The Role of Probiotics in Intestinal Inflammation


short-chain fatty acids, promotion of epithelial and immunological cell physiology, and protection against potential pathogenic bacteria.


Bacteria in general should not be regarded as solitary independent organisms, but influence the function of neighboring congeners. Bacterial cell-to-cell communication is known as quorum sensing and mediates bacterial behavior such as biofilm formation, expression of virulence factors, sporulation, and motility.3


Moreover, some bacteria


Finally, the biologic function and composition of the native microbiome can be influenced by non-digestible oligosaccharides, i.e. prebiotics, indicating that certain foods modulate the composition and biologic function of the intestinal microbiome.5


interfere with cell-to-cell communication of competitive strains, providing them with an advantage for niche occupation and colonization (bacterial competition).4


Probiotics and Normal Intestinal Barrier Function Of all body surfaces, the intestinal tract constitutes the largest area in contact with the exterior environment; the intestinal barrier is continuously exposed to a wide variety of different, potentially pathogenic micro-organisms requiring efficient strategies to prevent infectious events. The first line of defence consists of several antimicrobial mechanisms that mostly act independently of each other. The continuous lining of intestinal epithelial cells, with its tight junctions and brush border, is an important element in the innate defense mechanism. The intestinal epithelium undergoes rapid and perpetual self-renewal. During exfoliation of apoptotic cells at the top of the villus, mucus-resident bacteria are removed with the fecal stream. Furthermore, specialized intestinal epithelial cells (goblet cells and Paneth cells) are responsible for the secretion of antimicrobial substances (mucus, defensins, and trefoil factors) in order to edit the intestinal microbiome. This function is thought to be of particular benefit to the mucosal stem cells at the base of the crypts, allowing continuous mucosal renewal.


Goblet cells are distributed along the entire gastrointestinal tract and are responsible for the production of different mucin-type glycoproteins. The mucus membrane can be divided into different layers with compositional differences. Bacterial modulation of mucin secretion by goblet cells is a general microbiologic principle, as both probiotic and pathogenic bacteria are able to degrade mucus and modulate mucin production.6 Many experiments with human primary epithelial cell lines and rodents describe the ability of probiotic bacteria to promote mucin secretion.7 However, these experiments have not been performed in humans and the clinical relevance for adopting probiotics to improve mucus integrity remains promising but evidence is lacking.


Defensins are small proteins secreted by Paneth cells with broad antimicrobial activity, and are thought to play an important role in microbiome editing by the host. Interesting work by Schlee et al. has nicely delineated that Escherichia coli Nissle 1917, which has probiotic effects, and the probiotic mixture VSL#3 are able to induce the expression and secretion of human defensin-2 through activation of toll-like receptor-5 (TLR-5) by flagellin.8


However, flagellin and


enterotoxins from commensal and pathogenic bacteria, respectively, are also able to induce human defensin-2 in epithelial cells.9,10


The


induction of human defensin-2 expression appears to be a general microbiologic effect and the additive effect of probiotic-induced


US GASTROENTEROLOGY & HEPATOLOGY REVIEW Biological effects


Figure 1: A Discrepancy between In Vitro Biologic Effects and In Vivo Clinical Effects of Probiotics Exists Due to Several Modifying Factors Present in the In Vitro Situation


Modifying factors Prebiotics


Microbiome factors Host immunity Quorum effect


Clinical effects


Table 1: Summary of Probiotic Effects on Intestinal Barrier Function


Improvement of mucus secretion and composition by goblet cells6,7 Induction of antimicrobial peptide secretion by Paneth cells8 Improvement of tight-junction stability in epithelial cells11–13 Increased epithelial cell proliferation41,42 Decreased epithelial cell apoptosis43,44


Enhanced specific and non-specific immunoglobulin A secretion45


defensin secretion in a complex environment such as the intestinal microbiome remains doubtful. Although defensin production appears to be diminished in chronic inflammatory bowel disease, clinical studies showing a biologic effect of probiotics on defensin expression and/or secretion are lacking.


In contrast to microbial influence on defensin and mucus production, a clear distinction exists between probiotic and pathogenic effects on tight-junction stability. While pathogenic bacteria secrete various enterotoxins that intervene in cytoskeletal and tight-junction stability,11 probiotic bacteria stabilize tight junctions, with resulting increased barrier function during stress. This protective effect of probiotics is thought to be mediated by a soluble bacterial factor through protein kinase C (PKC) activation.12,13


In conclusion, intestinal barrier function can be influenced by probiotics in multiple ways but some of the effects are not unique. Commensal and/or pathogenic bacteria can have similar effects, making it difficult to assess the probiotic health effect. Tight-junction stability might be an exception in this regard.


Probiotics and Normal Mucosal Immune Function It is remarkable that the immune system is able to distinguish between the endless diversity of antigens present in the intestinal system and to decide when an immune response is needed. The most advocated theory for understanding this delicate regulation is the idea that the immune system functions by discriminating between self (defined early in life in the thymus) and non-self (anything that comes later), tolerating self, and attacking non-self. Although this principle is very useful in understanding many immunological processes, including auto-immunity, it is not very applicable to the induction of tolerance against the microbiome in the intestinal system. As mentioned earlier, the microbiome is enormously diverse and antigenic epitopes are modified during bacterial multiplication. Even though the composition


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