OBM Hepatology and Gastroenterology

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Communication

Gut Microbes and Pathophysiology of Sepsis: Spillage of Gut Microbial Products, rather than Systemic Dissemination of Gut Microbes, is the Potential Initiator of Septic Morbidity

Amale Laouar *

  1. Surgery Department & the Child Health Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University. 89 French Street, New Brunswick, NJ 08901, USA

Correspondences: Amale Laouar 

Received: July 22, 2018 | Accepted: August 22, 2018 | Published: September 10, 2018

OBM Hepatology and Gastroenterology 2018, Volume 2, Issue 3, doi:10.21926/obm.hg.1803010

Academic EditorTatsuo Kanda

Recommended citation: Laouar A. Gut Microbes and Pathophysiology of Sepsis: Spillage of Gut Microbial Products, rather than Systemic Dissemination of Gut Microbes, is the Potential Initiator of Septic Morbidity . OBM Hepatol Gastroenterol 2018;2(3):010; doi:10.21926/obm.hg.1803010.

© 2018 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Graphical abstract

Keywords

Sepsis; inflammation; gut; bacteria; immune; antibiotics

Sepsis is a major public health problem that is considered among the most expensive conditions treated in hospitals and a leading cause of death [1,2,3]. Even with advances in contemporary medicine, the new statistics published by the Centers for Disease Control and Prevention indicate that one in three patients who die in a hospital have sepsis [4]. For several decades, this disease was thought to be caused by the translocation of gut microbes across the intestinal barrier leading to systemic inflammation [5,6,7,8] and the multiple organ dysfunction syndrome in surgical and intensive care unit patients [9]. The ‘gut origin of sepsis’ concept is generally accepted, but some controversy remains about its clinical relevance [9]. For instance, more than half of patients who developed severe sepsis do not show evidence of bacterial contamination in systemic organs [8,10,11], and there are no published human studies that clearly explain this conceptual paradox. In this regard, a study in animal models attempted to explain this phenomena by investigating the possibility that uncontrolled spillage of secreted gut bacterial products, rather than gut bacteria themselves, may cause the initiation of systemic inflammatory responses leading to sepsis and death [12]. Testing this hypothesis required the in vivo investigation of the consequences of interaction between gut microbial components and systemic immune cells. In the 2015 study by Sinsimer and coworkers [12], two main questions were investigated. First, which immune cells were the primary drivers of systemic inflammation leading to sepsis; and second, which gut bacterial populations were predominantly responsible. Because prophylactic antibiotic treatments for sepsis are often administrated as a precautionary measure to patients before and/or during surgery [13,14], this investigation was also extended to explore whether common preoperative antibiotics [15,16] affect the immune and microbial processes involved in the pathology.

In this study, a cascade of events with three key discoveries was described [12]. First, ex-vivo experiments using intestinal luminal contents showed that components of gut anaerobes derived from the Bacteroidetes phylotype are the primarily inducers of pro-inflammatory responses which are mainly produced by myeloid dendritic cells [12]. Second, in vivo experiments using a sepsis mouse model [17] indicated that the common prophylactic Nichols-Condon therapy for sepsis, which consists of neomycin and metronidazole given orally to patients the day before surgery [18,19], is ineffective for clearing Bacteroidetes from the intestine. A point of critical consequence of this outcome is that, in response to acute intestinal injury, this prophylactic treatment induced increased systemic inflammation and premature death when compared to untreated animals [12]. Importantly, the findings indicate that conversely to the ‘gut origin of sepsis’ concept, the in vivo outcomes (increased systemic inflammation and premature death) are independent of gut bacterial spread [12]. Accordingly, a potential scenario was proposed (Figure 1). It would appear that when inflammation is established by microbial products of Bacteroidetes, potent inflammatory immune responses follow. These immune responses can be regulated by a network of pro-inflammatory cytokines including TNFα and pro-IL1β derived primarily from myeloid dendritic cells. This initial response may determine the systemic expansion of inflammation. Because Bacteroidetes’ products contain potent toxins and proteolytic enzymes of the epithelium [20], they may at later stages work in concert with other processes to increase the enzymatic destruction of the mucosal barrier and facilitate gut microbial dissemination within the host leading to immune collapse and faster death (Figure 1).

The notion that gut microbiota components and metabolites are associated with the modulation of immunity is not novel. In fact, gut microbial products do not only translocate into the systemic circulation, but are also likely to contribute to systemic immunity through the lymphatic circulation [21]. Indeed, several reports [22,23,24] have suggested that the microbiota continuously secretes metabolites into the systemic circulation, which in most cases are beneficial to the host physiology. On the negative side, this study shows that circulating gut microbial metabolites may have detrimental effects on the host physiology leading to the pathophysiology of sepsis [12]. With regard to the preoperative therapy, it is possible that neomycin and metronidazole also depleted other anaerobic taxa such as the Lachnospiraceae and Ruminocaceae families. These microorganisms are potent producers of short chain fatty acids (SCFAs) which are known for their potential to dampen the immune response [25,26]. It is therefore possible that the depletion of these gut microbes may be implicated in the detrimental outcomes seen in antibiotic-treated mice.

Overall, the findings of the original study point to an important observation that gut bacterial translocation may act as a promoter of septic morbidity, but not as the initiator as stated by the ‘gut origin of sepsis’ concept [12]. Such findings may explain why more than half of subjects who developed severe sepsis do not show evidence of bacterial contamination in peripheral organs.

Figure 1 Proposed model showing the impact of intestinal microbes in the initiation of sepsis and how preoperative antibiotics impact this process.

Model describes a potential scenario of the interplay between gut microbial products and host immune cells in response to the common prophylactic Nichols-Condon therapy for sepsis (which consists of neomycin and metronidazol metronidazole given orally the day before surgery) coupled with intestinal injury in mice. Source: Figure 1 was adapted from supplemental material in [12].

It is important to point out that this study was done in animals and extrapolating these murine data to the condition of human sepsis is a daunting challenge. It would however appear, based on this in vivo work, that the Nichols-Condon bowel preparation could be detrimental for leaky gut-prone individuals such as elderly individuals [27] and critically ill patients [28]. Therefore, from a clinical standpoint, it would seem inadvisable to prescribe this perioperative therapy to these groups of individuals. In this regard, both retrospective and prospective human studies will be required to validate or refute the proposed model. In conclusion, we believe that disseminating the key discoveries of the original study [12] is important to broaden the perspective of scientists and clinicians in the field of Gastroenterology & Perioperative Medicine as well as motivate further human epidemiological studies and in vivo investigations using metabolomics for the development of diagnostic tools for the management of sepsis.

Acknowledgments

This Short Commentary is based on a previous study [12] published under the terms of a Creative Commons license. Articles published under the CC-BY permit unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited and the use is non-commercial. The author apologizes to all investigators whose relevant work was not included in this commentary owing to space constraints. 

Author Contributions

A.L. wrote the whole manuscript.

Competing Interests

The author declares no competing interests.

References

  1. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al. Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA. 2017; 318: 1241-1249. [CrossRef]
  2. Torio CM, Andrews RM. National inpatient hospital costs: The most expensive conditions by payer, 2011: Statistical Brief #160. 2006.
  3. Liu V, Escobar GJ, Greene JD, Soule J, Whippy A, Angus DC, et al. Hospital deaths in patients with sepsis from 2 independent cohorts. JAMA. 2014; 312: 90-92. [CrossRef]
  4. Centers for Disease Control and prevention CDC 24/7: Saving Lives, protecting People TM. Available from: https://www.cdc.gov/sepsis/datareports/index.html
  5. Schweinburg FB, Frank HA, Frank ED, Heimberg F, Fine J. Transmural migration of intestinal bacteria during peritoneal irrigation in uremic dogs. Proc Soc Exp Biol Med. 1949; 71: 150-153. [CrossRef]
  6. Deitch EA, Maejima K, Berg R. Effect of oral antibiotics and bacterial overgrowth on the translocation of the GI tract microflora in burned rats. J Trauma. 1985; 25: 385-392. [CrossRef]
  7. Kinross J, von Roon AC, Penney N, Holmes E, Silk D, Nicholson JK, et al. The gut microbiota as a target for improved surgical outcome and improved patient care. Curr Pharm Des. 2009; 15: 1537-1545. [CrossRef]
  8. Lemaire LC, van Lanschot JJ, Stoutenbeek CP, van Deventer SJ, Wells CL, Gouma DJ. Bacterial translocation in multiple organ failure: cause or epiphenomenon still unproven. Br J Surg. 1997; 84: 1340-1350. [CrossRef]
  9. Deitch EA. Gut-origin sepsis: evolution of a concept. Surgeon. 2012; 10: 350-356. [CrossRef]
  10. O’Boyle CJ, MacFie J, Mitchell CJ, Johnstone D, Sagar PM, Sedman PC. Microbiology of bacterial translocation in humans. Gut. 1998; 42: 29-35. [CrossRef]
  11. MacFie J, O'Boyle C, Mitchell CJ, Buckley PM, Johnstone D, Sudworth P. Gut origin of sepsis: a prospective study investigating associations between bacterial translocation, gastric microflora, and septic morbidity. Gut. 1999; 45: 223-228. [CrossRef]
  12. Sinsimer D, Esseghir A, Tang M, Laouar A. The common prophylactic therapy for bowel surgery is ineffective for clearing Bacteroidetes, the primary inducers of systemic inflammation, and causes faster death in response to intestinal barrier damage in mice. BMJ Open Gastroenterol. 2015; 1: e000009. [CrossRef]
  13. Nichols RL, Broido P, Condon RE, Gorbach SL, Nyhus LM. Effect of preoperative neomycin-erythromycin intestinal preparation on the incidence of infectious complications following colon surgery. Ann Surg. 1973;178 : 453-62. [CrossRef]
  14. Napolitano F, Izzo MT, Di Giuseppe G, Angelillo IF; Collaborative Working Group. Evaluation of the appropriate perioperative antibiotic prophylaxis in Italy. PLoS One. 2013; 8: e79532. [CrossRef]
  15. Nichols RL, Smith JW, Garcia RY, Waterman RS, Holmes JW. Current practices of preoperative bowel preparation among North American colorectal surgeons. Clin Infect Dis. 1997; 24: 609-19. [CrossRef]
  16. Freeman CD, Klutman NE, Lamp KC. Metronidazole. A therapeutic review and update. Drugs. 1997; 54: 679-708. [CrossRef]
  17. Ayres JS, Trinidad NJ, Vance RE. Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota. Nat Med. 2012; 18: 799-806. [CrossRef]
  18. Vallance S, Jones B, Arabi Y, Keighley MR. Importance of adding neomycin to metronidazole for bowel preparation. J R Soc Med. 1980; 73: 238-240. [CrossRef]
  19. Arabi Y, Dimock F, Burdon DW, Alexander-Williams J, Keighley MR. Influence of neomycin and metronidazole on colonic microflora of volunteers. J Antimicrob Chemother. 1979; 5: 531-537. [CrossRef]
  20. Wexler HM. Bacteroides: the good, the bad, and the nitty-gritty. Clin Microbiol Rev. 2007; 20: 593-621. [CrossRef]
  21. Dickson RP. The microbiome and critical illness. Lancet Respir Med. 2016; 4: 59-72. [CrossRef]
  22. Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med. 2010; 16: 228-231. [CrossRef]
  23. Deshmukh HS, Liu Y, Menkiti OR, Mei J, Dai N, O'Leary CE, et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med. 2014; 20: 524-530. [CrossRef]
  24. Schuijt TJ, Lankelma JM, Scicluna BP, de Sousa e Melo F, Roelofs JJ, de Boer JD, et al. The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. Gut. 2016; 65: 575-583. [CrossRef]
  25. Chakraborty K, Raundhal M, Chen BB, Morse C, Tyurina YY, Khare A, et al. The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia. Nat Commun. 2017; 8: 13944. [CrossRef]
  26. Haak BW, Littmann ER, Chaubard JL, Pickard AJ, Fontana E, Adhi F, et al. Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT. Blood. 2018; 131: 2978-2986. [CrossRef]
  27. Qi Y, Goel R, Kim S, Richards EM, Carter CS, Pepine CJ, et al. Intestinal permeability biomarker zonulin is elevated in healthy aging. J Am Med Dir Assoc. 2017; 18: 810.e1-810.e4. [CrossRef]
  28. Assimakopoulos SF, Triantos C, Thomopoulos K, Fligou F, Maroulis I, Marangos M, et al. Gut-origin sepsis in the critically ill patient: pathophysiology and treatment. Infection. 2018. doi: 10.1007/s15010-018-1178-5. [CrossRef]