ReEstablishing Mucosal Tolerance Probiotics Prebiotics Worms and Toll Like Receptor Modulators

The coincidental rise in IBD in the developing world with the decline of helminthic parasitic infection is one aspect of a hygiene hypothesis that suggests that in a sanitary world the mucosal immune system has become functionally less important. An idle GI immune system may not necessarily be desirable. Indeed, reports indicating that administration of the helminths Trichuris suis or Heligmosomoidespolygyrus is effective at reversing the inflammation and inducing clinical remission41 directly support this notion.

The luminal microfloral environment profoundly influences the extent and severity of inflammation observed in many of the described preclinical models of colitis.42 Alternatively, administration of beneficial bacterial species (probiotics), poorly absorbed dietary oligosaccharides (prebiotics), or combined agents (symbiotics) can restore the balance of beneficial Lactobacillus and Bifidobacterium species over the pathogenic flora contributing to disease. For instance, when either IL10 _ /_ mice are treated with antibiotics or Lactobacillus GG,43'44 or DSS-induced colitic mice are treated with a preparation of Bifidobacterium longum,45 the extent of the inflammation is dramatically reduced. The most common chronic complication affecting UC patients following ileal pouch-anal anastamosis is the development of pouchitis, a further idiopathic inflammatory condition of the neorectal ileal mucosa. Antibiotics, in particular metronidazole and ciprofloxacin, are often used as first-line therapy, but increasingly probiotics are being considered. For instance the mixture VSL#3 (6 g day_ 1), containing a number of strains of Lactobacillus, Bifidobacterium, and Streptococcus, induces remission.46 While these observations are encouraging, and probiotics can contribute to sustaining clinical remission, a single combination of components has not been identified that induces remission and has clear benefit in the treatment of CD and UC.

As noted previously, the TLR system discriminates between many different microbial signatures and its role in controlling both normal gut immune homeostasis and pathogenesis is becoming dissected. Mucosal TLR4 expression is upregulated in UC patients and both the genetic epidemiology and the phenotype of the TLR4 _ /_ mouse in response to DSS47 would suggest that TLR4 antagonists might be one approach to the treatment of IBD, which builds on the experience with probiotics. E5564/Eritoran (8)48 is a synthetic TLR4 antagonist currently in clinical assessment for sepsis, but an assessment either preclinically or clinically in IBD models is awaited. In contrast, CRX-526, a close structural homolog to E5564, prevents the development of colonic inflammation in both DSS-induced colitis and the Mdr1a ~/ _ models, as well as suppressing TNF-a release from monocytes in vitro and in vivo.49 Similarly, TLR9 agonists (unmethylated CpG DNA of bacteria and viruses, or immunostimulatory oligodeoxynucleotides, such as CPG 7909 [5'-TCG-TCGTTTTGTCGTTTTGTC-GTT3']50) prevent or ameliorate the severity of colonic inflammation in either the IL10_ / _ or DSS-induced models of colitis.51,52 The mechanism by which TLR9 ligands are able to achieve this seems to be in part the ability to trigger an anti-inflammatory IFN-a/b response.6 Initial clinical studies have also recently confirmed the beneficial effects of type I interferons in the treatment of UC,53 supporting the notion that UC is a Th2 polarized disease. Our understanding of both the functional roles of specific TLR family members and the discovery of selective tools to investigate their function in disease is still in its infancy. However, the compelling connection between the components of innate and adaptive immunity (TLR, NOD2, etc.), the effect of probiotics, and the rise in IBD in a sanitized world, suggests that TLR-based therapeutics may have a significant contribution in future disease management.

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