Introduction
A well-known model of the systemic inflammatory response syndrome is an intestinal ischemia-reperfusion injury that involves intentionally inducing small intestinal ischemic conditions followed by reperfusion of the area with blood. Destruction of intestinal mucosal epithelium and villi, microvascular impairment, increased vascular and mucosal permeability causing edema, leukocyte clogging of capillaries, and systemic sequelae such as blood acidosis, sepsis, and multiple organ failure are considered to be an effect of intestinal reperfusion injuries. However, probiotics could be potential agents for the prevention of intestinal reperfusion injury in high-risk patients, such as those who will have small bowel surgery, either given alone or in conjunction with antibiotics.
What Is Intestinal Reperfusion Injury?
The serious condition known as intestinal ischemic reperfusion injury carries a significant fatality rate. Ischemia reperfusion (I/R) injury mostly occurs in cardiac, cerebral, and hepatic disorders, intestinal injury, and transplantation. Out of these organs, the gut is the most susceptible to I/R injury. Rapid cessation of blood flow in the mesenteric artery results in acute mesenteric ischemia (AMI), a classic intestinal I/R injury-related disorder. AMI can happen in a number of different clinical situations, such as small intestinal obstruction, mesenteric artery thrombosis, vascular surgery, shock, small bowel transplantation, and trauma. Acute mesenteric ischemia is broadly classified into:
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Nonocclusive Mesenteric Ischemia (NOMI): NOMI, an acute mesenteric circulation disease, is brought on by an endogenous blood artery obstruction. Due to the difficulty in getting a conclusive diagnosis, the condition readily progresses to irreversible intestinal necrosis in the majority of instances involving spasms of the superior mesenteric artery (SMA). Patients with NOMI typically have a mortality rate of more than 50 %, severe heart failure, hemodialysis, aortic insufficiency, septic shock, or myocardial infarction. The primary stage of NOMI causes damage to the intestine due to blood flow stoppage. Reperfusion could make the initial intestinal damage worse even though the basic injury could be healed by restoring the normal mesenteric blood flow. It is also known as intestinal reperfusion injury.
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Occlusive Mesenteric Arterial Ischemia: Acute mesenteric arterial embolism and acute mesenteric arterial thrombosis are subtypes of occlusive mesenteric arterial ischemia. However, embolisms and thrombosis occur rarely; this disease is considered to be a predominant ischemic injury rather than an I/R injury.
What Are the Mechanisms of Intestinal Ischemic Reperfusion Injury?
Many factors play a part in the I/R injury generation process, and the mechanisms behind the injury are intricate. The two most used techniques for evaluating intestinal I/R injury in rodents are permanent vascular blockage by ligation of the SMA or complete ischemia by transient vascular occlusion with vascular clips.
According to animal research, intestinal I/R injuries happen as a result of both ischemia injury and reperfusion injury. Microcirculatory flow problems are the root cause of ischemic damage. The main cause of damage to the small intestinal tissue at this stage is hypoxemia. Even though it exacerbates intestinal damage, blood flow must resume after the initial ischemic event in order for intestinal epithelial cells to survive. This type of injury is named reperfusion injury.
As the intestinal reperfusion injury develops, mucosal barrier function is disrupted and vascular permeability is enhanced. The heightened vascular permeability promotes inflammatory cell activation and adhesion. Protein kinases, proinflammatory chemokines, and reactive oxygen species (ROS) are all released by these inflammatory cells. The tumor necrosis factor (TNF), cyclooxygenase-2 (COX-2), interleukin (IL)-1, IL-6, prostaglandin, intracellular adhesion molecule, and E-selectin are examples of representative induced molecules.
What Are the Factors Associated With Intestinal Ischemic Reperfusion Injury?
There are many parameters linked with intestinal bacteria during the development of intestinal ischemia. TLR2, TLR4, and their adaptor protein, myeloid differentiation primary-response 88, are toll-like receptors (TLRs) linked to intestinal ischemia-reperfusion injury. With the development of intestinal ischemic reperfusion injury, intestinal bacteria are also linked to oxidative stress and nitric oxide.
1. Toll-Like Receptors (TLRs): TLRs are crucial components of the innate immune system. The NF-B and TNF- production, as well as other inflammatory responses, are triggered by the TLR signaling pathway. However, TLR2 and TLR4 are particularly significant in intestinal I/R injury.
- Bacterial peptidoglycans, which are abundantly produced on the outer membranes of gram-positive bacteria, and fungal compounds activate the membrane surface receptor TLR2. Microglia and inflammatory cells, including monocyte or macrophage, dendritic cells, B lymphoceles, and T lymphoceles, express the TLR2 receptor. TLR2 signaling generally results in the generation of TNF- and NF-B.
- The LPS (lipopolysaccharides) of gram-negative bacteria also activates the membrane surface receptor TLR4. TLR4 activation leads to a similar induction of TNF- and NF-B as that by the TLR2 signaling pathway. The TLR4 signaling pathway significantly worsens intestinal I/R injury.
2. Oxidative Stress: Many investigations have shown that during reperfusion of the ischemic small intestine, oxidative stress brought on by ROS and free radicals, such as superoxide anion radicals, hydrogen peroxide (H2O2), singlet oxygen (1O2), and hydroxyl radicals, has an impact on the gut. The key source of free radicals during I/R injury is the metabolism of xanthine oxidase (XO). In ischemia conditions, xanthine dehydrogenase is converted to XO by calcium-dependent proteases, which then catalyze the oxidation of xanthine and hypoxanthine into uric acid to produce singlet oxygen and hydrogen peroxide. This XO system can produce large levels of ROS throughout the development of the I/R damage. The purine derivative allopurinol inhibits XO, protecting the gut from I/R damage.
3. Nitric Oxide: An essential modulator of physiological and pathological processes is nitric oxide (NO). In relation to oxidative stress and intestinal I/R damage, nitrous oxide (NO) also plays a significant role. NO synthase converts the l-guanidine arginine group into NO (NOS). The gastrointestinal tract contains all four of the major NOS isoforms, including neuronal NOS (nNOS), endothelial NOS (eNOS), inducible NOS (iNOS), and mitochondrial NOS (mtNOS). Although nNOS and eNOS are naturally present, proinflammatory cytokines stimulate iNOS, which then creates NO. The inner membrane of mitochondria contains mtNOS, a Ca2+-dependent NOS subtype. Although constitutive NO synthase (nNOS and eNOS)-produced NO can be a significant protective molecule against intestinal I/R injury, excessive NO synthesis by iNOS may exacerbate inflammation.
Conclusion
Animal studies have shown that intestinal I/R injury is caused by various bacterial species, with TLR2, a receptor of bacterial peptidoglycans that is highly expressed in gram-positive bacteria, and TLR4, a receptor of gram-negative bacteria's LPS, both playing critical roles in the damage. To confirm the role of the bacteria in intestinal I/R damage, clinical studies evaluating the efficacy of antibiotics should be urgently carried out in addition to animal studies to investigate microbial characteristics and those using conditional knockouts of TLRs or specific agonists or antagonists against TLRs.
