Probiotic Therapy: Immunomodulating Approach Toward Urinary Tract Infection
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Urinary tract infection (UTI) is an extremely common health problem, with an unpredictable history. Members of enterobacteriaceae family such as Escherichia coli, which are normal inhabitants of human intestines, account for the majority of these uncomplicated infections. Rarely, UTI can result from virus or fungus. There is a close correlation between loss of the normal genital microbiota, particularly Lactobacillus species, and an increased incidence of genital and bladder infections. Although antimicrobial agents are generally effective in eradicating these infections, there is a high incidence of recurrence. Use of Lactobacillus species to combat UTI is now giving modern concept of modern genitourinary vaccine with the facts that it not only maintains low pH of the genital area, produces hydrogen peroxide and hinders the growth of E. coli but also activates Toll-like receptor-2 (TLR2), which produces interleukin-10 (IL-10) and myeloid differentiation factor 88 (MyD88). E. coli activates TLR4, which is responsible for the activation of IL-12, extracellular signal–regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). This process downregulates inflammatory reactions caused due to pathogens. Current review covers the probiotics-based TLR therapy and shed some knowledge for the use of Lactobacillus species as probiotics.
Urinary tract infection (UTI) is a common problem from neonate to geriatric age groups. It is a microbial infection caused by bacteria that affects the urinary tract. Although urine contains a variety of fluids, salts and waste products, it usually does not contain bacteria in it. It remains a measure health problem in women affected each year. Nearly 50–60% of women probably encounter with UTI in their lifetime . Recurrence of about 25–30% is seen in affected women . Various pathogens among bacteria that are responsible for UTI are Escherichia coli, Proteus, Klebsiella and Staphylococcus saprophyticus. Viruses, fungi and parasites can also cause UTIs. Escherichia coli have been found to be the most common causative organism of UTI in many countries .
In most of the cases, antibiotic treatment cures the disease, but still a significant number of patients suffer from UTI recurrence and sometimes lead to kidney damage [5, 60]. Almost 95% UTIs cases are caused by bacteria only, which multiply at the proximal part of the urethra and enter the bladder (known as the ascending route). Much less often, bacteria spread to the kidney from the bloodstream. UTI is caused by bacteria that can also live in the digestive tract, in the vagina or around the urethra, which is at the entrance to the urinary tract. Most often, these bacteria enter the urethra and travel to the bladder and kidneys . Usually, our body removes the bacteria, and we have no symptoms. However, some people including women and older people of both sexes are prone to infection. Urinary tract infections being the second most common type of infections affecting people accompany symptoms such as pain/burning while passing water, fever, tiredness/shakiness, urge to use the toilet often. . Doctors usually prescribe genitourinary drugs to kill the infection, and a relief can be experienced usually in a day or two. The biggest problem associated with a UTI is if it results in pyelonephritis, it in turns causes scarring and damage to the kidney and its tissues. Persistent infections may lead to damage in the kidney’s filter system. If there is enough damage to the filter system, waste products cannot be removed properly. This condition leads to kidney failure, and then, dialysis is the only solution, i.e., filtering the blood through an “artificial kidney”, which is an expensive treatment. Although another option is kidney transplant that also poses many risks and problems. Both of these problems may occur rapidly, but only if the infection is very severe. More often, the damage done by the initial infection, even if it is not compounded by future infections, progresses over many months or years. In particular, renal failure may not be complete until long after the first UTI.
In this era of increasing resistance against antimicrobial therapy, novel nonantibiotic therapy is the choice of treatment for deadly infectious conditions. Current social trends have changed from man-made chemicals toward the use of naturopathy and away from the chemotherapeutic regimens . Antibiotic therapy is a good option against UTI. Typical antibiotics used against UTIs include trimethoprim-sulfamethoxamole, nitrofurantoin, ciprofloxacin, levofloxacin or their chemical relatives and certain penicillins such as amoxicillin. It may decrease the consequences of UTI up to some extent, but the spiraling cost of antibiotic therapy and appearance of multidrug-resistant bacteria antibiotic therapy proved an unsatisfactory therapeutic option. So far, no appropriate and successful option for treating or preventing urinary tract infection is known . Beyond this, long-term antibiotic therapy leads to destruction in the population of normal flora of patients; also, the drug resistance is developed against the particular antibiotic . Antimicrobial treatment of urogenital infections is not as always most effective, and problems persist due to bacterial and yeast resistance. Patient concomitantly suffers from recurrent infections and side effects. Alternative remedies against UTI are of interest to patients and their caregivers [48, 54]. Toll-like receptors (TLRs) are highly conserved classical pattern recognition receptors of the innate immune system, enabling the host to discriminate between pathogen-associated molecular patterns (PAMPs) and self. Use of probiotic is a new emerging field. Lactobacillus-mediated TLR therapy for the clearance of uropathogen is a safe strategy for UTI patients. TLRs are components of innate immune system, which plays an important role in the pathogenesis of UTI and in the process of activation of the innate immune system. Present review has been aimed to shed some knowledge on the importance of probiotic-supplemented TLRs-mediated therapy against urinary tract infection.
Friendly Bacteria “The Lactobacilli”
The term “friendly bacteria” is often used as an alternative term for “probiotics”. Probiotics are microbial products which when administered in a particular number exert a beneficial effect on the host body. These are widely used nowadays instead of chemotherapeutic agents in yoghurts and probiotics drinks. Lactobacillus and Bifidobacterium species are the potential candidates of probiotics therapy. They have GRAS status (generally regarded as safe status) . Probiotics are used for their protective properties like antimicrobial, antioxidant, antidiarrheal, anticancerous, antilipidemic and also for their lactose intolerance activity. Probiotic organism helps in the treatment and prevention of diseases . Probiotics exerts beneficial effects by various protective mechanisms like: maintaining the acidic pH, bacteriocins, production of hydrogen peroxide, prevention of colonization of pathogen, antimicrobial activity, degrading the toxins and stimulation of immunity of the host [4, 9, 55].
Role in UTI
Lactobacillus is an important part of the normal flora, which is commonly found in the mouth cavity, gastrointestinal tract and female genitourinary tract . Reduction in number of Lactobacillus increases the risk of UTI.
Innate immune system is the first line of defense against microorganisms . Epithelial cells also secrete an array of chemokines and cytokines, which are crucial for the recruitment and activation of innate immune cells [26, 50]. In spite of these mechanisms, there are some receptors known as Toll-like receptors (TLRs), which are a class of proteins, spanning and noncatalytic entities. These recognized structurally conserved molecules derived from microbes. Toll-like receptors are now regarded as the key molecules that alert the immune system in the presence of microbial infections.
In humans, the TLR family consists of ten proteins, which have been a current interest of study subject during the past decade because of their critical role in immune protection and associated with certain diseases like Crohn’s disease , cystic fibrosis lung disease , inflammatory bowel disease , familial Mediterranean fever  and septic joint disease . TLRs along with interleukin-1 receptor form a receptor superfamily, known as the interleukin-1 receptor/Toll-like receptor superfamily; all members have in common a so-called Toll-IL-1 receptor (TIR) domain.
Toll-like receptors (TLRs) recognize microbial antigens commonly referred to as pathogen-associated molecular patterns (PAMPs). TLRs recognize various microbial products like lipopolysaccharide (LPS), peptidoglycan, lipoprotein and DNA. Stimulation of these receptors is responsible for the induction of acute inflammatory responses. It also improves the capacity of professional antigen-presenting cells to stimulate T cells. Hence, the system of pathogen recognition receptors including the Toll-like receptors (TLRs) is able to sense danger signaling and thus activate the host immune system of the genitourinary tract [19, 35]. Toll-like receptors are expressed on immune cells like lymphocytes, macrophages and dendritic cells as well as found in close proximity of epithelial cells .
Toll-like receptors were named after the fruit-fly receptor Toll, which was first discovered because it has an important role in early fly development and was later recognized as contributing to innate immunity in adult flies [1, 27]. TLRs have an amino-terminal extracellular domain composed of repeated motifs high in leucine and known as leucine-rich repeats (LRRs), followed by a single transmembrane domain and a globular cytoplasmic domain called the Toll/interleukin 1 receptor (TIR) domain, or TIR domain that is also found in IL-1 receptors as well as in adaptors of the TLR signaling pathway. Thirteen TLRs have been identified in mammals so far. TLRs recognize constituents of microbial cell walls or pathogen-specific nucleic acid. Most of the determinants recognized by these receptors are molecules essential to the integrity, function or replication of microbes or viruses, and therefore, the infectious agent cannot readily escape detection by changing them. For example, lipopolysaccharide (LPS), the major ligand for TLR4, is a central component of the outer membrane of gram-negative bacteria, and mutations that abate the enzymes required for the synthesis of LPS are lethal to most species of gram-negative bacteria. Recognition of LPS requires not only TLR4 but also a TLR4 accessory molecule, MD-2. Similarly, double-stranded RNA, the ligand for TLR3, is a central replication intermediate for all RNA viruses, so evasion of TLR3 recognition by these viruses is not easily achieve [3, 32, 34].
TLRs differentially activate distinct signaling events via cofactors and adaptor proteins, which leads to the activation and nuclear translocation of transcription factors. These factors modulate the expression of pro- and anti-inflammatory cytokines and chemokines, which in turn regulate the activities of the innate and the adaptive immune responses.
Advancement in the field of acquired immunity has expanding the field of immunology. More recent advances have proven that innate defense mechanisms play key roles in progression of several diseases, and these ‘danger signals’ (infectious as well as noninfectious) may act as the trigger mechanism to protect the body against these diseases [8, 20].
This receptor helps the host to discriminate between pathogen-associated molecular patterns (PAMPs) and self. TLR4 recognizes lipopolysaccharides (LPS), which is an important constituent in the cell wall of gram-negative bacteria and a causative agent of endotoxin shock [13, 14, 21, 43]. TLR4 belongs to the family of innate immunity receptors that possess a large unit of leucine-rich repeats, a single transmembrane segment and a smaller cytoplasmic signaling region that engages the adaptor protein myeloid differentiation factor-88 (MyD88) , Lipid binding protein (LBP), CD14 and CXCR4 .
It has been observed that TLR4 activates a sequence of intracellular signals, which further results in activation of the transcriptional factor, NF-κB, and the production of several NF-κB-dependent cytokines including some chemoattractants, reactive oxygen species that manages the phagocytic cells to clear the infection or infectious particles [31, 53, 61]. TLR4 stimulates a complex array of events that may lead to cell death and even cell proliferation in others .
The concept of probiotics is not new. It probably dates back to 1908, when Nobel laureate Eli Metchnikoff proposed that the long life of Bulgarian peasants resulted from their consumption of fermented milk products . With improved understanding of the physiology and therapeutic role of probiotics, definitions have evolved bolder claims, which now enter medical territory. Previous studies have shown that Lactobacilllus species in the form of probiotics reduces the risk of UTI and vaginal infections [11, 49]. The mechanism by which Lactobacillus protects the urinary tract is still very mysterious process. Lactobacillus defending mechanism is not fully understood till now . Some researchers have reported that downregulation of pro-inflammatory cytokines (IL-6, IL-8, TNF-alpha) is the basic mechanism . Some believed that Lactobacillus produce hydrogen peroxide, which protects the host against the uropathogenic E. coli . Some proposed that along with the production of hydrogen peroxide, it also incorporated with 29-kDa biosurfactant proteins . This protein enables Lactobacillus to the collagen present on the uroepithelial wall and inhibits uropathogen from binding . Xia and his coworkers proposed that L. crispatus blocks the uropathogen adherence .
Commensal bacteria like Lactobacillus species and Bifidobacteria species are known to produce immunoregulatory factors that may enhance infection in the host by modulating immune responses . Such immunomodulins may have important roles in maintaining intestinal health and quenching systemic inflammatory responses. It has been observed that the two major bacterial cell wall components, peptidoglycan in the case of gram-positive bacteria and lipopolysaccharides (LPS) in gram-negative bacteria, are important molecular markers recognized by the immune system . It has been observed that intestinal epithelium and uroepithelium contain several TLRs like TLR2, TLR3, TLR4 and TLR5 [17, 33, 41].
Mechanism Behind Action: Complementary Action of TLR2 and TLR4 Receptor for Clearance of Gram-Negative Bacteria
Conclusion and Future Directions
In this era of increasing bacterial resistance to antimicrobial therapy, development of alternative approaches and yet harmless is of major importance. Since infection, site-oriented probiotic therapy is one of the most encouraging therapeutic alternatives for the prevention of urinary tract infection in the post-antibiotic era. Probiotics have a great potential, particularly today with the increasing threat of antibiotic over-usage and prevalence of antibiotic-resistant microorganisms. It is essential that the search to be continued for the most appropriate probiotic strains to be used in reducing urinary tract infection. In this way, there is a clearance of bacteria and restitution to normalcy. The discovery of TLRs holds great promise in better understanding of pathogen-induced immunity and autoimmunity in the field of urology. This can be potentially be translated to beside in many exciting ways, including using small molecules to inhibit TLR signaling or employing selective TLR ligands as adjuvants to generate tolerance.
It is evident that the analysis of the impact of probiotics-mediated TLR therapy in urinary tract infections has entered a new and fascinating phase of research and that this effort is likely to offer novel and useful means to modulate host immunity for protection from, or treatment of, a wide variety of urinary tract infection in human.
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