Stress as a Contributory Factor to Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) affects over 3.1 million people in the United States and more than 2.5 million others in Europe. The number of people affected by the disease is increasing globally, particularly in regions such as South and Eastern Asia (Cao, 2018). IBD is characterized by continuing intestinal inflammation and extra-intestinal indicators, which are probably instigated by a combination of genetic and environmental factors that include medicine use, diet, and infection. The intricate pathophysiology of IBD entails a variety of cell populations in the gastrointestinal tract and different indicating paths from energy homeostasis to innate immune reactions. Cellular stress indications, comprising hypoxic stress, endoplasmic reticulum (ER) stress, and oxidative stress, has been associated in various human pathologies that include autoimmune disease, metabolic disease, cardiovascular disease, neurodegenerative disease, and cancer (Cao, 2018). However, there have been controversies about the role of psychological factors in the emergence of IBD. A conviction in the contribution of psychological aspects to IBD is not new. It emerged as early as in the 1930s (Sajadinejad, Asgari, Molavi, Kalantari, and Adibi, 2012). Experts in mental health such as gastroenterologists and psychoanalysts revealed that the heightening of intestinal complications is mainly instigated by emotional events encountered by people in their normal life. During that time, many people believed that IBD was a psychosomatic disease (Sajadinejad et al., 2012). Its association to stress and other psychological factors was strongly upheld that researchers saw no need to rely on the control group in their research. Some decades later, this belief was questioned mainly because of methodological limitations and uncontrolled studies in this subject (Sajadinejad et al., 2012). For some time, IBD was thought to be an organic condition, and psychological impacts were discounted as causative to it.
The Relationship between Stress and Inflammatory Bowel Disease
Different types of stress are responsible for the emergence of inflammatory bowel disease (IBD). Even minor stress conditions, that include prolonged endurance exercise and chronic mental stress, can prompt the dysfunction of the intestinal barrier (Brzozowski et al. 2016). Stress can perpetuate gastric microcirculation and cause damage to the gastric mucosa. Critically ill patients are at an increased risk of experiencing gastric mucosal lesions due to stress and gastrointestinal bleeding (Brzozowski et al. 2016). Subsequently, stress ulcerations, which are severe gastric mucosal hemorrhagic lesions, are common among severely ill patients after major surgery, trauma to the central nervous system, burns, or sepsis (Brzozowski et al. 2016). The upper and lower effects of stress arise due to the existence of a variety of psychological factors, perceived stress, persistent depression, psychosis, or brain trauma, which may influence a person’s susceptibility and bi-directionality of brain pathways, affecting functions.
Different studies highlight that stress is not the main cause of IBD but exacerbates the condition. Psychological stress can increase the permeability of intestines due to the changes in the cholinergic nervous system and the function of the mucosal mast cell (Sajadinejad, Asgari, Molavi, Kalantari, and Adibi 2012). Different types of mental and physical strain cause a myriad of effects on the elements building up intestinal barrier function. These effects augment the penetrability of intestines and increase the secretion of different substances that include mucus, ions, water, and IgA (Sajadinejad et al., 2012). Due to the increased penetrability, the effectiveness of the mucosal wall is lowered and bacteria-host interaction is adjusted. These factors play a critical role in the pathophysiology of IBD. Psychosocial stress may surge inflammation in different ways, including through influencing the sympathetic nervous system (Miller, Maletic, and Raison 2009). Subclinical low-level inflammation associated with IBD can persist for several years; thus, stress may instigate symptomatic IBD (Melinder, Hiyoshi, Fall, Halfvarson, and Montgomery 2017). Permeability may increase due to inflammation, compromising the strength of the gastrointestinal mucosal barrier. Notably, stress may increase the passage of bacterial pathogens through the epithelial barrier and activate mucosal immune responses.
A majority of IBD symptoms displayed by patients emerge due to stress-instigated changes in gastrointestinal (GI) function. The space between the enteric nervous system and its autonomic is supplied with a large number of nerves which connects the spinal to the central nervous system, dubbed the brain-gut axis (Sajadinejad et al., 2012). Gastrointestinal roles such as secretion, transmission, and sensing and its ability to sense pain can be hampered by emotional and psychological strain. These effects can arise directly or indirectly through the axis; however, they are restored by element P (SP), the protein contained in the vasoactive intestines, the large numbers of neuropeptides, hormones, and transmitters of neurons (Sajadinejad, Asgari, Molavi, Kalantari, and Adibi 2012). Stress increases the rate of discharge of the factor releasing corticotropin from the central and outlying regions of the central nervous system, hypothalamus and the cortex of adrenaline. As the central corticotropin-releasing factor manages the system of ACTH-cortisol, the peripheral corticotropin-releasing factor directly impacts on the motility of the gastro in the intestines. Endogenous factor releasing corticotropin controls the restraint instigated by the stress of the motility of the upper tract of the gastrointestinal and augments the motility of the colon (Sajadinejad et al. 2012). As a result, when symptoms like abdominal pain and variation in bowel function cause IBD without substantial disease involvement, they may be linked, at least in some cases, to changes in motor and sensory function due to psychological stress.
The activities of different stressors are directly associated with inflammatory effects in peripheral tissues that include the gut. The over-expression of substance P in the gut instigates inflammation by numerous independent mechanisms, such as acceleration of leukocyte, mostly white polymorphs, recruitment and consequent infiltration of tissue and facilitation of reactive oxygen metabolites generation, which increase the damage of tissues (Mazelin Theodorou, More, Emonds-Alt, Fioramonti, and Bueno 1998). Activated neutrophils exert antimicrobial activities and are a source of proinflammatory cytokines, which are common in patients with IBD at the place of inflammation. IBD is a chronic condition, and in most cases, patients with chronic diseases experience higher levels of anxiety compared to the general population (Scott et al. 2007). Anxiety disorder affects IBD patients more frequently than anticipated by chance and in particular with Crohn’s disease patients (Bannaga and Selinger 2015). Also, the patients suffering from ulcers of the colitis experience a disorder of anxiety at a higher rate, but this is not the situation with people in good health or those suffering from other types of health conditions. A study of individuals suffering from IBD in reducing and community controls confirmed that those suffering from Crohn’s disease normally experience increased levels of anxiety compared to those used as the control group (Bannaga and Selinger 2015). A different study comparing patients with IBD with healthy controls to evaluate anxiety symptoms revealed that IBD patients had increased levels of anxiety compared to the control group (Addolorato, Capristo, Stefanini, and Gasbarrini 1997). The predominance of anxiety disorder in IBD patients is rising (Goodhand et al. 2012). Among IBD patients, the level of anxiety has been projected between 29 per cent and 35 per cent during times of remission and as high as 80 per cent during relapses (Nahon et al. 2012). The link between symptoms and levels of anxiety are strong.
The indications of IBD can instigate changes in the patients’ mental status. Many researchers have established that mental strain and mood syndromes can result in relapses in IBD (Mawdsley and Rampton 2005). These findings were made in assessments conducted on rats. The researchers prompted an irritation like that caused by colitis that triggers ulcers using the dextran sodium sulfate. The researchers discovered that ulcerative colitis-like inflammation in rats instigates behaviours that resemble anxiety and ongoing abdominal discomfort (Chen et al. 2015). This experiment confirmed the impression of different physicians that physical symptoms can prompt anxiety. However, there is uncertainty on whether anxiety in IBD patients can cause a flare of their condition. The progression of IBD is closely associated with mental signs because anxiety instigates sparkles of IBD indicators. A study on individuals suffering from Ulcerative colitis proved that inflammation caused by the mucosal, which remains active, is as a result of more mental strain (Bernstein, Singh, Graff, Walker, Miller, and Cheang, 2010). For this reason, these findings confirmed that inflammation control is necessary for both the psychological and physical well-being of IBD patients.
Different types of stress change brain-gut axis contribute to a variety of gastrointestinal conditions such as IBD and irritable bowel syndrome (IBS) among many other functional gastrointestinal conditions. Incidences that cause psychological strain and diverse stressors also may influence the progress of IBD by heightening it (Brzozowski et al. 2016). The brain transmits the messages of different forms such as endocrine, neural, and circulatory to the gut through the configuration of the brain and the gut, reproducing modifications in hormones that discharge corticotrophin. These activities influence the pathogenesis of human IBD and animal colitis (Brzozowski et al. 2016). Stress initiates an increase in cortisol levels and hypothalamus-pituitary axis and triggers the autonomic nervous system and proinflammatory cytokines, such as interleukin-8, interleukin-6, interleukin-1beta, and tumour necrosis factor-alpha.
Studies reveal that psychological stress impacts on intestinal barrier function and interactions of bacterial-host. If rats are forced to undergo the experience of curtailed movement, they display augmented penetrability of their colons and jejunal, prompting the body organs to allow the passage of different substances. For instance, they allow the molecules of inert marker that comprise mannitol and Cr-EDTA to pass through. Also, they permit the passage of horseradish peroxidase among other proteins that are antigenic (Kiliaan et al. 1998). Ordinary conditions make it possible for horseradish peroxidase to penetrate the cells of the epithelial via pinocytosis; however, after long durations of stressing experiences triggered by curtailed movement, paracellularly penetrates the layer of epithelia. Even though the mucosa of the gut displayed ordinary appearance to exploration undertaken using a light microscope, when scrutinized using electron microscopy, it exposed amplified HRP within endosomes between the cells and in intersections of intraepithelial that contain cells that are tightly arranged (Santos et al. 1999). Also, chronic stress heightens the impact of acute stress because of initial separation of maternal increases restraint stress-induced high levels of permeability (Söderholm et al. 2002). The augmented penetrability triggered by stress were seen to be influenced by cholinergic innervation. These circumstances emerge as a result of their blockage by atropine and were more evident in rats of the Wistar-Kyoto group because they had insufficient cholinesterase (Saunders, Hanssen, and Perdue 1999). Cells of the mast are also instrumental in managing porousness variations since the rats that had insufficient mast cell and put in long-term stress from curtailed movement became slender at the same magnitude with the wild-type of rats. However, they did not exhibit changes in the penetrability of their intestines (Santos et al. 2000). Stress caused by curtailed mobility heightened the contents of histamine in the mast of the rats’ cells of the colon discharging mucus (Eutamene et al. 2003). This effect seemed to be dependent on both central factor that discharges corticotrophin and interleukin.
Reduced hypothalamic-pituitary-adrenal (HPA) axis function makes some organisms like rodents vulnerable to stress induced rises in gastrointestinal inflammation. If HPA axis function is minimized in IBD patients, this outcome may be relevant to stress prompted increases in disease activity (Mawdsley and Rampton 2005). LEW/N rats displayed minimal volumes of CRF in the nucleus of the hypothalamus and paraventricular, while the control groups showed more quantities of the substances (Mawdsley and Rampton 2005). They have a considerably abridged plasma ACTH and reaction of corticosterone to stimuli that are strenuous. Moreover, they are more prone to irritating conditions that include arthritis instigated by doses put on the articular of the walls of the cells of streptococci (Mawdsley and Rampton 2005). Also, LEW/N rats display an increased vulnerability to trinitrobenzene sulfonic acid (TNBS) induced colitis, an impact dependent on coexisting stress (Million, Taché, and Anton 1999). Therefore, although after seven days of TNBS application, the creatures that are naive to stress displayed a comparable degree of irritation of their intestine, there were higher degrees of irritation of the intestines in LEW/N rats. The level of irritation was minimal among the appropriate control animals if their movement was curtailed for six days after which they were subjected to TNBS.
IBD can lead to the emergence of innumerable problems that affect diverse systems of the body. A person can suffer from Crohn’s disease in any part of the digestive tract. It can occur anywhere from the mouth to anus. However, most often, the condition results in inflammation around the ileocaecal region (Selinger et al. 2014). The major complications experienced in the intestines due to Crohn’s disease include the extensive inflammation of the intestines. It can also be suffered in the form of perforation, ulcers, and blockade (Selinger et al. 2014). Notwithstanding the use of immunosuppressants, about 80 per cent of patients with perforation will eventually require surgery, most often for ileal structuring or refractory of the disease to medical interventions. Individuals suffering from refractory in most cases have to undergo a subsequent operation after some years of the initial resection of the intestines.
Pathogens, comprising enterotoxigenic E. coli (ETEC), EPEC, and enterohaemorrhagic E. coli (EHEC), may trigger myosin light chain kinase, resulting in the contraction of the circumferential actomyosin ring. This occurrence causes damage to cell junctions and impacts on the permeability (Yu et al. 2015). Also, pathogens can discharge toxins that target the proteins of tight junction such as Clostridium perfringes enterotoxin (CPE), Vibrio cholerae HA/P, and Bacteroides fragilis toxin, resulting in the disruption of the complexes of cell junction and reduced function of the barrier (Yu et al. 2015). Pathogens attack intestinal mucosal barrier through antigen presenting cells phagocytosis, dendritic, and microfold cells; or by entering the intestinal epithelial directly. A number of pathogens could destroy the cell junction across the epithelial cells and enter through the paracellular pathway to invade (Yu et al. 2015). Furthermore, some Lactobacillus could hamper the bonding of the pathogens and guard the strength of the mucosal barrier and cell junction.
Probiotics or prebiotics are beneficial to the animals and are widely used as functional foods because they can moderate the balance and functioning of the gastrointestinal (GI) microbiota. Different factors that include dietary and management limitations significantly impact on the activities and structure of gut microbial communities in animals such as livestock (Uyeno, Shigemori, and Shimosato 2015). Different studies have discovered the potential of probiotics and prebiotics in the nutrition of animals. Nevertheless, their effectiveness frequently changes and is inconsistent for different reasons, including due to the dynamics of the GI community (Uyeno, Shigemori, and Shimosato 2015). In stressed conditions, microbials that are directly-fed may be used to minimize the risk or intensity of scours emerging due to the interference with the normal intestinal environment. Also, the noticeable benefits of prebiotics may be insignificant in healthy calves in instances where the microbial community is moderately stable (Uyeno, Shigemori, and Shimosato 2015). However, strains of probiotic yeast have been applied with the intent of improving the efficiency of rumen fermentation by managing the pathways of microbial fermentation.
Although the causes of the major types of IBD have remained contentious for several years, research has shown that innumerable factors are the major contributors to their emergence or reduction. The most known IBD types are Crohn’s disease (CD) and ulcerative colitis (UC). One of the leading causative factors includes gut microbiota (Scaldaferri, et al. 2013). Gut microbiota is made up of at least one thousand distinct species and not less than 15,000 varieties of bacteria in an area whose capacity is the weight of around one kilogramme (Scaldaferri et al. 2013). Although there are a limited number of bacteria in the stomach and small intestines, there are more than 1012 types in the colon. A majority of these organisms are members of the phyla Firmicutes and Bacteroidetes (Scaldaferri et al. 2013). Eukarya and Archaea are also among the list of organisms in the stomach region and small intestines. Studies have also proved that there are a large number of viruses and bacteriophages in these regions. A large number of yeast species shield the microbiota of the gut microbiota. The main role of this organ is to facilitate the physiology of the intestines’ gastro, although there is uncertainty on whether it influences the emergence or progression of diseases (Scaldaferri et al. 2013). Many studies support the proposition that the microbiota of the gut is instrumental in the commencement of IBD, a proposition supported by several assessments conducted on some animals or in models of vitro. The most affected parts of the intestines among individuals suffering from IBD contain large numbers of bacteria (Scaldaferri et al. 2013). These findings confirm that the mice lacking germs do not instigate colitis. Moreover, the rate of the reemergence of Crohn’s disease usually experienced after operation and pouchitis is more when there is a subsequent formation of streams of faeces.
The use of antibiotics affects the gut microbiota. After this treatment is used, there are significant changes in the composition of gut microbiota composition. The impact decreases the diversity of microorganisms in the digestive tract from one-fourth to one-third area (Panda et al. 2014). The microbiota is comparatively strong and several weeks after the cessation of the drug use, it remains as it was before the treatment. Accordingly, an increase in the number of groupings of bacteria, such as Bacteroidetes and Gram-negative, causes a decline in the population of microorganism taxa by approximately 25 per cent; this is the most common outcome irrespective of the type of antibiotic applied (Panda et al. 2014). Many studies have revealed that bacteria species, especially those of the Bacteroides group, are highly responsive to amoxiclav and levofloxacin when culture strategies are utilized. These medications extensively multiply a wide variety of taxa from these groups of bacteria.
There are varied findings and thoughts regarding the extent to which stress is a contributory factor of inflammatory bowel disease. Some studies reveal that different varieties of stress, including the slightest stress conditions, cause IBD. Stress instigates the dysfunction of the intestinal barrier and propagates gastric microcirculation, damaging the gastric mucosa. These effects have been approved by evidence that seriously ill patients risk gastric mucosal lesions more than other people since the patients encounter stress and gastrointestinal bleeding. However, other studies confirm that stress is not the only cause of IBD, but it aggravates the disease. For instance, mental strain augments the penetrability of intestines because of the alterations made on the cholinergic nervous system and the functioning of the mast cell of mucus. Psychological stress affects the functions of the barriers of the intestines and interactions of bacterial-host. IBD causes a myriad of problems that affect a person’s body systems. The affected persons experience these problems in different parts of their digestive tracts. They suffer from the inflammation of their ileocaecal region since the attacks occur anywhere from the mouth to the anus.
Addolorato, G., Capristo, E., Stefanini, G. F. and Gasbarrini, G. (1997) Inflammatory bowel disease: a study of the association between anxiety and depression, physical morbidity, and nutritional status. Scand J Gastroenterol. 32(10) pp. 1013-21. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9361174
Bannaga, A. S. and Selinger, C. P. (2015) Inflammatory bowel disease and anxiety: links, risks, and challenges faced. Clinical and Experimental Gastroenterol. 8 pp. 111–117. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376063/
Bernstein, C. N., Singh, S., Graff, L. A., Walker, J. R., Miller, N. and Cheang, M. (2010). A prospective population-based study of triggers of symptomatic flares in IBD. Am J Gastroenterol. 105(9) pp. 1994-2002. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20372115
Brzozowski, B., Mazur-Bialy, A., Pajdo, R., Kwiecien, S., Bilski, J., Zwolinska-Wcislo, M., Mach, T. and Brzozowski, T. (2016) Mechanisms by which stress affects the experimental and clinical inflammatory bowel disease (IBD): Role of brain-gut axis. Curr Neuropharmacol. 14(8) pp. 892–900. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333596/
Cao, S. S. (2018) Cellular stress responses and gut microbiota in inflammatory bowel disease. Gastroenterol Research and Practice. 2018; 2018: 7192646. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031203/
Chen, J., Winston, J. H., Fu, Y., Guptarak, J., Jensen, K. L., Shi, X. Z., Green, T. A., Sarna, S. K. (2015) Genesis of anxiety, depression, and ongoing abdominal discomfort in ulcerative colitis-like colon inflammation. Am J Physiol Regul Integr Comp Physiol. 308(1) pp. 18-27. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281679/
Eutamene, H., Theodorou, V., Fioramonti, J. and Bueno, L. (2003) Acute stress modulates the histamine content of mast cells in the gastrointestinal tract through interleukin-1 and corticotropin-releasing factor release in rats. Journal of Physiology. 553(3) pp. 959-66. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14555722
Goodhand, J. R., Wahed, M., Mawdsley, J. E., Farmer, A. D., Aziz, Q. and Rampton, D. S. (2012) Mood disorders in inflammatory bowel disease: relation to diagnosis, disease activity, perceived stress, and other factors. Inflammatory Bowel Disease. 18(12) pp. 2301-9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22359369
Kiliaan, A. J., Saunders, P. R., Bijlsma, P. B., Berin, M. C., Taminiau, J. A., Groot, J. A. and Perdue, M. H. (1998) Stress stimulates transepithelial macromolecular uptake in rat jejunum. Am J Physiol. 275(5) pp. 1037-44. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9815034
Mawdsley, J. E. and Rampton, D. S. (2005) Psychological stress in IBD: new insights into pathogenic and therapeutic implications. Gut. 54(10) pp. 1481-91. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774724/#r95
Mazelin, L., Theodorou, V., More, J., Emonds-Alt, X., Fioramonti, J. and Bueno, L. (1998) Comparative effects of nonpeptide tachykinin receptor antagonists on experimental gut inflammation in rats and guinea-pigs. Life Sci. 63(4) pp. 293-304. Retrieved from https://www.researchgate.net/publication/223542111_Comparative_effects_of_nonpeptide_tachykinin_receptor_antagonists_on_experimental_gut_inflammation_in_rats_and_guinea-pigs
Melinder, C., Hiyoshi, A., Fall, K., Halfvarson, J. and Montgomery, S. (2017) Stress resilience and the risk of inflammatory bowel disease: a cohort study of men living in Sweden. BMJ Open. 7(1). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278277/
Miller, A. H., Maletic, V. and Raison, C. L. (2009) Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 65 pp. 732–41. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680424/
Million, M., Taché, Y. and Anton, P. (1999) Susceptibility of Lewis and Fischer rats to stress-induced worsening of TNB-colitis: protective role of brain CRF. American Journal of Physiology. 276(4) pp 1027-36. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10198347
Nahon, S., Lahmek, P., Durance, C., Olympie, A., Lesgourgues, B., Colombel, J.F., Gendre, J. P. (2012) Risk factors of anxiety and depression in inflammatory bowel disease. Inflammatory Bowel Disease. 18(11) pp. 2086-91. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22294486
Panda, S., El khader, I., Casellas, F., Vivancos, L. J., García, C. M., Santiago, A., Cuenca, S., Guarner, F. and Manichanh, C. (2014. Short-term effect of antibiotics on human gut microbiota. PLOS ONE, vol. 9, no. 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991704/
Sajadinejad, M. S., Asgari, K., Molavi, H., Kalantari, M. and Adibi, P. (2012) Psychological issues in inflammatory bowel disease: An overview. Gastroenterology Research and Practice, 2012, Article ID 106502, 11 pages. Retrieved from https://www.hindawi.com/journals/grp/2012/106502/
Santos, J., Saunders, P. R., Hanssen, N. P., Yang, P. C., Yates, D., Groot, J. A. and Perdue, M. H. (1999) Corticotropin-releasing hormone mimics stress-induced colonic epithelial pathophysiology in the rat. Am J Physiol. 277(2) pp. 391-399. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10444454
Santos, J., Benjamin, M., Yang, P. C., Prior, T. and Perdue, M. H. (2000) Chronic stress impairs rat growth and jejunal epithelial barrier function: role of mast cells. Am J Physiol Gastrointest Liver Physiology. 278(6) pp. 847-54. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10859213
Saunders, P. R., Hanssen, N. P. and Perdue, M. H. (1997) Cholinergic nerves mediate stress-induced intestinal transport abnormalities in Wistar-Kyoto rats. Am J Physiol. 273(2 Pt 1) pp. 486-90. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9277429
Scaldaferri, F., Gerardi, V., Lopetuso, L., Del Zompo, F., Mangiola, F., Boškoski, I., Bruno, G., Petito, V., Laterza, L., Cammarota, G., Gaetani, E., Sgambato, A. and Gasbarrini, A. (2013) Gut Microbial Flora, Prebiotics, and Probiotics in IBD: Their Current Usage and Utility. BioMed Research International, 2013, pp.1-9. Retrieved from https://www.hindawi.com/journals/bmri/2013/435268/
Scott KM, Bruffaerts R, Tsang A, Ormel J, Alonso J, Angermeyer MC, Benjet C, Bromet E, de Girolamo G, de Graaf R, Gasquet I, Gureje O, Haro JM, He Y, Kessler RC, Levinson D, Mneimneh, Z. N., Oakley, Browne, M. A., Posada-Villa, J., Stein, D. J., Takeshima, T. and Von Korff, M. (2007) Depression-anxiety relationships with chronic physical conditions: results from the World Mental Health Surveys. J Affect Disord. 103(1-3) pp. 113-120. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17292480
Selinger, C. P., Andrews, J. M., Titman, A., Norton, I., Jones, D. B., McDonald, C., Barr, G., Selby, W., Leong, R.W. and Sydney I. B. D. (2014) Long-term follow-up reveals low incidence of colorectal cancer, but frequent need for resection, among Australian patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 12(4) pp. 644-50. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23707778
Söderholm, J. D., Yates, D. A., Gareau, M. G., Yang, P. C., MacQueen, G. and Perdue, M. H. (2002) Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am J Physiol Gastrointest Liver Physiol. 283(6) pp. 1257-63. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12388189
Uyeno Y., Shigemori S. and Shimosato T. (2015), Effect of Probiotics/Prebiotics on Cattle Health and Productivity. Microbes Environment. 30(2) pp. 126–132. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462921/
Yu, Q., Yuan, L., Deng, J. and Yang, Q. (2015). Lactobacillus protects the integrity of intestinal epithelial barrier damaged by pathogenic bacteria. Front Cell Infect Microbiol. 5(26). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373387/
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