C URRENTO PINION Gut microbiota and host defense in critical illnessMax C.Jacobs a,Bastiaan W.Haak a,Floor Hugenholtz a,and W.Joost Wiersinga a,bPurpose of reviewThe review aims to discuss emerging evidence in the field of microbiome-dependent roles in host defenseduring critical illness with a focus on lung,kidney,and brain inflammation.Recent findingsThe gut microbiota of critical ill patients is characterized by lower diversity,lower abundances of keycommensal genera,and in some cases overgrowth by one bacterial genera,a state otherwise known asdysbiosis.Increasing evidence suggests that microbiota-derived components can reach the circulatorysystem from the gut and modulate immune homeostasis.Dysbiosis might have greater consequences for thecritically ill than previously imagined and could contribute to poor outcome.Preclinical studies suggest thatimpaired communication across the gut–organ axes is associated with brain,lung–and kidney failure.SummaryIn health,a diverse microbiome might enhance host defense,while during critical illness,the dysbioticmicrobiome might contribute to comorbidity and organ dysfunction.Future research should be aimed atfurther establishing the causes and consequences of dysbiosis seen in the critically ill,which will provideperspective for developing new strategies of intervention.Keywordscritically ill,gut microbiota,host defense,innate immunity,ICUINTRODUCTIONThe gut microbiota refers to the community of microbes that reside in our gastrointestinal tract, with whom we have developed a symbiotic relation-ship over the course of millions of years.These microbes,as we have learned in recent times,con-tribute to various physiological processes that are crucial for human homeostasis and health[1].These observations have guided the current paradigm that the gut microbiome could in fact be perceived as the latest discovered human organ.Critically ill patients in the ICU could potentially benefit from more insight into this nascent area of research,as virtually all of these patients will have a perturbed micro-biome.On any given day almost three-quarter of the patients treated on the ICU will receive antibiotics [2].Although antibiotics are administered to fight pathogens and/or to try to decrease the occurrence of nosocomial infections,we are becoming increas-ingly aware that this strategy may simultaneously open the door to a new and uncharted problem:the coinciding depletion of commensal gut bacteria[3].Despite the heterogeneity of disease states among critically ill patients,it has become apparent that ICU treatment is associated with an extreme and long-lasting shift in microbiome composition,with potentially negative impact on both short and long-term outcome[4&].Unfortunately,clinical research assessing therapeutic modalities that could strengthen the microbiome of patients on the ICU are sparse.This is probably in part explained be a clear lack of mechanistic insights on how a healthy and stable microbiome confers protection against (opportunistic)pathogens as well as organ damage.The review aims to discuss emerging evidence in the field of microbiome-dependent roles in host defense during critical illness with a focus on lung, kidney,and brain inflammation.Ultimately,we aim to breach the gap on how these insights could be used in the development of novel microbiome-based diagnostics and treatment modalities that a Center for Experimental and Molecular Medicine and b Division of Infectious Diseases,Department of Medicine,Academic Medical Center, University of Amsterdam,Amsterdam,the Netherlands Correspondence to Max C.Jacobs,Center for Experimental and Mol-ecular Medicine,Academic Medical Center,University of Amsterdam, Meibergdreef9,Room F0–117,1105AZ Amsterdam,the Netherlands. Tel:+31205665247;e-mail:m.c.jacobs@amc.uva.nl;w.j.wiersinga@amc.uva.nlCurr Opin Crit Care2017,23:000–000DOI:10.1097/MCC.0000000000000424REVIEWcould potentially enhance host defense in critically ill patients.FUNCTION OF THE GUT MICROBIOME: BASICSThe intestinal microbiota are hard to cultivate and study in the laboratory;so far up to77%of the bacteria in the gut have been cultivated[5].How-ever,the fast development of novel molecular tech-niques in the last few decades has considerably increased our insights into this complex ecosystem [6].In the large intestine the phyla Bacteroidetes and Firmicutes dominate and Actinobacteria,Pro-teobacteria,and Verrucomicrobia are important and lower abundance phyla[7].These gut microbiota degrade dietary plant polysaccharides and–in a lesser degree–proteins,which are fermented into a wide range of metabolites.The main end products of fermentation are short-chain fatty acids(SCFA), such as butyrate,acetate,and propionate.The SCFA profiles produced by members of the two dominant phyla differ,with a tendency for butyrate pro-duction by members of the Firmicutes phyla,while propionate production tends to be dominated by Bacteroidetes[8].SCFA play an essential role in the maintenance of colonic integrity and metabolism, as it has been shown that butyrate serves as the main energy source for the colonocytes[9,10].The optimal composition of a healthy microbiome is under debate[11];however,general features have been noted.Diversity indices need to be relatively high,where bacterial groups of Firmicutes,Bacter-oidetes,and Actinobacteria provide the majority of the richness(that is the number of different bacterial species observed;see Fig.1for an overview of the major taxonomic groups).Proteobacteria are usually also present,albeit in low numbers and preferably low richness.The above-mentioned features need to be in balance,and when this balance shifts we speak of a disturbed homeostasis or dysbiosis.Of special interest is the relationship of the gut microbiome in the host defense against specific pathogens,the role of which we are only just begin-ning to uncover.Within the gut,an intact micro-biome is able to maintain stability and homeostasis through numerous mechanisms.First,our commen-sals are able to directly outcompete intestinal patho-gens for available nutrients,or even kill potential invaders through the production of defensins and production of signaling(quorum sensing)mol-ecules[12&].Additionally,the microbiota are potent inducers of the immune system,which in turn target potential invaders in the gut.Elimination of these commensal bacteria by external factors,for example,antibiotics,is therefore hypothesized to lead to overgrowth of opportunistic pathogens[13]. THE GUT MICROBIOME DYNAMICS IN CRITICALLY ILL PATIENTSCritically ill patients admitted to the ICU have severely altered and unstable microbiomes [4&,14&&,15,16,17&&].However,so far,the number and types(e.g.,septic,nonseptic,location of sepsis) of ICU patients in clinical studies that investigated the microbiome have been limited.When compared to healthy controls,the gut microbiome of patients with sepsis is characterized by lower diversity,lower abundances of key commensal genera(such asKEY POINTSCritically ill patients have a severely perturbed gut microbiome.This is characterized by a loss of diversity, and susceptibility to overgrowth ofopportunistic pathogens.Dysbiosis can have a myriad of effects,which should be further investigated in critically ill patients.In general,it is suggested that the microbiome in a healthy setting might enhance host defense,whereas during illness,the dysbiotic gut microbiome might contribute to poor outcome.Impaired communication across the gut organ axes has been associated with organ dysfunction.It is warranted to translate the enormous amount of associative findings into causative mechanisms to better understand the immunomodulatory role of the microbiome in critical illness.The gut microbiome remains a high potential future therapeutic or diagnostic target.However,current evidence into microbiota-targeted therapies in critical illness remains sparse andambiguous.FIGURE1.Schematic overview of the microbiome gradient between homeostasis in healthy people and dysbiosis in critical ill.Metabolic supportFaecalibacterium,Blautia,Ruminococcus),and some-times overgrowth(over50%relative abundance)by one genera,like Clostridium difficile,Staphylococcus spp.,Escherichia spp.,Shigella spp.,Salmonella spp., and Enterococcus spp.[4&,15,16,14&&].The occurrence of the last feature–overgrowth by a single bacterial species–is only observed in roughly a third of cases, but does seem to increase with the time a patient stays on the ICU[14&&,15].Explanations for gut micro-biome dysbiosis in critically ill patients include(but are not limited to)the use of(par)enteral feeding, gastric acid inhibitory drugs,and antibiotics[18&]. Additionally,mechanical ventilation was recently shown to be an influencer of microbiome dynamics and,most probably as a result,the susceptibility to nosocomial infection[19&].DISTANT EFFECT OF THE GUT MICROBIOME DURING CRITICAL ILLNESS: THE CONCEPT OF THE GUT–ORGANAXESCurrently,it is hypothesized that microbiota-derived components,such as pathogen-associated molecular patterns and metabolites that derive from the gut can reach the circulatory system and interact at the systemic level to influence immune homeo-stasis[20].Murine models exerting manipulated gut microbiomes through breeding in sterile environ-ments(i.e.,germ-free mice),supplementation of antibiotics,or altered diets have been instrumental in obtaining these insights.Germ-free mice exhibit decreased numbers of immune cells residing in bone marrow,which was explained to be resulting from aberrant toll-like receptor signaling[21].Further-more,hematopoietic abnormalities seen in micro-biome depleted or germ-free mice models include aberrations in granulopoiesis and myelopoiesis as well as T-cell development,which,in turn,have been linked to deteriorated immunity against viruses,bacteria,and fungi[22–27].Diet is key in shaping the ecosystem of the gut microbiome and important in host metabolism[28,29&].Fiber-rich diets have demonstrated positive effects in intesti-nal barrier integrity,amelioration of intestinal inflammatory disease,and even protection against invading pathogens and sepsis in preclinical models [30–32].Of note,nondigestible dietary fiber intake is correlated to levels of circulating SCFA,which are implicated as important factors in pathogenesis of various inflammatory diseases(see review[33&]). Furthermore,in a murine study investigating the association between obesity and susceptibility to asthma,it has been suggested that a high-fat diet might result in impaired immune activation of air-way dendritic and regulatory T cells[34].Despite the mounting evidence emerging from preclinical models on the role of the gut microbiome in the host defense against inflammation,surpris-ingly little studies have been conducted in humans. One comprehensive study in a cohort of500healthy adults of whom fecal and blood samples were col-lected indicated that variations in cytokines responses,that is,interleukin1b,interleukin6, interleukin17,and interleukin22,tumor necrosis factor a and interferon g,are to some extent linked to specific gut microbiome organisms and sub-sequent functions[35&&].The authors suggested that host defense modulation most likely is orchestrated in part through specific gut microbiome-derived metabolites.In line,a small study conducted in 12healthy human adult study participants who were treated for1week with broad-spectrum anti-biotics,showed that gut microbiome depletion resulted in an impaired production of tumor necrosis factor a,in peripheral blood mononuclear cells,and interleukin6and interleukin1b,in whole blood,after ex-vivo lipopolysaccharide stimulation [36].Cytokine responses returned to normal6weeks after cessation of the antibiotics.However,a follow-up intervention trial in which healthy human study participants were pretreated with antibiotics prior to the administration of lipopolysaccharide intrave-nously showed that gut microbiota disruption by broad-spectrum antibiotics does not affect systemic innate immune responses during human endotox-emia[37&].These novel insights on the role of the microbiome in systemic immunity are increasingly being used in disease research,resulting in the development of theories of gut microbiome to organ interactions,popularly coined gut–organ axes. Gut–lung axisThe gut–lung axis refers to the crosstalk that is hypothesized to take place between the gut micro-biota and the lungs which might be important in diseases ranging from allergic asthma to lung infec-tion(reviewed[38&]).Evidence that the gut and the lung were closer connected than was initially thought emerged over20years ago from studies in rat models of trauma and hemorrhagic shock (THS)[39].It was demonstrated that during THS, gut-derived compounds translocate through mesen-teric lymph and cause distal lung injury[40].This phenotype could be rescued by ligation of the thora-cic lymph duct and,furthermore,it was shown that mesenteric lymph from postshock rats transferred into naı¨ve animals again provokes distal organ injury[41,42].Interestingly,vagal nerve stimulation was shown to decrease gut barrier permeability and abrogates THS-induced distal organ injury[43]. Gut microbiota and host defense in critical illness Jacobs et al.FIGURE 2.Schematic overview of gut microbiome states and their proposed effect on systemic host defense in critical illness;an example of the gut–lung axis.(a)The healthy gut microbiome resides in the intestinal lumen and comprises a diverse set of commensal bacteria that interact with one another and the mensal bacteria can metabolize dietary fiber andproduce short-chain fatty acids (SCFA)which provide an important energy source for intestinal epithelial cells.Besides,SCFA,pathogen-associated molecular patterns and bacteria themselves are believed to be translocated into the lamina propria andMetabolic supportConversely,a protective role of the gut microbiome along the gut–lung axis was suggested in several murine models of bacterial pneumonia and sepsis. Gut microbiome dysbiosis,caused by antibiotic administration,resulted in impaired immune acti-vation and increased mortality during murine Pneu-mococcal pneumonia[44].Additionally,it was demonstrated that specific absence of segmented filamentous bacteria in the gut of mice led to impaired Th17mucosal immunity and suscepti-bility to Staphylococcus aureus pneumonia[45]. Furthermore,recent work has described a crucial window of early exposure to and colonization with intestinal commensal bacteria in the effective devel-opment of innate lymphoid cell-mediated immun-ity against bacterial pneumonia in neonatal mice [46].Finally,translocation of gut bacteria along the gut–lung axis was recently reported in human study participants.[47&&].Sequencing provided evidence of lung microbiome enrichment with gut-associated bacteria in both mice suffering of experimental sepsis and human patients with acute respiratory distress syndrome,but not healthy controls.Gut–brain axisRecent research has shown extensive crosstalk between the gut microbiome and the brain,that is, through neuropeptides or endocrine,immune,and nerve signaling[48,49],which have resulted in the suggestion that the gut microbiome might play a role in cognitive function and behavior[50].Also,in critically ill patients this so-called gut–brain axis can be of importance.Mouse models showed that microbiota depletion could ameliorate outcome after ischemic brain injury,which was attributed to defec-tive trafficking of specific types of T cells to the ischemic brain area[51].Surprisingly,a similar study in mice showed that acute brain injury itself resulted in gut microbiome dysbiosis,intestinal barrier dys-function,and reduced intestinal motility,which underscores the notion that gut–brain communi-cation is bidirectional[52&].Of interest,(secondary) infections,mainly pneumonia,are a common medical complication and a leading cause of post-stroke death not directly attributable to stroke itself [53].However,conventional cultures of sputum derived from poststroke patients with lung infection samples are often negative suggesting that anaerobic bacteria might play a role.This,in turn,suggests that secondary pulmonary infection in poststroke patients could very well be gut derived.In correspondence,it was reported that gut-derived bacteria to comprise 70%of cultures samples taken from poststroke patients with secondary lung infection[54&&].These results were confirmed and expanded in mice exper-iments.Therein,it was shown that stroke leads to impaired intestinal barrier function,which could be causative for gut commensals to spread systemically and cause infection.Excitingly,the b-adrenergic receptor blocker propranolol could improve barrier function,which coincided with marked reduction of poststroke secondary infection[54&&].Gut–kidney axisThe overall incidence of acute kidney injury(AKI)in ICU patients ranges from20to50%[55].Recent murine studies have implicated a role for the gut microbiome and its derived metabolites in the out-come of this condition.It was shown that therapy with the SCFA’s acetate,propionate,and butyrate, was protective in an ischemia/reperfusion model of AKI injury[56&].Interestingly,another study using a similar model showed that gut microbiome depletion before induction resulted in protection against renal dysfunction,damage,and inflam-mation[57],suggestive of a deleterious effect of ‘normal’gut microbiome during AKI.For an overview of the proposed role of various gut microbiome states in immune priming and susceptibility to(secondary)infections,see Fig.2. CONCLUSION:THE ROAD AHEADAlthough the knowledge of the role of the gut microbiome in critical illness is increasing rapidly, numerous questions remain to be answered.One ofcirculatory systems were they contribute to priming of the immune system,(b)A singular course of antibiotics(depicted by the dark circles showing a white(a)may be prescribed to fight infections.Sensitive commensal bacteria can be depleted leading to reduction in diversity.This results in less effective production of SCFA,which may contribute to decreased local epithelial cell condition and reduced translocation and immune priming.Reduced immune priming may cause susceptibility to secondary infections(c)In a scenario were infections are severe or recurrent,repeated,or broad-spectrum antibiotics treatment can result in marked reduction in commensal bacteria and dysbiosis.This can lead to overgrowth of(opportunistic)pathogens that can lead to local infections and immune problems.Impaired or absent production of SCFA can contribute to intestinal epithelium damage and reduced barrier function,and impaired immune priming.Translocation of pathogenic bacteria through leaky barrier may contribute to secondary infections.(c)The poststroke gut microbiome becomes(e.g.,with concomitant antibiotics treatment)dysbiotic.Also,stroke can lead to decreased barrier function.In this condition commensal bacteria may translocate in systemic circulation,turn pathogenic and cause secondary infections.Gut microbiota and host defense in critical illness Jacobs et al.the most pressing unanswered question is what comprises a healthy gut microbiome,and to what extent is microbiota composition generalizable on a population wide scale?To begin to answer these questions a multidisciplinary scientific approach is required,as it entails wide ranges of fundamental and medical biology.Furthermore,it will be of particular interest to learn which gut microbiome species and metabolites account for the hypothes-ized effects on host health.What can be stated is that in a healthy situation at least two factors appear to be present,that is,a diverse,symbiotic gut microbiome and an intact intestinal barrier.We have discussed research wherein it was shown that environmental factors, for example,diet and oral antibiotics,as well as critical disease itself(or its treatment)can influence either one or both of these factors,which in turn might contribute to an unfavorable outcome.Para-doxically,when intestinal barrier function is com-promised,which is seen in sepsis or after stroke,an otherwise‘healthy’microbiome might be account-able for medical complications such as secondary infections.Overall it appears that–at least for now –no simple black and white answers can be formu-lated with respect to the gut microbiome’s role in the host defense during critical illness.However, despite reasonable gaps in our knowledge base,cur-rent therapeutic developments based on the manip-ulation of gut microbiomes are showing great potential.The success story of the usage of fecal microbiota transplantation to fight recurrent C.dif-ficile infection–also in the ICU setting–serves as a leading example[58&].Other therapeutic develop-ments were reviewed here recently[59&].Now that the field moves from association studies toward establishing causation it will be of importance to see where these scientific endeavors will bring us in the near future.Particularly,whether we will be able to learn from fundamental studies into microbiome–host interaction and(pre)clinical studies to the point that they initiate the development of novel strategies to manipulate gut microbiomes of patient to ameli-orate clinical outcome of critically ill patients suffer-ing from sepsis or brain injury.Overall,a concept emerges that the gut microbiome makes for a high potential target for intervention to improve clinical outcome.Future research should be aimed at estab-lishing causation in gut microbiome dysbiosis seen in critically ill,which will provide perspective for devel-oping new strategies of intervention. AcknowledgementsWe would like to thank our colleagues of the Marie Curie Innovative Training Network(MC-ITN)European Sepsis Academy for fruitful discussions leading to this article.Financial support and sponsorshipThe work was supported by the Netherlands Organiz-ation for Scientific Research(NWO).Conflicts of interestThere are no conflicts of interest.REFERENCES AND RECOMMENDED READINGPapers of particular interest,published within the annual period of review,have been highlighted as:&of special interest&&of outstanding interest1.Sekirov I,Russell SL,Antunes LCM,Finlay BB.Gut microbiota in health anddisease.Physiol Rev2010;90:859–904.2.Vincent J,Marshall J,Anzueto A,et al.,EPIC II group of investigators.International study of the prevalence and outcomes of infection in intensive care units.JAMA2009;302:2323–2329.3.Blaser M.Antibiotic overuse:stop the killing of beneficial bacteria.Nature2011;476:393–394.4.&Wischmeyer PE,McDonald D,Knight R.Role of the microbiome,probiotics, and‘dysbiosis therapy’in critical illness.Curr Opin Crit Care2016;22:347–353.Excellent review on current status of microbiota targeted therapies,such as novel probiotics and fecal transplants.gier JC,Khelaifia S,Alou MT,et al.Culture of previously unculturedmembers of the human gut microbiota by culturomics.Nat Microbiol2016;1:16203.6.Rajilic-Stojanovic M,Smidt H,de Vos WM.Diversity of the humangastrointestinal tract microbiota revisited.Environ Microbiol2007;9:2125–2136.7.Rajilic-Stojanovic M,de Vos WM.Thefirst1000cultured species ofthe human gastrointestinal microbiota.FEMS Microbiol Rev2014;38:996–1047.8.Mun˜oz-Tamayo R,Laroche B,Walter E´,et al.Kinetic modelling of lactateutilization and butyrate production by key human colonic bacterial species.FEMS Microbiol Ecol2011;76:615–624.9.Cook SI,Sellin JH.Review article:short chain fatty acids in health anddisease.Aliment Pharmacol Ther1998;12:499–507.10.Morrison DJ,Preston T.Formation of short chain fatty acids by the gutmicrobiota and their impact on human metabolism.Gut Microbes2016;7:189–200.11.Zhernakova A,Kurilshikov A,Bonder MJ,et al.,LifeLines cohort study.Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity.Science2016;352:565–569.12.&Klingensmith NJ,Coopersmith CM.The gut as the motor of multiple organ dysfunction in critical illness.Crit Care Clin2016;32:203–212.Excellent overview of the role of the gut and gut microbiota in multiorgan failure and critical illness.13.Pamer EG.Resurrecting the intestinal microbiota to combat antibiotic-resis-tant pathogens.Science2016;352:535–538.14.&&Lankelma JM,van Vught LA,Belzer C,et al.Critically ill patients demonstrate large interpersonal variation in intestinal microbiota dysregulation:a pilot study.Intensive Care Med2017;43:59–68.Recent pilot study to investigate the intestinal microbiota in critical ill patients,with a special focus to septic patients.Here,critical ill patients had less or no abundances of butyrate-producing genera in their intestinal microbiota compared with human volunteers.15.Zaborin A,Smith D,Garfield K,et al.Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during pro-longed critical illness.MBio2014;5:e01361–e1414.16.Ojima M,Motooka D,Shimizu K,et al.Metagenomic analysis reveals dynamicchanges of whole gut microbiota in the acute phase of intensive care unit patients.Dig Dis Sci2016;61:1628–1634.17.&&McDonald D,Ackermann G,Khailova L,et al.Extreme dysbiosis of the microbiome in critical illness.mSphere2016;1:.doi:10.1128/mSphere.00199-16.Editor.First study to sample fecal,oral,and skin for microbiota analysis in critical ill patients admitted at the ICU within2days and at10days or discharge.Indicated increasing microbiota dysbiosis in the patients during their stay,with health promoting commensal disappearing and overgrowth of pathogens.18.&Haak BW,Wiersinga WJ.The role of the gut microbiota in ncet Gastroentrol Hepatol2017;2:135–143.Excellent overview of the latest studies on the role of the intestinal microbiota in (acquiring)sepsis.Metabolic support19. &Zakharkina T,Martin-loeches I,Matamoros S,et al.The dynamics of the pulmonary microbiome during mechanical ventilation in the intensive care unit and the association with occurrence of pneumonia.Thorax2017.Interesting study in ICU patients showing the effect of mechanical ventilation on the respiratory microbiome.20.Levy M,Blacher E,Elinav E.Microbiome,metabolites and host immunity.CurrOpin Microbiol2016;35:8–15.21.Balmer ML,Schurch CM,Saito Y,et al.Microbiota-derived compounds drivesteady-state granulopoiesis via MyD88/TICAM signaling.J Immunol2014;193:5273–5283.22.Josefsdottir KS,Baldridge MT,Kadmon CS,King KY.Antibiotics impairmurine hematopoiesis by depleting intestinal microbiota.Blood2016;129:729–739.23.Khosravi A,Ya´n˜ez A,Price JG,et al.Gut microbiota promote hematopoiesis tocontrol bacterial infection.Cell Host Microbe2014;15:374–381.24.Trompette A,Gollwitzer ES,Yadava K,et al.Gut microbiota metabolism ofdietaryfiber influences allergic airway disease and hematopoiesis.Nat Med 2014;20:159–166.25.Zhang D,Chen G,Manwani D,et al.Neutrophil ageing is regulated by themicrobiome.Nature2015;525:528–532.26.Abt MC,Osborne LC,Monticelli LA,et mensal bacteria calibrate theactivation threshold of innate antiviral immunity.Immunity2012;37:158–170.27.McAleer JP,Nguyen NL,Chen K,et al.Pulmonary Th17antifungal immunity isregulated by the gut microbiome.J Immunol2016;197:97–107.28.Sonnenburg ED,Smits SA,Tikhonov M,et al.Diet-induced extinctions in thegut microbiota compound over generations.Nature2016;529:212–215.29. &Sonnenburg JL,Ba¨ckhed F.Diet-microbiota interactions as moderators of human metabolism.Nature2016;535:56–64.Excellent updated review on how the diet,microbiota,and its metabolites interact with the host and play a crucial role in the host metabolism.30.Monk JM,Lepp D,Wu W,et al.Chickpea-supplemented diet alters the gutmicrobiome and enhances gut barrier integrity in C57Bl/6male mice.J Funct Foods2017;In press.31.Morowitz MJ,Di Caro V,Pang D,et al.Dietary supplementation with non-fermentablefiber alters the gut microbiota and confers protection in murine models of sepsis.Crit Care Med2017;45:e516–e523.32.Monk JM,Lepp D,Zhang CP,et al.Diets enriched with cranberry beans alterthe microbiota and mitigate colitis severity and associated inflammation.J Nutr Biochem2016;28:129–139.33. &Richards JL,Yap YA,McLeod KH,et al.Dietary metabolites and the gut microbiota:an alternative approach to control inflammatory and autoimmune diseases.Clin Transl Immunol2016;5:e82–e182.The review summarizes how diet,microbiota and SCFAs can modulate the progression of inflammatory diseases and autoimmunity.34.Pizzolla A,Oh DY,Luong S,Prickett SR.High fat diet inhibits dendritic cell andT cell response to allergens but does not impair inhalational respiratory tolerance.PLoS One2016;11:1–18.35. &&Schirmer M,Smeekens SP,Vlamakis H,et al.Linking the human gut microbiome to inflammatory cytokine production capacity.Cell2016; 167:1125–1136.Human cohort study showing that microbiome-dependent metabolic pathways drive distinct immune responses in healthy volunteers.nkelma JM,Belzer C,Hoogendijk AJ,et al.Antibiotic-induced gut micro-biota disruption decreases TNF-a release by mononuclear cells in healthy adults.Clin Transl Gastroenterol2016;7:e186.37. &Lankelma JM,Cranendonk DR,Belzer C,et al.Antibiotic-induced gut micro-biota disruption during human endotoxemia:a randomised controlled study. Gut2016;1–8.Epub ahead of print.The study indicated that the systemic innate immune responses are not affected by broad spectrum antibiotics in healthy volunteers.38. &Budden KF,Gellatly SL,Wood DL,et al.Emerging pathogenic links between microbiota and the gut-lung axis.Nat Rev Microbiol2017;15:55–63.Excellent review on the link of the microbiota in the gut–lung axis.39.Magnotti LJ,Upperman JS,Xu DZ,et al.Gut-derived mesenteric lymph but notportal blood increases endothelial cell permeability and promotes lung injury after hemorrhagic shock.Ann Surg1998;228:518–527.40.Deitch EA,Xu DZ,Lu Q.Gut lymph hypothesis of early shock and trauma-induced multiple organ dysfunction syndrome:a new look at gut origin sepsis.J Organ Dysfunct2006;2:70–79.41.Wohlauer MV,Moore EE,Harr J,et al.Cross-transfusion of postshockmesenteric lymph provokes acute lung injury.J Surg Res2011;170:314–318.42.Reino DC,Pisarenko V,Palange D,et al.Trauma Hemorrhagic shock-inducedlung injury involves a Gut-Lymph-induced TLR4pathway in mice.PLoS One 2011;6:e14829.43.Levy G,Fishman JE,Xu D,et al.Vagal nerve stimulation modulates gut injuryand lung permeability in trauma-hemorrhagic shock.J Trauma Acute Care Surg2012;73:338–342.44.Schuijt TJ,Lankelma JM,Scicluna BP,et al.The gut microbiota plays aprotective role in the host defence against pneumococcal pneumonia.Gut 2015;65:575–583.45.Gauguet S,Ortona SD,Ahnger-pier K,et al.Intestinal microbiota of miceinfluences resistance to Staphylococcus aureus pneumonia.Infect Immun 2015;83:4003–4014.46.Gray J,Oehrle K,Worthen G,et al.Intestinal commensal bacteria mediatelung mucosal immunity and promote resistance of newborn mice to infection.Sci Transl Med2017;9:1–14.47.&&Dickson RP,Singer BH,Newstead MW,et al.Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome.Nat Microbiol2016;1:16113.The study reports evidence that the lung microbiome is enriched with intestinal microbiota both in a murine model of sepsis and in humans with acute respiratory distress syndrome.The authors demonstrate that these diseases have potentially a shared mechanism of pathogenesis.48.Holzer P,Farzi A.Neuropeptides and the microbiota-gut-brain axis.Adv ExpMed Biol2014;817:195–219.49.Carabotti M,Scirocco A,Maselli MA,Severi C.The gut-brain axis:Interactionsbetween enteric microbiota,central and enteric nervous systems.Ann Gas-troenterol2015;28:203–209.50.Foster JA,McVey Neufeld KA.Gut-brain axis:how the microbiome influencesanxiety and depression.Trends Neurosci2013;36:305–312.51.Benakis C,Brea D,Caballero S,et mensal microbiota affectsischemic stroke outcome by regulating intestinal gd T cells.Nat Med 2016;22:516–523.52.&Singh XV,Roth XS,Llovera G,et al.Microbiota dysbiosis controls the neuroinflammatory response after stroke.J Neurosci2016;36:7428–7440.Demonstration of a bidirectional association between the gut microbiome and the brain in a model of stroke.53.Chamorro A´,Urra X,Planas AM.Infection after acute ischemic stroke:amanifestation of brain-induced immunodepression.Stroke2007;38:1097–1103.54.&&Stanley D,Mason LJ,Mackin KE,et al.Translocation and dissemination of commensal bacteria in poststroke infection.Nat Med2016;22:1277–1284.A comprehensive study showing evidence that the gut microbiome might be animportant source of secondary infections after stroke.55.Case J,Khan S,Khalid R,Khan A.Epidemiology of acute kidney injury in theintensive care unit.Crit Care Res Pract2013;2013:479730.56.&Andrade-Oliveira V,Amano MT,Correa-Costa M,et al.Gut bacteria products prevent AKI induced by ischemia-reperfusion.J Am Soc Nephrol2015;26:1877–1888.Interesting study suggesting at a therapeutic role for SCFAs in a murine model of AKI.57.Emal D,Rampanelli E,Stroo I,et al.Depletion of gut microbiota protectsagainst renal ischemia-reperfusion injury.J Am Soc Nephrol2016;28:1–12.58.&van Nood E,Vrieze A,Nieuwdorp M,et al.Duodenal infusion of donor feces for recurrent Clostridium difficile.N Engl J Med2013;368:407–415.Clinical trial showing fecal microbiota transplants benificial in patients with recurrent C.difficile infection.59.&Haak BW,Levi M,Wiersinga WJ.Microbiota-targeted therapies on the intensive care unit.Curr Opin Crit Care Rev2017;23:167–174.Recent overview on current and new possibilities for microbiota-targeted therapies.Gut microbiota and host defense in critical illness Jacobs et al.。
