#123: Liping Zhao, PhD: Changing Gut Bacteria Ecology w/ Chinese Medicines and Berberine

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About Dr. Liping Zhao

Zhao Liping PhD, is Distinguished Professor of Microbiology and Director for Laboratory of Molecular Microbial Ecology and Ecogenomics, as well as School of Life Sciences and Biotechnology at Shanghai Jiao Tong University. He is also Director for Laboratory of Nutritional Systems Biology, Shanghai Center for Systems Biomedicine and Director for SJTU-Perfect (China) Joint Center for Microbiota and Health.
 

Related Researched Conducted by Dr. Zhao

Structural modulation of gut microbiota during alleviation of type 2 diabetes with a Chinese herbal formula

Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers.

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Show Notes

00:08 Dr. Liping’s Journey into Microbiome Research: Liping Zhao is professor of microbiology at Shanghai Jiao Tong University. Mike and many expert guests have quoted Dr. Liping’s research.  He had already begun work on the microbiota when he read a paper on the microbiome and fat storage. He had been obese for nearly 15 years by then.  Dr. Liping was inspired. He shifted the focus of his research to how the microbiome may contribute to the development of metabolic diseases: obesity and diabetes. Both of these are important health issues in China.

03:14 Connection between Endotoxin Bacteria and Obesity and Diabetes: Endotoxin is a group of large molecules on the surface of gram-negative bacteria. It is a normal component of those bacteria; however there are potentially pathogenic members of gram-negative bacteria. These bacterium power our innate immunity like microphage. They can stimulate inflammation and immune cells, so they are called endotoxins.

04:28 Dr. Liping Studies only Humans: He takes a systems theory concept approach to look at the human body using urine, blood and fecal as emergent functions for health monitoring. Gut microbiota in fecal samples have a very important role for providing information, answering important questions. What kind of bacteria are they? What kind of metabolites do they produce? If you look at urine and blood, you may discover what kind of metabolites produced by gut bacteria get into the bloodstream. Eventually, it can be detected in urine. It is a way to monitor changes in the microbiome and how it might impact the host’s health.

06:28 Using Plants from Traditional Chinese Medicine: In China they have a tradition of using diet to improve health or prevent disease. In traditional Chinese medicine plants have been tested over thousands of years, so they are clinically safe. They are published in a list called “Traditional Chinese Medicine or Food” by the Chinese Minister of Health. Dr. Liping found that many can change the microbiome, creating variations of structure and function of the microbiome. This can also induce changes in the host’s immunity and metabolism to a better state of health. He profiles the possible changes using DNA sequencing, metabolomics, and data mining/pattern recognition to discover which bacteria, when it is increasing or decreasing, is associated with changes in the host’s phenotype.

08:45 Studying Endotoxin-Producing Bacteria: There was already research on endotoxin from which to build. Published papers showed that injections of low dosage endotoxin into mice, which were fed a normal/natural diet. Lean mice become obese and insulin resistant after 8 weeks. To Dr. Liping, it shows that when these pathogenic bacteria in the gut release low chronic levels of endotoxins into bloodstream. It induces low-grade inflammation. That inflammation may impair the host’s metabolism and lead to obesity and insulin resistance.

10:07 Dr. Liping’s Ultimate Research Goals: The microbiota ecosystem is a model system with which to work. Dr. Liping’s questions are “What kind of bacteria are there? Who does what, with whom and how?” in terms of the progression of obesity and diabetes progression.

11:45 Endotoxin in the Induction of Obesity: Before the importance or causal ranking of endotoxins, Dr. Liping says they need to find out more about specific endotoxin bacteria and that relationship. In his paper published in 2012, he revealed the discovery of specific strain, b29, of endotoxin producing bacteria called enterobacter cloacae. It can grow to nearly 1/3 of the total gut bacteria population of obese volunteers. After a specific diet of 23 weeks, subjects lost over 50 kilograms and recovered from diabetes, inflammation, hyperlipidemia and hypertension. They also lost the endotoxin-producing bacterium within 4 weeks into the diet. Dr. Liping isolated that bacterium and sequenced the genome. He inoculated this bacterium into germ-free mice. Studies have shown that germ-free mice are resistant to high-fat-diet induced obesity. When the guts of germ-free mice were colonized with the endotoxin-producing bacterium, the mice became obese, insulin resistant, had fatty liver, inflammation and they also experienced inhibition of the gene required for burning stored fat in the gut, along with several genes in the liver for synthesizing fat. When there is not a high fat diet, even though there is a verifiable population of the endotoxin-producing bacteria in the gut, the endotoxin does not enter the bloodstream and there is no health issue.  If you switch to a high fat diet, endotoxin enters the bloodstream and all of the health issues ensue.

15:03 The Conditions Which Contribute to Obesity: There are specific bacterial strains in the human gut which have the genetic capacity, given the right environmental conditions, to directly contribute to obesity induction and development. There are so many different bacteria which can produce endotoxins and may have this capacity.  The question is, “Who can outcompete other bacteria and become predominant in the gut?” Only then can it contribute to the problem. Having the capacity to produce endotoxin is only one condition for the bacterium to be able to contribute to obesity. Dr. Liping’s team is working on the molecular mechanism and confirming the role of endotoxin and other gene which can explain why this particular can outgrow, outcompete other bacteria and grow to the point of become 1/3 the total of gut bacteria. You need a virulent factor, like endotoxin to contribute. You also need ecological factors so it can become dominant and ensure enough abundance to produce enough of the virulent factor in such a compact highly competitive environment. He says that we are far from understanding the ecological factors that contribute to this overgrowth.

18:29 Immune Tolerance of the Bacterial Takeover: The b29 strain can takeover more than 30% of the total gut population, yet the host immune system appears to tolerant to this particular bacteria. If it is an infectious pathogen, there would an acute immune reaction.  The endotoxin in the bloodstream activates inflammation. They were able to capture it pathogenetically, and in virulence tests, it produced no symptoms. What happened in the first few days or months of life to create the host tolerance of this bacterium? When Dr. Liping spoke to the parents of his test subjects, they found that during the first few days or months of life, their test subjects had serious infections, diarrhea and fever, from which they recovered. From there, they quickly became obese.  So there might be something about this early infection that makes the immune system tolerate this bacterium.  There are so many critical questions, even for this one single pathogenic strain, that we still don’t know. Dr. Liping believes that it is now something that is now knowable with our technology.

22:37 Dietary Changes to Influence These Bacterium: In his study, Dr. Liping’s subjects lost over 100 pounds (51.4 kg) in 23 weeks, with no exercise and no work. They used a top-down approach. The gut’s ecosystem is complex. Overgrowth of certain bacteria in the gut happened because the bacteria that would stop them are not active in enough numbers. They are meant to be in balance. They have two questions in their minds when trying to understand the gut ecosystem. In ecosystems like the rainforest, the most important species is the tall tree. It is the foundation species of the entire ecosystem. Is there a foundation species like this in our gut ecosystem?  If there is, could it be planted in the gut to bring about balance to keep pathogenic bacteria in check? In micro-ecosystems, species are not independent from each other, most form a guild or functional group that grows together and thrive together or decline together. Is this the case in our gut bacteria?

27:08 Bacterial Strain-Specific Analysis: You must recognize strains within the gut ecosystem and observe their behavior. Genus-level analysis forces you to lump many different functional bacteria into one unit. Some of the species in the same genus may be positively associated with your disease, negatively associated, and some may not be associated. How do you recover the entire forest without knowing which species is the foundation species and which species form a guild with other species.

28:52 Top down Approach: They did everything they could think of to promote beneficial bacteria and inhibitive to detrimental bacteria. In the diet, they added plants containing non-digestible fermentable carbohydrates in diverse structures. Though they could not determine what exactly was required, they hypothesized that it would be able to use a wide range of carbohydrates. They also explored Chinese medicines and bitter compounds that had been used by doctors to treat diabetes, obesity, reducing food intake, etc.  They also focused on providing balanced micronutrients for the human host. They took urine, blood and fecal samples.

31:27 The Approach is Effective with Genetic Forms of Obesity: They applied this approach to children with Prader-Willi Syndrome, a genetic form of obesity and they were able to show that it was helpful, recovering their gut microbiome, losing weight and recovering from associated issues.

32:58 Bacterial Analysis: They were able to assemble high quality individual genomes for more than one hundred individual strains out of 161prevelant bacteria. They sampled blood, urine and feces in obese children during the weeks of the diet.  They were able to identify a little over 2 million non-predominant genes and were able to run a correlation analysis of all 2 million genes. Using various grouping methods, they found that 161 of those strains are shared by more than 20% of the samples.  Some species had only one strain. Some species had over 9 strains. After the analysis, they found one particular group containing 3 bacterial species which grew significantly in abundance with their dietary intervention. These kept detrimental bacteria in check. These have the potential of being the foundational bacteria mentioned previously. Over time, they change the entire ecosystem to be inhospitable to many existing detrimental bacteria, like the tall canopy tree changes the rainforest.

40:08 Bacterial Guilds: Different species within the gut form guilds. With guild-level analysis, you can lump together abundance of individual strains within a guild to get group-level abundance.  The members of a guild increase or decrease, correlating with changes in the microbiota. They use group level abundance to correlate with individual phenotypes.   Some groups, like the groups containing the potentially foundational species of bacteria, can correlate with 12 phenotypes, negatively, like BMI, body weight, and inflammatory markers. They were able to distill 2 million variables to 18 variables.

45:05 Dr. Liping’s Favorite Herb, Botanical or Food Substance: Eat whole grains as whole grains, not as processed whole grains like whole grain flour.   When you cook your food, use whole seeds to preserve all of the nutrients the seeds can offer you, like protein, fats, carbohydrates, vitamins and minerals and it promotes beneficial bacteria. It is all there in one whole seed.

49:37 Dr. Liping’s Health Tip for the World: In everyone’s gut there are about 1.5 kg of bacteria and, like it or not, we need to grow them with our diet. We need to determine a diet to feed our people and our beneficial bacteria.  At a policy level, we need to change the way we process food and cook food.