A Therapeutic Drug of "Live Bacteria" Born from Microbiome Research

2019/09/13

Recently, you may have heard the term "gut environment" in magazines and on TV. This term describes the balance of bacteria living in the intestines (referred to as good bacteria/bad bacteria), based on the idea that the activity of resident bacteria in the gut can improve or worsen intestinal health. There are also products that claim to help maintain health by increasing the number of beneficial bacteria in the gut. It is said that there are about 1,000 types of bacteria (intestinal bacteria) in the human gut, but much about their functions in the human body remains to be elucidated. Amidst this, it has been discovered that some intestinal bacteria have functions that enhance immunity, prevent infections by pathogenic bacteria, and strengthen anti-cancer immune responses.

A research team led by Professor Kenya Honda of the Department of Microbiology and Immunology at the Keio University School of Medicine has succeeded in identifying 11 types of bacteria (11 strains) from the intestines of healthy individuals that induce CD8 T cells (cells that play a central role in anti-cancer immunity). Professor Honda created a cocktail combining the 11 strains in a live state. He demonstrated that when mice were first given this cocktail and then infected with pathogenic bacteria such as Listeria, the pathogens were quickly eliminated from the mice's intestines, and their symptoms were alleviated. Furthermore, it was found that this 11-strain cocktail has the effect of enhancing cancer immunotherapy. In mice that were administered immune checkpoint inhibitors after drinking this cocktail, the proliferation of cancer cells was significantly suppressed compared to mice that did not drink it.

It was found that these bacteria are not effective individually; the 11 strains work together to enhance immunity. These results suggest the possibility of a new method for preventing infectious diseases and treating cancer by using a combination of live bacteria.

What was the driving force behind Professor Honda's research? After graduating from the School of Medicine, the first field Professor Honda entered was radiology. Here, he was involved in the diagnosis and treatment of cancer. However, treating cancer was difficult, and he says he felt a sense of powerlessness, thinking, "I'm not helping my patients," as he witnessed the patients he was in charge of pass away. Driven by the thought that he needed to study more to cure his patients, he began basic research in immunology at Kyoto University's graduate school. At this time, in his clinical practice, he was in charge of gastroenterology and began seeing patients with inflammatory bowel disease.

Inflammatory bowel disease is a condition where one's own immune cells attack the cells of the intestine, causing symptoms such as chronic diarrhea, bloody stools, and abdominal pain. It tends to affect people at a young age, and once it develops, a complete cure is difficult, often requiring lifelong treatment. Furthermore, inflammatory bowel disease is a life-threatening condition, as cancer is said to develop easily from the affected areas.

Professor Honda, who had been dedicated to researching immune diseases with the desire to help these patients, began to focus more on intestinal bacteria research around 2008, when a genome analysis device called a next-generation sequencer appeared. This device made it possible to decode genomes in an overwhelmingly short period and at a low cost.

"What used to take a year to decode just one chromosome 20 years ago now takes less than a few days. This has been a major force in accelerating research," says Professor Honda.

As genome decoding became easier, new ways of thinking emerged in resident bacteria research. Instead of looking at each bacterial species individually, the new approach was to view bacteria coexisting in the same place as a single community (bacterial flora) and to consider all the genomes of that community as a single entity (Microbiome). Large-scale Microbiome projects utilizing the power of next-generation sequencers were conducted worldwide.

In the United States, the Microbiomes of several locations in healthy individuals, such as the nasal cavity, oral cavity, skin, and digestive tract, were studied. This revealed which resident bacteria inhabit which parts of the body and what bacteria-derived genes are active in those locations. In Europe, comparative studies of the gut Microbiome in healthy individuals, obese individuals, and patients with inflammatory bowel disease were conducted to examine the impact of differences in gut bacterial flora on health.

In this context, Professor Honda, feeling the importance of intestinal bacteria, began research on gut bacterial flora, applying his expertise in immunology to aim for the development of treatments for inflammatory bowel disease.

"The human gut contains about 1,000 types of intestinal bacteria, and these bacteria possess genes that humans do not have. The number of human genes is said to be around 25,000, which is not much different from that of a fly. However, flies have only a few types of intestinal bacteria, and the number of genes derived from these bacteria is also very small. In contrast, humans have 1,000 types of intestinal bacteria, which together possess about 500,000 to 1 million genes. Humans rely heavily on this. The presence of so many bacteria in the human gut is not a coincidence; it is thought to be the result of humans actively incorporating many bacteria into their bodies.

Even today, people living traditional lifestyles, such as hunter-gatherers in Africa, have an extremely vast variety of intestinal bacteria. This number decreases significantly in agricultural peoples and even more so in people living in cities. For example, as we miss the opportunity to inherit resident bacteria from the mother during birth due to cesarean sections, are sterilized by the administration of antibiotics, and our food becomes more artificial, humanity has been progressively losing its intestinal bacteria."

Professor Honda also points out that the loss of intestinal bacteria is weakening humanity.

"'A decrease in intestinal bacteria means that the functions carried out by bacterial genes are weakened. I believe it is better to have as many types of bacteria as possible. I think the increase in allergic diseases like hay fever and conditions such as ulcerative colitis is also greatly related to the loss of intestinal bacteria. I also believe that among the diseases that have been on the rise in recent years, quite a few are related to intestinal bacteria. I believe we can treat these diseases by transplanting the intestinal bacteria from a healthy person into the gut of a sick person, thereby replacing their intestinal bacteria,' says Professor Honda."

Professor Honda, who continues to teach and conduct research at the Department of Microbiology and Immunology at the Keio University School of Medicine, speaks about the appeal of the university as follows.

"'I have conducted research at various universities, but I feel that at Keio University, there is a very strong sense of cooperation among the faculty. Also, the collaboration between industry and academia is successful here. This is something not often seen at other universities. In October 2017, we also opened the " JSR-Keio University Medical and Chemical Innovation Center (commonly known as JKiC) " for the purpose of joint research with the chemical materials manufacturer JSR. Companies actively support academic research. Companies then firmly connect the resulting achievements to subsequent industrialization. This virtuous cycle has taken our research to the next level.'"

Leveraging these environments, Professor Honda is working on developing numerous bacterial cocktails with therapeutic effects through basic research, as well as their clinical application.

"'We are aiming for a treatment method using 'live bacteria.' Currently, there are products available on the market, but the effects of the bacteria they contain are not strong, and they often do not go as far as curing diseases. Within this context, we are pursuing a strategy of treating diseases with bacterial cocktails.

For example, 'antibiotic-resistant bacteria,' for which there is no effective treatment, have become a global problem. The current situation is that even if we try to sterilize them with stronger antibiotics, some patients die because there are no effective drugs left after repeated infections. Instead of hitting the bad bacteria with strong antibiotics, we administer good bacteria to replace them, thereby eliminating the bad bacteria and restoring a healthy bacterial flora. We are working on developing a bacterial strain cocktail that can do this.

Also, things like gaining weight, losing weight, and developing diabetes are related to metabolism, and intestinal bacteria play an important role in metabolism as well. We are also attempting to find bacteria that can control metabolism and improve diabetes and obesity.'"

Prior to this 11-strain cocktail, the professor's team also succeeded in identifying a 17-strain cocktail that suppresses the immune system.

"'The 11 strains can be expected to have a therapeutic effect on cancer and infectious diseases by activating the immune system. In contrast, the 17 strains induce 'regulatory T cells' that suppress the immune system, potentially allowing for the treatment of inflammatory bowel disease, ulcerative colitis, and other conditions caused by excessive immune responses. We aim to find cocktails combining 10 to 20 types of bacteria, each capable of tilting the immune system in a different direction, and use them as therapeutic drugs. Alternatively, we would like to establish treatment methods that use them in combination with existing drugs to enhance their therapeutic effects.'"

Professor Honda is also starting research on resident skin bacteria, suggesting that conditions like atopic dermatitis could potentially be cured with a topical bacterial medication. We asked him what he emphasizes in promoting a wide range of resident bacteria research.

"'Our mission is to improve clinical practice. Although there are many parts of the intermediate mechanism that are not well understood, for example, it is difficult to fully clarify why the 11 strains induce CD8 cells (cells that play a central role in anti-cancer immunity). There is research that explores the mechanisms, but we are proceeding with a policy that emphasizes the results and rapidly brings them to the clinic.'"

From his time as a resident physician interacting with cancer patients, to his graduate school days when he was engrossed in basic research while examining patients with inflammatory bowel disease, Professor Honda has continued his research with the single-minded desire to treat patients suffering from intractable diseases. Thanks to the research of Professor Honda's team, the practical application of treatment methods using 'live bacteria' and their 'cocktails'—still uncommon in Japan—is drawing near. A future treatment method is now about to be born.

Kenya Honda

1994: Graduated from Kobe University School of Medicine. 2001: Completed the Doctoral Programs in the Major in Medical Sciences, Graduate School of Medicine, Kyoto University. PhD (Medical Science). 2001: Assistant, Department of Immunology, Graduate School of Medicine, The University of Tokyo. 2007: Associate Professor, Department of Immunoregulation, Graduate School of Medicine, Osaka University. 2009: Associate Professor, Department of Immunology, Graduate School of Medicine, The University of Tokyo. 2013: Team Leader (concurrent), Laboratory for Gut Homeostasis, RIKEN Center for Integrative Medical Sciences (IMS). 2014–present: Professor, Department of Microbiology and Immunology, Keio University School of Medicine.

*Affiliations and titles are as of the time of the interview.