2018 The Second Asian Microbiome Conference

Held by Biotools Co., Ltd and Chang Gung University’s Microbiota Research Center, the second Asian Microbiome Conference took place at the Farglory FICC on January 10, 2018. It was the product of a concerted and coordinated effort with the Ministry of Science and Technology’s life sciences department (MOST-LS), Taipei Biotech Association (Bio Taipei), Taiwan Association of Lactobacillus (TALAB), and Taiwan Society of Microbiology. The conference provided a platform for scholars from Taiwan and abroad to gather and exchange their research findings in gastrointestinal microbiota and drive further development in the field. The keynote speaker lineup of the 2018 AMC was filled with industry heavyweights, who gave brilliant speeches, and elicited many passionate discussions.

 

Trust your “gut” and eat something tasty!

Dr. Yuan-Kun Lee, a professor at the National University of Singapore’s School of Medicine, shared his findings from a large-scale study on local children’s gastrointestinal microbiota beginning in 2009 that spanned 10 cities in 5 Asian countries. Results showed that the most significant contributing factor to the differences in gastrointestinal bacteria lies in dietary habits, followed by genetic encoding. Lee further divided food intake two categories—fats and carbohydrates. After more than a year of observation, Lee found that frequent meat eaters have a more active microbiota in their guts and thus better cholic acid metabolism, synthesis, and absorption, compared with those who eat less meat. This provides evidence for the hypothesis that fat and carbohydrate intake can affect the growth of gastrointestinal microbiota. It is worth noting that ethnic Mongolians share similar microbiota with Southeast Asians who prefer carbohydrates, despite having a meat-based diet like the Europeans. Does this negate Lee’s hypothesis? To address this, the research team found that the discrepancy is caused by different varieties of starch consumed: the carbohydrates consumed in Europe, America, Japan, Korea, and China are easier to digest, whereas those consumed in Mongolia, Thailand, and Africa are not. Because starch absorbs gall in the intestines, it reduces the ability to digest fats, which in turn causes a change in the person’s gastrointestinal microbiota. In conclusion, Lee compares the human digestive system to Tai-ji and said humorously, “If you like steak, eat it with Thai rice instead of potatoes or bread to help with cholic acid metabolism; if you don’t like meat, then choose starch alternatives that are easier to digest in order to maintain a healthy gastrointestinal microbiota. As a follow-up study, Lee actually asked 50 Mongolians to test out this hypothesis. Unfortunately, only 10 completed the experiment because “the rice of northeast China is not fit for human consumption!” As Lee jokingly put it, “One must choose food that tastes good in addition to being healthy.”

Germ-free mice and gnotobiotic mice are here to help with gastrointestinal microbiome research

Dr. Hsiao-li Chuang of National Laboratory Animal Center gave a talk on the importance and application of germ-free or gnotobiotic rodents in gastrointestinal microbiota research. In her detailed speech, Chuang mentions that many human diseases have been found to be linked to gut microbiome in recent years, including Alzheimer’s Disease and obesity. A school of scholars had even proposed the concept of “gastrointestinal microbiota as an indispensable organ of the human body,” precisely because they play an irreplaceable role in moderating drug metabolism and hormone secretion, both of which are related to the development of the brain, antioxidative stress, and athletic abilities. Pregnancy, lifestyles, and diets are some of the major factors that influence gut flora. The National Institutes of Health (NHI) has invested in approximately 8 million US dollars in this line of research. Nevertheless, medical research invariably must rely on clinical trials. The first step to this is animal testing. Thanks to the availability of germ-free and gnotobiotic rodents, microbiome experiments that were previously impossible can now be carried out with great success, offering researchers further insights. Newborn rodents are acquired through hysterectomy and bred by female germ-free rodents. These germ-free rodents are used to simulate all kinds of microbial flora. For example, a specimen can be extracted from a patient’s excrement and injected a germ-free mouse’s intestines. Although this method cannot create a complete replica of the patient’s intestinal microbiota, it is quite useful in determining the prognosis of certain diseases by simulating a similar environment. Gnotobiotic rodents, on the other hand, can help scientists conduct certain in vivo experiments. In conclusion, the establishment of an animal testing platform provides an improved toolkit for researchers to carry out genetic and proteomic studies.

The intricate relationship between gastrointestinal microbiota and the skin

Dr. Jeffrey Jong-Yang Yen, a researcher from Academia Sinica’s Institute of Biomedical Sciences, notes that skin is the human body’s largest organ, and many skin diseases (or dermatitis) are closely related to changes in gastrointestinal microbiota. Human genes and environmental factors act as indirect agents for volatility in skin immunity by influencing humans’ gut flora. For example, atopic dermatitis (AD), a complicated chronic skin condition, is believed to be linked to genetic encoding and several environmental factors. Although genetic factors affect skin immunity, the exact pathology of it remains to be explored. Through genome-wide mutagenesis screening, Yen found that defective ZDHHC13 genes are related to certain conditions that cause skin and hair abnormalities. In experiments conducted on mice, subjects with ZDHHC13 defects were more prone to bacterial infections from the surrounding environment and more likely to develop symptoms similar to those of AD patients. However, the phenotype saw significant improvement in a pathogen-free environment, and symptoms were successfully treated with antibiotics. Results also show that defects in the RAG1 gene did not have significant impact on skin immunity, indicating that skin inflammations are mostly caused by microorganisms in the environment rather than congenital immunodeficiency disorders.

On the contribution of big data analytics and the Taiwan Gut Project

Dr. Yu-Lun Kuo, Head of Bioinformatics at Biotools Co., Ltd., also emphasized the relationship between gastrointestinal microbiota and human diseases. According to Kuo, dozens of common medications on the market could have their efficacy reduced by microorganisms in the human body, with some possibly increasing the toxicity of drugs. As such, relevant research and its data collection process must be standardized in order for big data analytics to be efficiently utilized. Here, Kuo introduced the Taiwan Gut Project, a project led by Kuo which offers the opportunity for the general public to participate in microbiome research and receive a report on their own gastrointestinal microbiota. The ultimate goal is to promote awareness of the topic and increase the sample size of said research. As of January 10, 2017, 485 cases have been conducted, consisting of patients with allergic & atopic dermatitis (28%), gastrointestinal diseases (21%), metabolic syndromes (8%), and cardiovascular diseases (7%), as well as other conditions. Dr. Kuo cited the success of the American Gut Project and similar projects throughout the world that are dedicated to gastrointestinal microbiota studies and hopes that this will encourage people from industry, academia, research institutions, and the general public to participate in the Taiwan Gut Project, with a view to propelling Taiwan’s competitiveness in microbiome research.

Colorectal cancer and gastrointestinal microbiota go hand in hand

Prof. Jun Yu, Head of Gastrointestinal Cancer Research Center at the Chinese University of Hong Kong, collected 271 case studies from China, Germany, France, and the United States, as well 255 colorectal cancer specimens—526 subjects in total—and conducted a meta-analysis of genome-microbiome association with a view to finding the causal relationship between colorectal cancer patients’ intestinal microbiota and their prognosis, attempting to identify a common biomarker for people of all ethnicities and irrespective of geography. According to Prof. Yu, the progression of colorectal cancer, beginning from normal tissues to adenomas and to Stage 1, takes approximately 10–15 years. During this time many factors can influence its course, including environmental stimuli, congenital factors, genetic factors, and the genome as a whole. However, the correlation between gastrointestinal microbiota and colorectal cancer remains to be verified. Through the aforementioned meta-analysis, Prof. Yu and her research team were able to find correlation between the two. They concluded based on their findings that no matter which country people are in, the gut flora in healthy subjects differs significantly from that of colorectal cancer patients, despite the underlying difference due to regionality. This provides evidence for the theory that changes in intestinal bacteria will have a drastic accelerative effect on the formation of colorectal cancer. Furthermore, Yu and her team identified 7 biomarkers applicable to all humans by isolating bacteria with a higher volatility of abundance level among healthy subjects and cancer patients. As a follow-up study, Prof. Yu’s team plans to explore the mechanism of changing the microbiome through 16S rRNA sequencing in order to distinguish between protective and carcinogenic bacteria and to facilitate clinical application in the future.

Fecal “matters” as disease indicators

Dr. Ming-Shiang Wu is the Head of Internal Medicine at National Taiwan University Hospital. As a physician, he points out bluntly that the practical “treatments” in clinical application of “theories” is what he cares about the most. Wu notes that the number of gastrointestinal bacteria residing in a human body is 10 times the number of total human cells of the person, and their gene expressions have 200 to 300 times more variety than those of the human genome. Unsurprisingly, these bacteria are associated with not only diseases, but also our metabolism and immunity. Wu compares metabolism to the financial system and immunity to the justice system. When either system is disrupted, many problems would arise. This analogy helps the audience understand the many issues that may occur when there is an imbalance in gastrointestinal microbiome, such as non-alcoholic steatohepatitis (NASH), Parkinson’s disease, and other neurological and mental disorders. Dr. Wu summarizes a number of research findings that may be applied in a clinical environment to improve existing treatments, namely through dietary control, antibiotics, probiotics, and FMT.

1. Dietary control: “You are what you eat.” Careful dietary control can help you maintain a balanced microbiome in your guts.
2. Antibiotics: Apart from its current use as infection medication, antibiotics can lessen a number of non-inflammatory conditions such as irritable bowel syndrome (IBS), hepatic encephalopathy, and non-inflammatory bowel disease.
3. Probiotics: Probiotics were previously never considered as drugs, but a journal article in Nature reported that administering probiotics to newborn infants in India drastically reduced the chance of septicemia. Perhaps after further research, probiotics may become an indispensable tool in clinical treatments.
4. FMT: FMT is in essence a means to achieve a balanced microbiome in the gastrointestinal tract, but the general public seems averse to it. It is one of the FDA-approved standard treatments for gastroenteritis, and was used as early as the Eastern Jin Dynasty, where it was known as the Huang Long Tang (literally, the “Yellow Dragon Soup”).

Research in gastrointestinal microbiome is still maturing, but future studies are sure to provide an even greater array of treatments.

Shaping a healthy microbiota in babies by breastfeeding

Prof. Jane Chen-Jui Chao points out that breast milk is rich in nutrition, antibodies, essential fatty acids, white blood cells, macrophages, as well as traces of hormones, growth factors, microorganisms, and probiotics. Research has shown that baby formulas cannot simulate breast milk perfectly, with the latter comparatively more beneficial to infants’ gastrointestinal and immunity functions, even alleviating gastroenteritis and allergies. It was also proven that breastfed infants have better immunity and a lower chance of contracting diseases when they grow up. Microbiome exists in the milk of humans and other mammals, chiefly consisting of Proteobacteria, Acinetobacter baumannii, Bacteroides, Firmicutes, and other bacteria. The abundance of bacteria comprising the microbiome begins increasing in the third trimester of pregnancy, peaks when the baby is born, and decreases or even disappears when the baby starts to eat other food. Researchers have attempted to link the microbiome in breast milk to that in the gastrointestinal tract and in fecal matters but to no avail, suggesting that said microbiome could either be transferred from the intestines or pre-existent in the mammary glands. According to literature, breast milk microbiomes vary by ethnicity. Moreover, Prof. Chao claims that no significant differences are observed in the mother’s breast milk in terms of premature vs. normal births, C-section vs. natural births, and male vs. female infants. What really matters, according to Chao, is the nutrition intake during pregnancy, which can have a significant impact on the microbiome in breast milk and, in turn, that in the infant’s gastrointestinal tract. Prof. Chao concludes with the suggestion that mothers should take supplements that include pre- and probiotics (or both) to nurture beneficial microbiomes and help their babies grow up to become healthy human beings.

Research shows microbiomes can boost our immune functions!

Dr. Chuan-Sheng Lin, an assistant researcher at Chang Gung University’s Microbiota Research Center, mentions that the microbiome modulates human immunity in response to environmental conditions and diseases throughout our lives, beginning in infancy and continuing towards adulthood. Accordingly, an imbalanced microbiota can lead to the occurrence of a wide range of diseases, especially infectious ones. The focus of microbiome research is twofold: on the one hand are the pathogen-associated molecular patterns (PAMPs) of microorganisms, which can be identified by human immune system; on the other are the metabolites created from the interaction between microorganisms and the host. Previous research has found that the polysaccharide-based polymers produced by Ganoderma lucidum (aka Lingzhi) and Cordyceps sinensis (aka caterpillar fungus) can modulate human gut flora. An immune imbalance occurs when vicious bacteria multiply while beneficial bacteria decrease. Considering the immunity stimulus effect of certain groups of bacteria, “bad” bacteria should be defined as positive stimulators of immunity. According to research, gastrointestinal bacteria (CSL-14 in particular) can modulate TNF-α, macrophages, and monocytes, which work in tandem to moderate immunity in the lungs and fight against mycobacterial infections. Dr. Lin points out further that comparative analysis must be conducted between different bacteria groups to understand precisely their modulation mechanism before they can be applied to humans. Lin believes that precision medicine is the future. Therefore, simply isolating a bacterium is not enough. Rather, researchers must understand how to modulate it in order to apply it to clinical treatments or other fields (e.g. agriculture).

Trends in next generation sequencing (NGS) application in microbiome research

Director Meng Wang of Novogene Co., Ltd. shared the company’s technology in analyzing the differences (blood pressure, body fat, etc.) between different experiment groups (controlled by species and environmental factors) through amplicon sequencing, the results of which were entered a specific database for further analysis. Another important test conducted by the company is metagenomics sequencing, which involves scafftigs assembly, database matching, and genetic prediction. Through this process, the level of species diversity and functional diversity can be determined, helping researchers find their answers using visual analytics and multivariate statistics. Wang goes on to talk about the application of microbiome next generation sequencing (NGS) in medicine, biology, agriculture, manufacturing, and other industries. A few examples follow: FMT can change the blood pressure of mice, the quantity of microbes making up a microbiome influences T cell activity, and microbiome diversity in sewage is closely related to population density. Wang concluded his speech by touching upon the latest trends in China regarding database analytics platforms, gut microbiome research companies, and studies on the correlation of CAG and MGS to understand the lifestyles and pathogeneses of bacteria.

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