Effective bifidogenic growth factors cyclo-Val-Leu and cyclo-Val-Ile produced by Bacillus subtilis C-3102 in the human colonic microbiota model

Abstract

Bifidobacterium species are known to fulfill important functions within the human colon. Thus, stimulating the activity of bifidobacteria is important to maintain host health. We revealed that culture supernatants of Bacillus subtilis C-3102 (referred to as C-3102) stimulated the growth of Bifidobacterium species. In this study, we isolated and identified six bifidogenic growth factors, which were cyclo (D-Val-D-Ile), cyclo (L-Val-D-Ile), cyclo (D-Val-L-Ile), cyclo (L-Val-L-Ile), cyclo (D-Val-L-Leu) and cyclo (L-Val-L-Leu). These six cyclic dipeptides increased the growth of Bifidobacterium species and had no effect on potentially harmful gut organisms. Moreover, supplementation with a mixture of these six cyclic dipeptides significantly increased the abundance of microorganisms related to the genus Bifidobacterium in a human colonic microbiota model culture system, although supplementation with a single type of dipeptide had no effect. These results show that cyclic dipeptides containing Val-Leu and Val-Ile produced by C-3102 could serve as bifidogenic growth factors in the gut microbial community. In the past few decades, the human gut microbiota has been reported to play an important role in the promotion of health, and several illnesses are known to be influenced by imbalances of gut microbiota 1. Therefore, manipulation of the gut microbiota is a clinical target for the treatment of gut microbiota-related diseases 2. Bifidobacterial populations belonging to the phylum Actinobacteria are the most dominant microbial group present in the healthy infant gut 3. The population of Bifidobacterium in the human gut decreases gradually from infancy to childhood, then remains relatively stable during an adult's life, and ultimately decreases in old age 4. Numerous health-promoting effects have been ascribed to certain strains of the genus Bifidobacterium, which are widely used as probiotics 5. For instance, one Japanese study reported that allergic children had less bifidobacteria compared to non-allergic children at an early stage, 4 months of age, and prenatal supplementation of bifidobacteria to mothers and postnatal supplementation to infants reduced the risk of allergies 6. It has also been reported that ingestion of Bifidobacterium breve has an anti-obesity effect in mice fed a high-fat diet 7 , and ingestion of Bifidobacterium infantis was effective in relieving symptom of irritable bowel syndrome in women 8,9. These findings suggest an important role for bifiodobacteria in regulating intestinal homeostasis. Some Bacillus subtilis strains are safe, survive passage through the human gastrointestinal tract, and do not induce any undesirable physiological effects in human subjects 10,11. One reported probiotic effect of B. subtilis was associated with inhibiting the growth of pathogenic bacteria such as Salmonella enterica to improve the growth of beneficial bacteria such as lactobacilli 12. In our previous study, B. subtilis C-3102 (hereinafter, referred to as C-3102) was tested using the TNO Gastro-Intestinal Mod...

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