The gut is an organ that absorbs nutrition and water, and it also plays a critical role as an immunoregulatory organ. Recent basic and clinical research studies have reported the relationships among the gut microbiota, intestinal immunoregulatory, and the incidence of several diseases. Especially, recent papers have reported the significance of gut bacterial flora in the pathogenesis of obesity and metabolic diseases including diabetes mellitus. Similarly, several papers have reported the significance of gut microbiota and the intestinal immune system in atherogenesis. In this article, we introduce and summarize the state of the art of this research area and discuss future perspectives.

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Generally, normal bacterial microbiota play an important role in inhibiting the growth of pathogenic bacteria in the intestine or on the skin, and stimulate the immune responses of host animals. In aquaculture, mortalities of larvae and fry of cultured fish due to viral diseases remain a major problem for regular food production. Although vaccines can be useful to control viral diseases, because of a immature immune system, they are not effective during the early stages of larval growth. Therefore alternative strategies to control viral diseases are required for sustainable aquaculture and seed production. We investigated fish pathogenic viruses in an aquatic environment in order to understand their survival and interactional relationships with bacteria for the prevention of fish viral diseases in aquaculture. In a series of studies of the microbial ecosystem, we found that many bacteriaproducing antiviral substances could be isolated from aquatic environments, such as hatchery water supply, river mouth water, beach water, and intestinal contents of aquatic animals. Intestinal bacteria, such as Aeromonas spp. and Vibrio spp. producing anti-viral substances were isolated from intestinal contents of masu salmon (Oncorhynchus masou), Japanese flounder (Paralichthys olivaceus), barfin flounder (Verasper moseri) and Pacific oyster (Crassostrea gigas). Aeromonas strains produced anti-infectious hematopoietic necrosis (IHNV; Novirhabdovirus) substances, and Vibrio strains showed anti-IHNV, salmonid herpesvirus Oncorhynchus masou virus (OMV; Salmonivirus), hirame rhabdovirus (HIRRV), barfin flounder nervous necrosis virus (BF-NNV; Nodavirus) and feline calicivirus (FCV) activities. When A. hydrophila strains M-26 and M-38 were mixed with food pellets and fed to rainbow trout (O. mykiss) and masu salmon, both bacteria became dominant in the intestinal microbiota and anti-IHNV activity was observed in homogenates of intestinal contents. These rainbow trout and masu salmon fed the Aeromonas spp. showed more resistance to artificial IHNV challenge tests. Barfin flounder fed Vibrio spp. strains 2IF6 with Altemia sp. showed anti-IHNV, OMV, HIRRV and BF-NNV activities in their intestinal contents. Larvae fed the Vibrio spp. showed a higher survival rate than the control fish. In the case of Japanese flounder larvae fed with V. alginolyticus strain V-23 manipulated rotifer showed anti-OMV (FHV; flounder herpesvirus surrogate) activities in the intestinal contents and rearing water in the tank. Furthermore, V. neptunis strain V-176 and Vibrio sp. Strain V-4 isolated from intestinal contents of Pacific oyster showed anti-feline calicivirus (FCV; Norovirus surrogate) and OMV (Ostreid herpesvirus-1 microvariant (OsHV-1 μVar) surrogate) activities. Norovirus and OsHV-1μVar will hopefully be inactivated in the intestines of oysters fed V. neptunis V-176 or Vibrio sp. V-4 with Chaetoceros gracilis, respectively. These results show that, by manipulating diets with anti-viral substance-producing bacteria, the resistance of fish or shellfish larvae to viral disease can be improved thereby helping to ensure regular food production through aquaculture.

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A few studies have investigated the effect of fermented product of soybean milk on human health. This study evaluated the effects of soybean milk-fermented product (SFP) on the intestinal flora of humans, and colorectal carcinogenesis in animals. SFP was prepared by culturing soybean milk with lactic acid bacteria and yeast. The effect of SFP (450 mg/day) on human fecal flora was determined by comparing the changes in intestinal flora between human volunteers consuming SFP and those taking a placebo. The occupation rate of Bifidobacterium of more than 25% was greater in the SFP group (n=11) than in the placebo group (n=10, P<0.05). The occupation rate of Clostridium in fecal flora of the volunteers (n=5) increased after shifting from a traditional Japanese diet (TJD) to a Western diet (WD), in which a total daily amount of 300 g of meat (900 kcal) was eaten once at lunch for 3 days (P<0.05). The occupation rate of Clostridium in the WD group was reduced by SFP ingestion (900 mg/day) to a level similar to that in the TJD group. Meanwhile, the occupation rate of Bifidobacterium was higher in the SFP ingestion group than in the WD group. β-Glucuronidase activity in the feces was up to 5 times higher when lunch was changed from TJD to WD, but this was recovered by SFP inclusion in the WD diet (P<0.05). The above findings suggest the possibility that SFP inhibits colon cancer carcinogenesis. To investigate this notion further, a colon cancer-inducing substance, 1,2-dimethylhydrazine (DMH), was given to CF#1 mice. SFP administration significantly decreased the incidence of colon cancer, compared to controls. We also examined the mechanism of SFP tumor suppression. A Winn assay was performed using spleen cells. SFP given for more than 6 days inhibited tumor growth compared to tumor cells inoculated with Meth-A alone (P<0.05). This result indicates the possible induction of anti-tumor immune cells in SFP-treated spleen cells. Furthermore, the number of spleen cells increased more in gnotobiotic BALB/c mice in association with Bifidobacterium than in saline-treated germ-free mice. The number of spleen cells in germ-free mice given SFP or soybean milk (10 mg/day and 0.2 ml/day, respectively) for 4 weeks was not significantly different compared to the saline-treated germ-free animals. Our results suggest that the suppressive effect of SFP on tumorigenesis was mediated by the involvement of the host immune response induced by intestinal bacteria. Further studies are required to clarify the mechanism of this phenomenon.

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