Irritable Bowel Syndrome (IBS)
Irritable bowel syndrome (IBS) is a chronic disorder of the gastrointestinal tract, characterized by abdominal pain and alterations in bowel habits. IBS is the disorder most commonly encountered by gastroenterologists, and diagnosis is made according to a symptom-based classification system, the Rome Criteria, with the latest version, Rome IV, recently released (Drossman, 2016). Prevalence rates in North America have been reported as approximately 12%, and symptoms occur more often in patients less than 50 years of age.Patients with IBS suffer not only from gastrointestinal distress, but approximately 40–60% experience comorbid psychological disorders, such as depression or anxiety. In addition, patients with IBS report higher levels of somatization compared to patients without IBS but with gastrointestinal symptoms. Not surprisingly, IBS has been shown to negatively impact patients’ quality of life, as well as to adversely affect society’s financial resources.
Despite the substantial cost of IBS to both patients and society, curative, medical interventions have yet to be discovered. The development and persistence of IBS symptoms have been acknowledged as multifactorial in nature, making treatment of the disorder a complicated, clinical endeavor. Approaches are based on the reduction of patient symptomatology, and current pharmacological management often provides suboptimal relief.
Evidence of biological dysregulation has been reported in patients with IBS, and efforts are ongoing to advance understanding of the neurohormonal underpinnings of the disorder. Although gains have been made in understanding the pathophysiology of IBS, exact mechanisms leading to symptom development are not completely understood.
Inflammatory bowel disease (IBD)
The inflammatory bowel diseases primarily include Crohn’s disease and ulcerative colitis. Crohn’s disease is an IBD that causes inflammation anywhere along the lining of the digestive tract, while ulcerative colitis causes long-lasting inflammation in some part of the digestive tract (mainly the colon). The exact etiology of IBD is not well known.There are several factors that have been postulated to influence the development of this group of diseases, which include but are not limited to bacterial contamination, a change in the immune system, and genetic variations. For instance, a mutation in the NOD2 gene is associated with an increased susceptibility to IBD via production of proinflammatory cytokines. While genetic predisposition plays a key role in immune-mediated diseases, the major influence appears to be due to environmental factors.
Current research suggests that autoimmune diseases are most prevalent in highly industrialized nations but rare in less developed countries. Moreover, studies have shown that increased consumption of milk protein, animal protein, and polyunsaturated fatty acids can increase the risk for IBD, and that consumption of tobacco increases the risk of Crohn’s disease.
The major subtypes of IBD, including Crohn’s disease and ulcerative colitis, have a high prevalence rate in the world, with North America noting the highest frequency of people suffering with Crohn’s disease. In addition, statistics show that an estimated 129,000 people live with the disease in Canada. Although the onset of the disease usually occurs during adulthood, children are increasingly being diagnosed with IBD.
Treating IBD often involves use of medications that can diminish the symptoms and decrease the inflammation in the colon lining. A group of anti-inflammatory drugs including 5-aminosalicylic acid is commonly used to treat IBD. Other drugs such as infliximab are also indicated in patients who have failed conventional therapy and are hospitalized with severe IBD. Infliximab is a chimeric monoclonal antibody against tumor necrosis factor alpha (TNF-α), a cytokine involved in intestinal inflammation.
Several other immunomodulatory drugs, such as thalidomide, can also be used to treat a patient with severe IBD. Formerly used as a sedative and hypnotic, this synthetic drug has been shown to significantly reduce the inflammation associated with IBD. However, under certain circumstances, when medical therapy fails, surgery may be considered. This operation is known as colectomy and involves removal of the large intestine. While ulcerative colitis is cured upon removal of the colon, Crohn’s disease unfortunately can still recur after surgery.
While medication is commonly used to treat IBD, most pharmaceutical compounds have side effects such as headache, diarrhea, and nausea, which can reduce patient compliance and result in worsening of the condition. Therefore, different approaches to therapy like the use of peptides, can provide promising results for those who have gut inflammatory disorders.
What is the difference between IBD and IBS?
Inherently, IBD is an organic disease, as evidenced by mucosal inflammation, whereas IBS lies more in the spectrum of a functional disorder, with no evidence of organic disease. IBS symptoms are nonspecific and may precede diagnosis of both IBS and IBD by many years.See the Venn diagram below to understand the relationship among IBD and IBS.
What is KPV Peptide?
α-MSH is a neurohormone with extensive immunomodulatory effects on certain cell types. It exhibits potent anti-inflammatory effects by binding to melanocortin receptors in the skin. It is reported that the anti-inflammatory activity of α-MSH is mediated by the three terminal amino acids, Lysine-Proline-Valine (KPV).KPV lacks the entire sequence motif required for binding to the MC-Rs, but still retains almost all the anti-inflammatory capacity of the parent hormone. This is also because peptides (like KPV) often act as hormones and relay information from one tissue through the blood to another via biologic messengers. The inflammatory activity of KPV is suggested to be mediated via inhibition of interleukin (IL)-1β.
Unlike α-MSH, KPV is free from the melanotropic effects and thus does not cause any pigmentation. Additionally, it is smaller in size and more chemically stable than α-MSH. These attributes make KPV a suitable candidate for the treatment of inflammatory skin disorders. KPV has a molecular weight of 383.49 Da and an Isoelectric point (pI) of 14 and hydrophilic in nature.
KPV is more stable and exerts less side effects, as it shares its sequence with human proteins. KPV might therefore be an interesting, easy to produce, and inexpensive therapeutic option in the treatment of inflammatory bowel disease that must be elucidated in future clinical trials.
Research Example #1:
Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease
Background: Despite some progress in recent years, the options for treating inflammatory bowel disease (IBD) are still dissatisfying, and surgery rates are still high. The anti-inflammatory effects of melanocortin peptides such as alpha-melanocyte-stimulating hormone (alpha-MSH) have been described recently in, for example, dextran sodium sulfate (DSS) colitis in mice. The aim of this study was to investigate the therapeutic potential of the melanocortin-derived tripeptide alpha-MSH(11-13) (KPV) and its mode of action in 2 models of intestinal inflammation.Methods: The anti-inflammatory activity of KPV was analyzed in 2 well-described models of IBD: DSS colitis, and CD45RB(hi) transfer colitis. Furthermore, animals expressing a nonfunctional melanocortin-1 receptor (MC1Re/e) received DSS for induction of colitis and were treated with KPV. The course of inflammation was monitored by weight loss and histological changes in the colon as well as by myeloperoxidase (MPO) activity.
Results: In the DSS-colitis model, treatment with KPV led to earlier recovery and significantly stronger regain of body weight. Histologically, inflammatory infiltrates were significantly reduced in KPV-treated mice, which was confirmed by the significant reduction of MPO activity in colonic tissue after KPV treatment. Supporting these findings, KPV treatment of transfer colitis led to recovery, regain of body weight, and reduced inflammatory changes histologically. In MC1Re/e mice, KPV treatment rescued all animals in the treatment group from death during DSS colitis.
Conclusions: The melanocortin-derived tripeptide KPV showed significant anti-inflammatory effects in 2 murine models of colitis. These effects seem to be at least partially independent of MC1R signaling. In conclusion, our data suggest KPV as an interesting therapeutic option for the treatment of IBD.
Research Example #2:
PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation
Background & aims: KPV is a tripeptide (Lys-Pro-Val), which possesses anti-inflammatory properties; however, its mechanisms of action remain unknown. PepT1 is a di/tripeptide transporter normally expressed in the small intestine and induced in colon during inflammatory bowel disease (IBD). The aim of this study was to 1) investigate whether the KPV anti-inflammatory effect is PepT1-mediated in intestinal epithelial and immune cells, and 2) examine the anti-inflammatory effects in two models of mice colitis.Methods: Human intestinal epithelial cells Caco2-BBE, HT29-Cl.19A, and human T cells (Jurkat) were stimulated with pro-inflammatory cytokines in the present or absence of KPV. KPV anti-inflammatory effect was assessed using a NF-kappaB luciferase gene reporter, Western blot, real-time RT-PCR and ELISA. Uptake experiments were performed using cold KPV as a competitor for PepT1 radiolabeled substrate or using [(3)H] KPV to determine kinetic characteristics of KPV uptake. Anti-inflammatory effect of KPV was also investigated in DSS- and TNBS-induced colitis in mice. KPV was added to drinking water and inflammation was assessed at the histologic level and by proinflammatory cytokine mRNA expression.
Results: Nanomolar concentrations of KPV inhibit the activation of NF-kappaB and MAP kinase inflammatory signaling pathways and reduce pro-inflammatory cytokine secretion. We found that KPV acts via PepT1 expressed in immune and intestinal epithelial cells. Furthermore, oral administration of KPV reduces the incidence of DSS- and TNBS-induced colitis indicated by a decrease in pro-inflammatory cytokine expression.
Conclusions: This study indicates that KPV is transported into cells by PepT1 and might be a new therapeutic agent for IBD.
What is BPC-157 Peptide?
BPC 157 is a penta-decapeptide containing a partial sequence of the body protection compound (BPC) isolated from the human gastric juice]. It is stable and resistant to hydrolysis or digestion by enzymes. Previous studies have demonstrated the promoting effect of BPC 157 on the healing of different tissues, including skin, mucosa, cornea, muscle, tendon, ligament and bone in animal studies. The mechanism by which penta-decapeptide BPC 157 accelerates healing is not clearly understood. It has been suggested to include up-regulation of growth factors, proangiogenic effect, and modulation of nitric oxide (NO) synthesis. BPC 157 may also control functions of collagen fragments that are associated with bone morphogenic proteins.Research Example #1:
Stable gastric penta-decapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia) heals ileoileal anastomosis in the rat
Purpose: Gastric penta-decapeptide BPC 157 (BPC 157), which has been shown to be safe in clinical trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia), may be able to cure intestinal anastomosis dehiscence. This antiulcer peptide shows no toxicity, is limit test negative, and a lethal dose is not achieved. It is stable in human gastric juice. In comparison with other standard treatments, it is more effective for ulcers and various wounds, and can be used without a carrier needed for other peptides, both locally and systemically (i.e., perorally, parenterally). We studied the effectiveness of BPC 157 for ileoileal anastomosis healing in rats.Methods: We assessed ileoileal anastomosis dehiscence macroscopically, histologically, and biomechanically (volume [ml] infused through a syringe-perfusion pump system (1 ml/10 s), and pressure [mmHg] to leak induction [catheter connected to a chamber and a monitor, at 10 cm proximal to anastomosis]), at 1, 2, 3, 4, 5, 6, 7, and 14 days. BPC 157 (10 microg, 10 ng, 10 pg/kg i.p. (or saline [5 ml/kg]) was first administered after surgery, while it was last given 24 h before either assessment or sacrifice.
Results: Throughout the experiment, both higher doses of BPC 157 were shown to improve all parameters of anastomotic wound healing. The formation of adhesions remained slight, the blood vessels were filled with blood, and a mild intestinal passage obstruction was only temporarily observed. Anastomosis without leakage induces markedly higher volume and pressure values, with a continuous increase toward healthy values. From day 1, edema was markedly attenuated, and the number of granulocytes decreased, while from days 4 or 5 necrosis decreased and granulation tissue, reticulin, and collagen formation substantially increased, thus resulting in increased epithelization.
Conclusion: This study showed BPC 157 to have a beneficial effect on ileoileal anastomosis healing in the rat.
Research Example #2:
Penta-decapeptide BPC 157 positively affects both non-steroidal anti-inflammatory agent-induced gastrointestinal lesions and adjuvant arthritis in rats
Besides a superior protection of the penta-decapeptide BPC 157 (an essential fragment of an organ protective gastric juice peptide BPC) against different gastrointestinal and liver lesions, an acute anti-inflammatory and analgetic activity was also noted. Consequently, its effect on chronic inflammation lesions, such as adjuvant arthritis, and non-steroidal anti-inflammatory agents (NSAIAs)-induced gastrointestinal lesions was simultaneously studied in rats. In gastrointestinal lesions (indomethacin (30 mg/kg sc), aspirin (400 mg/kg ig) and diclofenac (125 mg/kg ip) studies, BPC 157 (10 μg or 10 ng/kg ip) was regularly given simultaneously and/or 1 h prior to drug application (indomethacin). In the adjuvant arthritis (tail-application of 0.2 mL of Freund's adjuvant) studies (14 days, 30 days, 1 year) BPC 157 (10 μg or 10 ng/kg ip), it was given as a single application (at 1 h either before or following the application of Freund's adjuvant) or in a once daily regimen (0–14th day, 14–30th day, 14th day–1 year). Given with the investigated NSAIAs, BPC 157 consistently reduced the otherwise prominent lesions in the stomach of the control rats, as well as the lesions in the small intestine in the indomethacin groups. In the adjuvant arthritis studies, the lesion's development seems to be considerably reduced after single penta-decapeptide medication, and even more attenuated in rats daily treated with BPC 157. As a therapy of already established adjuvant arthritis, its salutary effect consistently appeared already after 2 weeks of medication, and it could be clearly seen also after 1 year of application. Taking together all these results, the data likely point to a special anti-inflammatory and mucosal integrity protective effect.What is VIP Peptide?
Vasoactive intestinal peptide (VIP) is a 28-residue amino acid peptide first characterized in 1970 that was initially isolated from porcine duodenum. A member of the secretin/glucagon hormone superfamily VIP is evolutionarily well conserved with sequence similarity among fish, frogs, and humans; among mammals, except for guinea pigs and chickens, the sequence similarity is at least 85%.VIP was initially discovered owing to its potent vasodilatory effects (as its name implies). VIP is widely distributed in the central and peripheral nervous system as well as in the digestive, respiratory, reproductive, and cardiovascular systems as a neurotransmitter and neuroendocrine releasing factor. These effects contribute to an extensive range of physiological and pathological processes related to development, growth, and the control of neuronal, epithelial, and endocrine cell function. VIP has also been implicated in the regulation of carcinogenesis, immune responses, and circadian rhythms.
How does VIP work?
The two receptors that recognize VIP, termed VPAC1 and VPAC2, are class B of G-protein-coupled receptors (GPCRs), also known as the secretin receptor family, which includes receptors for VIP, PACAP, secretin, glucagon, glucagon-like peptide (GLP)-1 and -2, calcitonin, gastric inhibitory peptide (GIP), corticotropin-releasing factor (CRF)-1 and -2, and parathyroid hormone (PTH). VPAC1 and VPAC2 are activated by VIP and PACAP, whereas PACAP has its own specific receptor, named PAC1, for which VIP has very low affinity. Through these receptors, VIP can mediate an extensive number of GI functions such as regulating gastric acid secretion, intestinal anion secretion, enzyme release from the pancreas, cellular motility, vasodilation, and intestinal contractility. The localization of VIP, VPAC1, and VPAC2 is closely related to their physiological and pathological functions.Research Example #1:
Vasoactive intestinal peptide decreases inflammation and tight junction disruption in experimental necrotizing enterocolitis
Background and PurposeExcessive inflammatory cell infiltration and accumulation in the intestinal mucosa are pathological features of necrotizing enterocolitis (NEC) leading to intestinal barrier disruption. Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent that regulates intestinal epithelial barrier homeostasis. We previously demonstrated that VIP-ergic neuron expression is decreased in experimental NEC ileum, and this may be associated with inflammation and barrier compromise. We hypothesize that exogenous VIP administration has a beneficial effect in NEC.
Methods
NEC was induced in C57BL/6 mice by gavage feeding, hypoxia, and lipopolysaccharide administration between postnatal day (P) 5 and 9. There were four studied groups: Control (n = 6): Breast feeding without stress factors; Control + VIP (n = 5): Breast feeding + intraperitoneal VIP injection once a day from P5 to P9; NEC (n = 9): mice exposed to NEC induction; NEC + VIP (n = 9): NEC induction + intraperitoneal VIP injection. Terminal ileum was harvested on P9. NEC severity, intestinal inflammation, (IL-6 and TNFα), and Tight junctions (Claudin-3) were evaluated.
Results
NEC severity and intestinal inflammation were significantly decreased in NEC + VIP compared to NEC. Tight junction expression was significantly increased in NEC + VIP compared to NEC.
Conclusion
VIP administration has a beneficial therapeutic effect in NEC by reducing inflammation and tight junction disruption.
Research Example #2:
Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system
Vasoactive intestinal peptide (VIP), a gut peptide hormone originally reported as a vasodilator in 1970, has multiple physiological and pathological effects on development, growth, and the control of neuronal, epithelial, and endocrine cell functions that in turn regulate ion secretion, nutrient absorption, gut motility, glycemic control, carcinogenesis, immune responses, and circadian rhythms. Genetic ablation of this peptide and its receptors in mice also provides new insights into the contribution of VIP towards physiological signaling and the pathogenesis of related diseases. Here, the researchers discuss the impact of VIP on gastrointestinal function and diseases based on recent findings, also providing insight into its possible therapeutic application to diabetes, autoimmune diseases and cancer.
