**5. Therapeutic options for the improvement of the IB dysfunction in sepsis**

Although it has been known that BT is strongly associated with the progress of sepsis and septic morbidity, no decisive clinical therapy is proposed for the repair of the impaired IB and the treatment of sepsis [14]. However, some strategies such as modulation of the IB, inhibiting immoderate bacterial growth, regulating the effects of immune mediators, endotoxins, and NO, preventing oxidative stress, and improving intestinal ischemia and reperfusion injury were reported the severity of sepsis-associated BT [38].

### **5.1 Selective elimination of pathogenic bacteria**

Removal of pathogenic bacteria, including gram-negative bacilli and symbiotic anaerobic bacteria, by the treatment with non-absorbed oral antibiotics such as polymyxin E, polymyxin B, amphotericin B, and tobramycin were suggested to reduce mortality [103, 104]. Although the treatment with non-absorbable antibiotics was believed to reduce the incidence of infection by pathogenic gram-negative bacteria and improve mortality rates, antibiotic resistance appeared as a limiting factor [105]. Since sepsis is an acute disease with high morbidity and mortality in intensive care units leads to intestinal flora disturbance, induces IB impairment, causes BT, systemic inflammation, and MODS; broad-spectrum antibiotics are frequently used in severe sepsis treatment [106]. Antibiotics are reported to affect the inflammatory process and ameliorate intestinal microcirculation in sepsis [107]. *Intestinal Barrier Dysfunction, Bacterial Translocation and Inflammation: Deathly Triad… DOI: http://dx.doi.org/10.5772/intechopen.99554*

It was recently demonstrated that broad-spectrum antibiotics prevent BT to distant organs such as the liver and lungs in septic rats [108]. There is, however, evidence that broad-spectrum antibiotics can lead to an imbalance in the intestinal micro ecological environment, promote BT in sepsis, and cause drug resistance and pathogenicity, especially when MODS develops [109]. High-dose antibiotic therapy is also suggested to promote the translocation of native symbiotic bacteria and induce an inflammatory response, leading to late-onset sepsis [110]. It was concluded that metronidazole, an antibacterial and antiprotozoal drug used to treat giardiasis, anaerobic infections, and inflammatory bowel disease, reduces colonic bacterial counts and improves intestinal inflammation by suppressing cellular immunity [111]. Erythromycin was shown to increase gastric motility by affecting the motilin receptors in smooth muscle cells of the stomach, facilitating gastric emptying and decreasing the acidity and residual gastric fluid volume [112]. Treatment with antibiotic combinations (vancomycin, neomycin, and polymyxin b) prevented the translocation of intestinal bacteria to the pancreas by inhibiting the pancreatic NLRP3 pathway and inhibiting intestinal-pancreatic inflammatory responses [113].

#### **5.2 Modulation of immune function and oxidative stress**

During the attack of pathogenic bacteria, which destroys the IB or at decreased IAP conditions and increased LPS levels, the TJs are disintegrated. Macrophages are activated to produce pro-inflammatory cytokines, which also activate macrophages in circulation and cause the transportation of bacteria and LPS into the blood circulation [14, 114]. As previously mentioned, both the quantity and the functions of the secreted IgA diminish during pathological conditions [38]. Oral sIgA supplementation was shown to increase local sIgA levels in the intestine. Epithelial growth factor is suggested to promote the regeneration of intestinal mucosal epithelial cells, maintain the normal structure of intestinal mucosa, protect the intestinal mucosal immune barrier, and prevent BT [115]. Studies indicated that glutamine and growth hormone supplementations reduce intestinal BT and regulate inflammatory pathways [38].

Exogenous IAP administration was suggested to improve the IB function, while oral or enteral administration of IAP ameliorated the disintegrated IB [116, 117]. It was recently reported that high fat, Western-type diet-induced IB dysfunction, improved glucose intolerance, and orally administered IAP improved severe ulcerative colitis patients [118]. Since it was reported that anti-TNFα antibodies and inhibition of myosin light chain kinase (MLCK) prevented the impaired barrier function, treatment with these antibodies and inhibitors was suggested to reduce the severity of inflammatory bowel diseases. As IL-13 induces the disruption of barrier function by upregulation of claudin-2 expression, inhibition of IL-13 or claudin-2 seems to be proper targets for the treatment of BT [14]. The antimicrobial peptide cathelicidin-BF (C-BF) inhibited small IB dysfunction in the LPS-induced septic model in rodents [119].

Curcumin reduces the LPS/IL-1β-induced impairment of TJs [120], while berberine decreases the effects of LPS-mediated signaling through the Wnt/betacatenin pathway to restore intestinal permeability in a rat model of sepsis [121]. It was suggested that cortisol reduces the expression of TJ proteins by alleviating the glucocorticoid receptor (GR) binding to the occludin and increases paracellular permeability and lubiprostone prevents stress-induced IB dysfunction [122]. A new GR agonist, 16α-hydroxytrametenolic acid (from edible mushrooms), is suggested to ameliorate the barrier dysfunction through PI3K/Akt/NF-κB signaling pathway [123]. Metformin is introduced to be beneficial for the protection of IB dysfunction by the inhibition of JNK activation through the AMPKα1-dependent signaling pathway [124]. Treatment with resveratrol increased the expression of sirtuin-1 in obese septic mice

and decreased the inflammatory response. Sirtuins also play a significant role during the late onset of septic "hypo-inflammation"; SIRT-2 inhibition in obese septic mice preserved a decreased microvascular inflammation and protected against thrombotic events [125]. Tezosentan, a non-selective ETA and ETB receptor antagonist, improved intestinal microcirculation in intestinal ischemia–reperfusion injury by reversing the BT and cellular disintegrate of the intestinal mucosa [50]. Allopurinol, vitamin C, coenzyme A, Quercetin, *Ginkgo biloba* extract, and N-acetyl cysteine are suggested to inhibit ROS production, protect the cell membrane, and intestinal mucosa against ROS-related damage [38]. Rhubarb, the edible petioles of species and hybrids (culinary rhubarb) of Rheum in the family Polygonaceae, was shown to reduce intestinal BT and intestinal mucosal permeability through ROS scavenging and protection of the intestinal mucosa integrity [126]. Huoxue Jiedu Ling, a mixture of wormwood, *salvia miltiorrhiza*, white-headed weng, rhubarb, and licorice, is suggested to inhibit intestinal BT and reduces the oversecretion of cytokines by macrophages [127]. Shen-Fu Decoction (SFD), a traditional Chinese herb formulation, has been widely used to treat sepsis in China. A recent study showed that SFD significantly prevented intestine and liver damage, relieved sepsis-induced intestinal permeability and inflammation, ameliorated sepsis-induced impaired intestinal permeability by regulating the expression of ZO-1, Occludin, Claudin-1, and p-VASP [128].

## **5.3 Probiotics**

The World Health Organization (WHO) describes *probiotics* as "live microorganisms which when administered in adequate amounts confer a health benefit on the host" [129]. The most known microorganisms used as probiotics are the Lactobacillus, Bifidobacterium genera, Enterococcus, Streptococcus, and Escherichia, which have been suggested to benefit some gastrointestinal disorders by ameliorating the gut microbiota ecosystem [130]. *Prebiotics* are non-digestible food component fibers selectively inducing the growth and activity of probiotic bacteria, and *synbiotics* are described as the mixtures of probiotics and prebiotics, which are expected to be more beneficial in many pathological conditions. These microecological regulators promote the intestinal flora by inhibiting the colonization of exogenous bacteria and excessive growth of endogenous pathogenic bacteria, maintaining the ecological balance in the intestine, and reducing BT [131]. In addition, it is believed that probiotics produce bacteriocins to kill pathogens, synthesize IgA and reduce inflammation by stimulating regulatory lymphocytes through interleukin (IL)-10 and transforming growth factor signaling [132]. It was reported that *Lactobacillus rhamnosus* GG pretreatment in a septic mouse model effectively reduced mortality, possibly by improving intestinal permeability and modulating microbiota dysbiosis [133]. Studies showed that supplementation of Bifidobacterium breve strain Yakult and *Lactobacillus casei* strain Shirota as probiotics and galactooligosaccharides as prebiotics reduced the incidence of infectious complications such as enteritis, pneumonia, and bacteremia in patients with severe SIRS compared to those who did not receive synbiotics [134]. Synbiotics are a potential treatment option for sepsis patients since the complications of enteritis, and ventilation-associated pneumonia was significantly decreased in the patients treated with synbiotics [135]. However, the application of probiotics on sepsis has been limited due to the theoretical risk of aggravating bacteremia in patients with critical illnesses [136].

#### **5.4 Fecal microbiota transplantation**

Clinical studies showed that sepsis is influenced by gut microbiota disruption [137]. Fecal microbiota transplantation (FMT) is the administration of fecal material

#### *Intestinal Barrier Dysfunction, Bacterial Translocation and Inflammation: Deathly Triad… DOI: http://dx.doi.org/10.5772/intechopen.99554*

from a healthy donor into a patient's intestinal tract with an altered gut microbiota to restore its functions. Randomized controlled trials showed that FMT is successfully applied in treating recurrent *C. difficile* infections. In addition, it helped restore bacterial communities in cecal crypts crucial in protecting intestinal stem cells, preserving immunological pathways by enhancing the expression of toll-like receptors and introduce the short-chain fatty acids, bile acids, eukaryotic, and prokaryotic viruses to the intestinal ecosystem [138, 139]. It has been postulated that if the symbiosis between the commensal bacteria and the human host becomes imbalanced, the innate and adaptive immune systems are disturbed [140]. Protective anaerobes are lost in fecal specimens with severe sepsis, indicating that pathobiota may dysregulate the immune system during sepsis [137]. Thus, FMT provides the restoration of intensive care unit-associated dysbiosis and intestinal decolonization of multidrugresistant (MDR) organisms.

Furthermore, the introduction of symbiotic bacteria may decrease the antibiotic resistance genes present in the microbiome [139]. Treatment with FMT provides a complete reversal of dysbiosis, decreases the levels of inflammatory mediators, and normalizes T helper-(Th-)1/Th2 and Th1/Th17 ratios. However, since MDR is a leading cause of sepsis complications in intensive care unit patients, FMT has been evaluated in different case series. Results cannot be easily analyzed because of the high risk of bias in smaller studies, results of different studies cannot be conclusive because of different patient populations (with the most common organisms are carbapenem-resistant Enterobacteriaceae, vancomycin-resistant Enterococci, and extended-spectrum β-lactamase-producing bacteria, and Pseudomonas, methicillin-resistant *S. aureus*, and Acinetobacter [141].
