Crosstalk in the Abdomen: The Interface of the Omentum and the Microbiome in Sepsis

Anatomic and Functional Perspectives

The greater omentum, originally described by anatomists as redundant adipose tissue, hangs from the stomach and transverse colon, blanketing the abdominal viscera. Surgeons have classically viewed this structure as a vestigial organ of occasional utility as an autologous substrate for tissue reconstruction, but also one which more often “gets in the way” or forms troublesome intra-peritoneal adhesions.^1–3 However, a macroscopic omental response to acute peritoneal inflammation or infection is well described, and we now recognize active participation by the omentum in immune defense against intra-abdominal and peritoneal disease.^4,5 Composed of two mesothelial sheets, comprised predominantly of adipocytes and aggregates of mononuclear phagocytic cells embedded within loose connective tissue, the omentum possesses innate immune function, absorptive capabilities, and the ability to aid in peritoneal inflammation sequestration.^6,7 Peri-vascular leukocyte aggregates, termed milky spots, form a glomerular network of lymphatic capillaries that permit exchange of particles and cells between the omentum, the intra-abdominal cavity, and the systemic circulation. ² When exposed to a foreign body or bacterium, omental blood flow increases, and the proportion of stromal tissue expands. Inflammatory, hemostatic, and chemotactic factors are expressed, leading to the recruitment of inflammatory cells within the peritoneal cavity. ⁸

Peritoneal Cavity Immune Responses

Homeostatic interactions occur between peritoneal and omental immune-active cells. With inflammation and infection, peritoneal tissue damage and antigen exposure elaborate chemokines and cytokines that activate omental hematopoietic cells. Subsequently, cell proliferation and differentiation in milky spots leads to local cellular and biochemical responses, which can progress to a systemic response via migration into the systemic circulation. There is overlap with neutrophil trafficking when there is more than one site of inflammation besides the peritoneal space. ⁹ Immune function in the omentum is not limited to the milky spots. Indeed, visceral adipose demonstrates both metabolic and functional differences compared to axial adipose. ¹⁰ Unlike axial adipose, visceral adipose secretes pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), interleukins, and complement. ¹¹ These mediators may interface with adjacent organs such as the intestine.

The intestine has long been considered the largest lymphoid organ in the body and its microbiologic ecosystem has been implicated in the pathogenesis of inflammatory bowel disease, obesity, gastrointestinal malignancies, and sepsis.^12–15 Alterations in the intestinal epithelium, its microbiome, and its immune system all contribute to the inflammatory host response. Moreover, the role of individual bacterial species in the microbiota steady state is increasingly clear. For example, the intestinal microbiome aids in homeostasis, including immune function as well as gut barrier protection. Microbiota stimulate mucosal barrier protection, aid in T-helper cell development, and aid in regulation of the host inflammatory state. ¹⁶ Loss of normal intestinal microbiota structure and function has been associated with several pathologic states, including inflammatory bowel disease, neurologic disease, autoimmune diseases, and obesity. ¹⁷ Alterations in the microbiome that decrease diversity and establish the predominance of certain organisms have been linked with outcomes following episodes of intra-abdominal sepsis. ¹⁸ An altered microbiome is commonly termed a dysbiome when the normally balanced microbiome is distorted in a maladaptive fashion with regard to host interfaces.

Gut Microbiota and Intestinal Function

The intestinal epithelium is a single layer responsible for nutrient absorption, mucus production, and hormone and defensin release. ¹⁹ These functions aid in the intestine-microbiota interactions and integrity of the gut mucosa immune system. In health, the microbiome and gut immune system have an intricate and symbiotic relation to ensure homeostasis in the metabolism and digestion of ingested nutrients, secretion of gastrointestinal peptides, response to infectious stimuli, and even development of allergic reactions, as in the case of food protein-induced enterocolitis syndrome. ¹⁵

The gut immune system consists of Paneth cells, Peyer's patches, mesenteric lymph nodes, and intra-epithelial lymphocytes. Interaction of lymphocytes with luminal antigens triggers differentiation of B and T cells in the draining lymph nodes. In pre-clinical models, host response to enteric and systemic pathogens relies on maintenance of intestinal microbiome integrity. However, the presence of bacteria alone does not lead to inflammatory response. A complex interaction between pathogen, host and stress response, and alteration in these interactions can then lead to virulence.^20,21 Microbiomes that are distorted to evidence pathogenic bacteria are termed pathobiomes and have substantial implications for surgical care, especially regarding anastomotic healing.

Dysbiosis

To maintain a healthy state between the host microbiome and intestinal mucosa a delicate balance must be maintained across an increasing density of microbiota as one proceeds aborally along the gastrointestinal tract (Fig. 1). Disruption of this balance leads to dysbiosis. Dysbiosis in chronic microbiome-immune imbalance leads to mucosal inflammation, influences inflammatory cell proliferation, and enhances predisposition to systemic infection. ²² Local mucosal inflammation is increased in several disease states including inflammatory bowel disease and many gastrointestinal cancers.^23,24 Insults such as broad-spectrum antibiotic agents, gastroenteritis, gastrointestinal surgery, burns, and injury can have an overwhelming and long-lasting effect on microbiome diversity.^25,26 Repeated insults, as in the case of tertiary peritonitis or chronic critical illness following incomplete surgical rescue, increases the likelihood of microbiome recovery and may augment the genesis of multi-drug–resistant organisms.^27,28 Many of the peri-operative interventions established in gastrointestinal surgery, including mechanical bowel preparation as well as surgical site infection prevention antibiotics, disrupt the microbiome.^21,29 These disruptions allow for commensal organisms to become virulent, possibly increasing post-surgical complications such as enteric anastomotic leaks. ³⁰

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FIG. 1.

This figure demonstrates populations of the gastrointestinal microbiome in health.

Dysbiosis and Sepsis

Peritonitis, in response to hollow visceral perforation, anastomotic disruption, ischemic necrosis, or other injuries of the gastrointestinal tract, often drives acute care in the emergency department, operating room, and the intensive care unit. ²⁷ Pre-clinical studies have established a link between the intestinal microbiome and sepsis while specifically exploring interactions between the intestinal endothelium, immune system, and microbiome during states of physiologic stress such as sepsis or septic shock. ³¹ Alteration of microbiome-epithelium-immune system balance can lead to non-specific symptoms of intestinal failure, especially in critically ill or injured patients. ³² No single symptom of intestinal failure, including high gastric residual volumes, emesis, diarrhea, distention, or gastrointestinal hemorrhage, serves as an independent predictor of worse outcomes in critically ill or injured patients. ³³ However, the presence of three or more concurrent symptoms, as can be the case with sepsis or septic shock, clearly increases mortality.

Although intestinal microbiome alteration has been associated with increased sepsis susceptibility, maintaining intestinal epithelium integrity improves sepsis survival. ³⁴ Multiple hypotheses have addressed the interactions of the host microbiome and the inflammatory response that impacts remote host domains (Fig. 2). Mechanisms such as increased intestinal permeability with decreased barrier function that lead to bacterial and bacterial bioproduct translocation, as well as intestinally driven sepsis, have all been proposed as triggers of microbiome-immune system dysregulation.^35–37 For instance, microbiome dysbiosis allows for proliferation of pathogenic intestinal bacteria, as in the case of Clostridium difficile infection, potentiates a dysregulated systemic pro-inflammatory response, and diminishes beneficial microbiome byproducts. ¹⁸ In critically ill patients, intestinal microbiome dysfunction increases the incidence of multisystem organ failure. ³⁸ Fecal stool sample analysis in patients with sepsis noted a correlation between the incidence of altered fecal pH, bacteremia, and increased mortality. ³⁹ Furthermore, an alteration in the pattern of bacteria strain—specifically a decrease in obligate and facultative anaerobes—correlated with increased mortality in patients who developed multisystem organ failure. ⁴⁰ Although the gastrointestinal track microbiome derangements are increasingly well understood, as outlined above, the role of the omentum in those derangements is much less well appreciated.

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FIG. 2.

This figure depicts key aspects of immune dysfunction and crosstalk between the omentum and the intestinal microbiota during peritonitis.

Omental Immunologic Response to Injury

The omentum is capable of basic immune functions including allorecognition, natural cytotoxic reactions, and elaboration of cytokines. ⁸ The omentum plays a role in peritoneal defense by adhering to sites of inflammation, clearing bacteria and other contaminants, and providing leukocytes for local immune response. ⁴¹ Leukocytes aggregate in the peri-vascular adipose tissue of the omentum, are present in different stages of maturation, and can easily enter or leave milky spots. ⁴² The milky spots architecture allows for direct exposure of postcapillary venules to peritoneal inflammatory stimuli such as peritonitis as a result of locally increased blood flow. ⁴³ The vascular endothelium that lines the omental capillaries is either discontinuous or fenestrated rendering them well adapted to facilitate transmigration of neutrophils and macrophages.^44–46 Similarly, there is an absence of basal lamina in the submesothelial connective tissue, allowing for rapid extravasation of resident leukocytes as well as recruitment from the circulation. ⁴⁷

Macrophages contained within the omentum serve as scavengers. They differentiate and proliferate within the milky spots and transform into dendritic-shaped cells with phagocytic abilities. The milky spots provide the optimal microenvironment and growth factors for cellular proliferation and maturation. These macrophages appear to be the principal effectors of phagocytosis of pathogens cleared from the peritoneal cavity. The omentum also serves as a site of B-lymphocyte development, distinct from the thymus or the bone marrow; their specific function of omentally derived B-lymphocytes remains imprecisely known. ⁴⁸ Nonetheless, it is reasonable to consider that omental B-cells are functionally indistinguishable from those emanating from the thymus and bone marrow. Augmented local humoral immunity may also have some overlap with adhesion formation.

Most surgeons have experienced the ability of the omentum to adhere to sites of intra-abdominal inflammation or infection, including foreign bodies. The formation of a fibrin exudate at the site of injury that bridges between the injured site and the omentum is thought to mediate omental adhesion.^49–52 This fibrin scaffold promotes the migration of leucocytes (especially macrophages, neutrophils, and fibroblasts) to the site of injury leading to collagen deposition around the offending zone. Activated omentum becomes a reservoir of stromal cells that express stem cell markers and vascular endothelial-derived growth factor (VEGF).^41,53,54 Mature macrophages leave the milky spots and enter the peritoneal cavity, whereas neutrophils are recruited from the peripheral circulation and enter the peritoneal cavity via the post-capillary venules of the milky spots (i.e., trafficking).^55,56 Although omentectomy reduces the incidence of peritoneal dialysis catheter obstruction and improves peritoneal dialysis drainage it also impairs peritoneal defense mechanisms and reduces survival in experimental models of peritonitis. ⁵⁷ A retrospective review compared patients having proctocolectomy with ileoanal anastomosis plus omentectomy, to those without omentectomy. Patients in the omentectomy group had a higher incidence of postoperative sepsis, without differences in postoperative partial or complete small bowel obstructions secondary to adhesive disease. ⁵⁸ Therefore, despite the need for operative mobilization and adhesiolysis—especially during re-operative surgery—the omental contribution to peritoneal immune competence is certainly adaptive.

Hemostasis and Neovascularization

The omentum promotes angiogenesis when applied to other structures, but also promotes hemostasis. Human omental microvascular endothelial cells express the angiogenic peptide basic fibroblast growth factor. ⁵⁹ The rich omental blood supply supports its ability to deliver a high concentration of tissue factors in a local fashion. Neovascularization aided by the omentum enables healing of ischemic and inflamed tissues, supporting its use for reconstructive surgery, especially after infection management that leaves behind a dead space. The omentum has been used in intra-abdominal surgery in a variety of fashions including, but not limited to, closure of gastrointestinal tract perforations, reinforcement of enteric and vascular anastomoses, and for hemostasis at sites of liver injury. ³ Similarly, pedicled as well as free vascularized omentum grafts have been applied to sternal, mediastinal, perineal, and even head and neck wounds.^58,60,61

Conclusions

The omentum can harbor, recruit, and activate immune cells to aid in innate and adaptive immune response, hemostasis, angiogenesis, and repair. It aids in adaptive cellular trafficking but also influences humoral immunity. Our understanding of the interactions between the peritoneal cavity, the omentum, and the intestinal microbiome is limited but is poised to expand using recently developed and deployed technology. Understanding the dynamic interplay between the intestinal microbiome, omentum, and peritoneum in health and disease will help us improve the diagnosis and treatment of patients with intra-abdominal sepsis.