Inflammatory bowel diseases (IBD) consist mainly of two forms, ulcerative colitis (UC) and Crohn's disease (CD). The occurrence rate of these two diseases in Japan is about 1/5-1/10 of that in the West, however the incidences of UC and CD have been increasing by about 10% per year in Japan. Previously, the pathogenesis of IBD was thought to be autoimmune disease, however, in recent years, intestinal bacteria are believed to be involved in the initiation and perpetuation of IBD. In IBD animal models such as the IL-10 KO mouse and of DSS colitis, probiotics such as lactobacilli and bifidobacteria ameliorate or cure the inflammation and it is worth noting that probiotics are therapeutic agents for IBD. In fact, there is mounting evidence that probiotics are effective for UC patients but not for CD patients. This review examines the data of all fully published articles currently available on the role of probiotics in the treatment of IBD.

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Inflammatory bowel diseases (IBD) are caused by excessive tissue damage through chronic inflammatory responses in the gut wall, and commonly take persistent courses. According to present understanding, the diseases are caused by infiltrated colitogenic effector/memory CD4⁺ T cells within the inflamed mucosa, which are presumably primed by commensal antigen-loading dendritic cells in lymphoid tissues. However, the nature of colitogenic CD4⁺ T cells over time during chronic colitis under the persistent presence of commensal bacteria remains largely unknown. Toll-like receptors (TLRs) that mediate the recognition of pathogen-associated molecular patterns (PAMPs) are widely expressed on/in cells of the innate immune system. However, recent findings have demonstrated that certain TLRs are also expressed in conventional TCRαβ⁺ T cells that are critically involved in the acquired immune system, suggesting that TLR ligands can directly modulate T cell function in addition to various innate immune cells. We here report that in a murine model of chronic colitis induced in RAG-2^-/- mice by adoptive transfer of CD4⁺CD45RB^high T cells, both CD4⁺CD45RB^high donor cells and the expanding colitogenic lamina propria (LP) CD4⁺CD44^high memory cells expressed a wide variety of TLRs along with MyD88, a key adaptor molecule required for signal transduction through TLRs. Although RAG-2^-/- mice with adoptive transfer of MyD88^-/- CD4⁺CD45RB^high cells developed colitis, the severity was reduced with delayed kinetics of clinical course, and the expansion of colitogenic CD4⁺ T cells was significantly impaired as compared with control mice with adoptive transfer of MyD88^+/+ CD4⁺CD45RB^high cells. When RAG-2^-/- mice received the same number of MyD88^+/+ (Ly5.1⁺) and MyD88^-/- (Ly5.2⁺) CD4⁺CD45RB^high cells, MyD88^-/- CD4⁺ T cells showed significantly lower proliferative responses as assessed by the in vivo CFSE division assay, lower expression of anti-apoptotic Bcl-2/Bcl-xL molecules and less production of IFN-γ and IL-17, compared to recipients of paired MyD88^+/+ CD4⁺ T cells. In conclusion, we demonstrated that the MyD88-dependent pathway, which mediates downstream signals of TLRs, is crucially involved in the proliferative and survival responses of colitogenic CD4⁺ T cells which are required for the perpetuation of chronic colitis. Thus, in addition to the specific commensal antigens, homeostatic cytokines, and co-stimulatory molecules, therapeutic approaches targeting PAMPs may be feasible in the treatment of IBD.

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Using rats as experimental animals, the authors obtained evidence that in the hypoglycemic condition, foods, scents and music affect physiological phenomena via changes in autonomic neurotransmissions. Intracranial injection of 2-deoxy-D-glucose, an inhibitor of glucose metabolism, excited sympathetic nerves innervating the pancreas, liver and adrenal gland, elevating blood glucose. L-carnosine which is synthesized in muscles, was released into the blood during exercise and inhibited sympathetic nerves innervating the pancreas, liver, kidney and adrenal gland, reducing the blood pressure and the blood glucose levels. Olfactory stimulation with the scent of grapefruit oil excited sympathetic nerves innervating the white and brown fats, adrenal gland and kidney, increasing lipolysis, body temperature, the blood glucose and blood pressure levels, and suppressed the gastric parasympathetic nerve, lowering appetite and the body weight. However, olfactory stimulation with the scent of lavender oil inhibited sympathetic nerves innervating the white and brown fats, adrenal gland and kidney, decreasing lipolysis, body temperature, the blood glucose and blood pressure levels, and enhanced the gastric parasympathetic nerve, increasing appetite and body weight. Acuostic stimulation with the music of Traumerei inhibited the renal sympathetic nerve and lowered the blood pressure. There were diurnal rhythms in these responses and lesions of the hypothalamic suprachiasmatic nucleus (SCN), a master circadian clock, or histamine receptor blockers eliminated these responses. With respect to lactobacilli, intestinal injection of Lactobacillus Johnsonii La1 (NCC533) suppressed sympathetic nerves innervating the adrenal gland and kidney, lowering the blood glucose and blood pressure levels, and facilitated the gastric parasympathetic nerve elevating appetite and the body weight. Intestinal injection of Lactobacillus paracasei ST11 (NCC2461) excited sympathetic nerves innervating the white and brown fats and adrenal gland increasing lipolysis, and body temperature, and suppressed the gastric parasympathetic nerve reducing appetite and body weight. Infradiaphragmatic vagotomy eliminated the suppression of renal sympathetic nerve activity by NCC533, but did not affect excitation of the renal sympathetic nerve by NCC2461. Moreover, lesions of the SCN or a histamine H3-receptor antagonist, thioperamide, eliminated the suppression of renal sympathetic nerve activity and blood pressure, the enhancement of the gastric parasympathetic nerve induced by NCC533; and a histamine H1-receptor antagonist, diphenhydramine, abolished elevations of renal sympathetic nerve activity and blood pressure due to NCC2461. These facts suggest that the SCN and histamine neurons are involved in the effects of these lactobacilli on autonomic nerves and physiological phenomena.

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