response did not affect the ability of these mice to clear bacteria. Resident neutrophils and macrophages from septic mice with TSLPR deficiency exhibited an increased ability to produce proinflammatory cytokines. Collectively, our findings suggest that the effects of TSLP on myeloid cells are crucial in reducing the multiple organ failure that is associated with systemic inflammation, which highlights the significance of this cytokine in modulating the host response to infection and in reducing the risks of sepsis development.Keywords: sepsis; inflammation; myeloid cells; thymic stromal lymphopoietin Clinical RelevanceInfections can lead to sepsis, a complex, incompletely understood, and often fatal disorder that is considered to reflect dysregulation of the host immune response. Early diagnosis and treatment of sepsis is critical to prevent the cascade of the complex processes that lead to severe sepsis and septic shock. However, the best available diagnostic and treatment strategies have failed, which underscores the need for a better understanding of the pathophysiological mechanisms regulating the inflammatory host response during sepsis. Our study provides evidence that thymic stromal lymphopoietin is part of a mechanism that is initiated by the host to restore homeostasis during the inflammatory response against bacterial infections to reduce the risk of sepsis development.

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Section: Discussionsupporting

confidence: 58%

Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis

Piliponsky

Lahiri

Truong

et al. 2016

Am J Respir Cell Mol Biol

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“…Importantly, a diverse microbial community resists pathogen overgrowth and helps modulate both innate and adaptive immune responses (21). It is possible that dysbiosis may increase the likelihood of systemic inflammatory response syndrome and subsequent organ dysfunction by up-regulating the host inflammatory response (39,40). Inflammasomes, which trigger the inflammatory cascade, are activated after gut microbial perturbations and are followed by a rapid sepsis-like death in the animal model (41).…”

Section: Discussionmentioning

confidence: 99%

Hospitalization Type and Subsequent Severe Sepsis

Prescott

Dickson²,

Rogers

et al. 2015

Am J Respir Crit Care Med

144

102

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Rationale: Hospitalization is associated with microbiome perturbation (dysbiosis), and this perturbation is more severe in patients treated with antimicrobials.Objectives: To evaluate whether hospitalizations known to be associated with periods of microbiome perturbation are associated with increased risk of severe sepsis after hospital discharge.Methods: We studied participants in the U.S. Health and Retirement Study with linked Medicare claims (1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010). We measured whether three hospitalization types associated with increasing severity of probable dysbiosis (non-infection-related hospitalization, infection-related hospitalization, and hospitalization with Clostridium difficile infection [CDI]) were associated with increasing risk for severe sepsis in the 90 days after hospital discharge. We used two study designs: the first was a longitudinal design with between-person comparisons and the second was a self-controlled case series design using within-person comparison.Measurements and Main Results: We identified 43,095 hospitalizations among 10,996 Health and Retirement Study-Medicare participants. In the 90 days following non-infectionrelated hospitalization, infection-related hospitalization, and hospitalization with CDI, adjusted probabilities of subsequent admission for severe sepsis were 4.1% (95% confidence interval [CI], 3.8-4.4%), 7.1% (95% CI, 6.6-7.6%), and 10.7% (95% CI, 7.7-13.8%), respectively. The incidence rate ratio (IRR) of severe sepsis was 3.3-fold greater during the 90 days after hospitalizations than during other observation periods. The IRR was 30% greater after an infectionrelated hospitalization versus a non-infection-related hospitalization. The IRR was 70% greater after a hospitalization with CDI than an infection-related hospitalization without CDI.Conclusions: There is a strong dose-response relationship between events known to result in dysbiosis and subsequent severe sepsis hospitalization that is not present for rehospitalization for nonsepsis diagnoses.

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“…The gut normally plays an important role as a barrier against potentially harmful bacteria in the lumen of the intestine and relies on an integrated system of epithelial cells and immune cells to prevent gut inflammation (41). After injury, a combination of epithelial barrier failure and immune cell activation and mobilization serves as the "motor" for the SIRS response that leads to distant organ injury (34).…”

mentioning

confidence: 99%

Neuroenteric axis modulates the balance of regulatory T cells and T-helper 17 cells in the mesenteric lymph node following trauma/hemorrhagic shock

Coimbra

Langness

Eliceiri

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Morishita K, Coimbra R, Langness S, Eliceiri BP, Costantini TW. Neuroenteric axis modulates the balance of regulatory T cells and T-helper 17 cells in the mesenteric lymph node following trauma/hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol 309: G202-G208, 2015. First published June 4, 2015 doi:10.1152 doi:10. /ajpgi.00097.2015 ϩ dendritic cells (DCs) continuously migrate from the intestine to the mesenteric lymph nodes (MLNs) and maintain tolerance by driving the development of regulatory T cells (Treg) in the gut. The relative expression of Treg and T-helper 17 (Th17) cells determines the balance between tolerance and immunity in the gut. We hypothesized that trauma/hemorrhagic shock (T/HS) would decrease the CD103 ϩ DC population in the mesenteric lymph and alter the Treg-to-Th17 ratio in the MLN. We further hypothesized that vagus nerve stimulation (VNS) would promote tolerance to inflammation by increasing the Treg-to-Th17 ratio in the MLN after injury. Male rats were assigned to sham shock (SS), trauma/sham shock (T/SS), or T/HS. T/HS was induced by laparotomy and 60 min of HS (blood pressure 35 mmHg) followed by fluid resuscitation. A separate cohort of animals underwent cervical VNS after the HS phase. MLN samples were collected 24 h after resuscitation. The CD103 ϩ DC population and Treg-to-Th17 cell ratio in the MLN were decreased after T/HS compared with SS and T/SS, suggesting a shift to an inflammatory response. VNS prevented the T/HS-induced decrease in the CD103 ϩ DC population and increased the Treg-to-Th17 ratio compared with T/HS alone. VNS alters the gut inflammatory response to injury by modulating the Treg-Th17 cell balance in the MLN. VNS promotes tolerance to inflammation in the gut, further supporting its ability to modulate the inflammatory set point and alter the response to injury. vagus nerve; gut inflammation; mesenteric lymph; systemic inflammatory response

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Redefining the gut as the motor of critical illness

Cited by 271 publications

References 96 publications

Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis

Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis

Hospitalization Type and Subsequent Severe Sepsis

Neuroenteric axis modulates the balance of regulatory T cells and T-helper 17 cells in the mesenteric lymph node following trauma/hemorrhagic shock

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