Hokkaido University: Institute for Genetic Medicine

Laboratories

Probiotics Immunology

Clarification of mechanism for the regulation of biological function by probiotics to prevent and treat diseases

  • Professor Tadaaki MIYAZAKIi, PhD
  • Assistant Professor Hisako NAKAGAWA, PhD

Probiotics have been widely known as microorganisms that improve the intestinal flora balance, beneficially affecting the host animal and also as substances that stimulate the growth of microorganisms. Different from antibiotics, which are used to cure illnesses, probiotics serve as a form of “preventive medicine”, stopping illnesses from the developing. Some studies report that probiotics, once ingested, are delivered intact to the intestinal tract of humans and that they remain there, improving the intestinal flora balance by suppressing the growth of harmful bacteria. The objective of our proposed study is to elucidate how probiotics affect living organisms and prevent illness. We aim to demonstrate how the probiotics that we analyze serve to prevent illnesses and diseases (and will provide therapies for these) by examining the expressions and changes in apoptosis induction molecules and genes that affect aging and life span. By elucidating the mechanisms of regulating the induction of apoptosis, and the functions of molecular interactions and changes in intracellular localization, we will be able to develop and translate probiotics into their therapies.

Investigation of the host defense mechanisms against influenza viruses

Influenza is a worldwide occurring infectious disease causing numerous deaths annually. It is now accepted that apoptosis may contribute to the spread of influenza viruses and to the severity of the conditions of infected victims. It has been known that the expression of death receptors which induce apoptosis, such as Fas, DR4, and DR5, in infected cells increases in conjunction with viral infections. Signals transmitted through these death receptors are thought to induce apoptosis in infected cells and work to promote virus propagation.
Here, an explosive multiplication of influenza virus numbers trigger acute inflammatory reactions, and the secretion of large amounts of TNF-α, FasL, TRAIL which induce apoptosis, and inflammatory cytokines are released into the blood. These are thought to worsen viral infections as these cytokines induce apoptosis in the cells of organs. Therefore, it would appear to be possible to improve the disease condition of patients and to reduce the number of deaths by controlling the induction of apoptosis. As shown in the figure, we have shown that Siva-1 is critical for the regulation of influenza virus replication and apoptosis induction. Recently, by administering mice with lactic acid bacteria, we have confirmed that certain molecules regulate apoptosis induction and inflammatory cytokine expressions, and alleviate symptoms, as well as increase the survival rate. Therefore, we aim to elucidate the mechanisms that regulate apoptosis and inflammation using probiotics, and use the knowledge gained for prevention and treatment of infectious diseases.


Analysis of IgA production by probiotics and the mechanism in the small intestine

Probiotic bacteria provide benefits in enhancing host immune responses and protecting against infection. Induction of IgA production by oral administration of probiotic bacteria in the intestine has been considered to be one reason for this beneficial effect, but the mechanisms of the effect are poorly understood. Lactobacillus gasseri SBT2055 (LG2055) is a probiotic bacterium with properties such as bile tolerance, ability to improve the intestinal environment, and it has preventive effects related to abdominal adiposity. In this study, we have found that oral administration of LG2055 induced IgA production and increased the rate of IgA+ cell population in Peyer’s patch and in the lamina propria of the mouse small intestine. The LG2055 markedly increased the amount of IgA in a co-culture of B cells and bone marrow derived dendritic cells (BMDC), and TLR signal is critical for it. In addition, it is demonstrated that LG2055 stimulates BMDC to promote the production of TGF-β, and BAFF, critical for IgA production from B cells. Combined stimulation of B cells with BAFF and LG2055 enhanced the induction of IgA production. Further, TGF-β signal was shown to be critical for LG2055-induced IgA production in the B cell and BMDC co-culture system, but TGF-β did not induce IgA production in a culture of only B cells stimulated with LG2055. Furthermore, TGF-β was involved in the production of BAFF from LG2055-stimulated BMDC. As shown in the figure, these results demonstrate that TGF-β was produced by BMDC stimulated with LG2055 and it has an autocrine/paracrine function essential for BMDC to induce the production of BAFF.

 

Investigation of mechanisms regulating longevity

Dr. Metchnikoff who discovered that the phagocytosis of leucocytes is important for immunity and who received the 1908 Nobel Prize for Physiology or Medicine has suggested that yogurt may contribute to longevity since there are many persons surviving to very high ages in Bulgaria. It has been established that the life of C. elegans (Caenorhabditis elegans) can be extended by replacing the E.coli bacteria, which it is usually feeding on, with lactic acid bacteria, and our study has shown the effectiveness of lactic acid bacteria in extending the lifespan of C. elegans; however, details of the molecular mechanisms involved are unknown.
C. elegans is a transparent nematode, about 1mm in length, which lives in soil feeding on bacteria. Since C. elegans can be examined under a microscope, has few cells (about 1000), and its lifecycle is about 21 days, it has been used as a model animal to elucidate apoptosis induction mechanisms or life and aging mechanism since the 1960s. C. elegans is very useful for analyzing the mechanisms of molecules, enabling identification of causative genes in experiments using RNAi for gene expression. Focusing on how lactic acid bacteria and the products of these bacteria contribute to life span mechanisms, we will analyze the relations of molecules that regulate cell death, which are related to cell longevity, and attempt to determine the molecular mechanisms that determine the life span of organisms.