The Latest News on Heart Health

Could gut bugs be the global obesity epidemic culprit?

By Dr. Michael Sarin, Toronto Rehab’s Cardiac Rehabilitation & Secondary Prevention Program

A global pandemic of diabetes is on the horizon. According to International Diabetes Federation, diabetes is expected to affect nearly 400 million people; about seven per cent of the adult population by 2025. Diabetes kills 3.8 million people every year; the same number of people as HIV/AIDS . India and China have the highest number of people with diabetes; about 40 million each. Diabetes is spreading fastest in Eastern Mediterranean and Middle Eastern countries. More children and teens are being affected by diabetes. Without a doubt, these occurrences are linked to an epidemic of obesity and overweight which has a strong link with the onset of Type 2 Diabetes.

Is this all due to a lifestyle of poor eating habits and inactivity occurring simultaneously worldwide? This is a crucial question which is receiving urgent attention by global public health agencies and obesity researchers alike.

A startling alternative explanation has been proposed:
A new type of research called pyrosequencing, previously used to assess the richness of bacterial ecosystems in marine environments and soil, is being used to look at the ecosystem within our bodies.
Living in each of us - on our skin, in our mucous membranes, and in our gut - are microorganisms whose numbers dwarf the number of our own cells and genes. Although some of these microbes are pathogens, most are harmless and even beneficial. The body's assortment of microorganisms, collectively called the microbiota, is similar to an organ in that it performs functions essential for our survival. Some microbes produce vitamins and other essential nutrients. Many metabolize food that we cannot digest on our own. They also break down drugs and toxins and regulate many aspects of innate and acquired immunity; protecting the host from infections and chronic inflammation as well as possibly many immune-based disorders. When an environmental agent alters the function of the microbiota, the result can be disease. This reaction may also be what happens in the beginning stages of the development of heart and lung disease.

Most environment-microbiota research has focused on the gut; home to about 100 trillion microorganisms—the vast majority of our complement of microbes. Shifts in the microbial species that reside in our intestines have been associated with a range of health issues including autoimmune disorders, obesity and even different types of cancer.

Each of us carries thousands of bacterial species in our gut along with a few species of other types of organisms. Although all humans have grossly similar microbiota, no two people have exactly the same composition of bacterial species in their guts. In fact, each individual's microbial consortium may turn out to be as unique as a fingerprint. Yet a study published in Nature(January 22, 2009) reported that, “although individual bacterial species can differ widely between people, the species tend to encode the same metabolic pathways”.

Outside influences such as antibiotic use, diet and psychological stress have shown strong correlations with what lives inside our bodies. Researchers are just beginning to understand how these environmental factors may affect our health. Recent advances in genomic sequencing technologies have pushed the field forward. In the past, scientists could only study microorganisms. Now they can sequence the entire collection of DNA in a microbial sample and identify the component species. This approach is known as pyrosequencing and has been key to many recent advances in understanding the relationship between our microbiota and health.

Jeffrey I. Gordon of Washington University School of Medicine, recently reported findings of his research studies in Nature. Using genetically obese and lean mice, the study aimed to discover the differences that occurred when the mice were given identical feeds. The gut microorganisms were found to be different in these two breeds. Obese mice were found to have guts teeming with bacteria which were efficient at super-digesting food and were able to harvest more calories from the food they ate leading to obesity. Lean mice had gut bacteria which were not as efficient in extracting calories from the food they ate. The issue then was to determine which came first: the fat or the bacteria. To find out, the lab took mice that had never been exposed to any bacteria, whose guts were totally germ-free. Half of them received bacteria taken from skinny mice and the other half received bacteria from obese mice. Overall, the mice that received bacteria from obese donors gained more fat over the course of the experiment.

More recently, this research was applied to humans. His team of researchers compared the gut flora of 12 obese volunteers with that of lean subjects. Similar findings confirmed the hypothesis. Furthermore, as the 12 people lost weight over the year, their gut population of bacteria changed to resemble that of the skinny mice. The study did not attempt to transfer the bacteria from obese human volunteers to the gut of lean subjects for ethical reasons.

Many questions remain. It is unclear what determines the make-up of a person's gut flora. It might be the microbes they pick up from their mothers; it might be their exposure to antibiotics. It is also unclear how fat tissue and gut flora might affect one another and whether the change in gut bacteria causes or is a result of the weight loss.

Other promising aspects of microbiota research include advances in sequencing technologies that allow huge numbers of humans and their microbes to be studied. Global surveys of human microbiota, for example, may start to address issues of how geography, history, diet, and culture all feed into determining bacterial structure and function. Genome wide association studies are also coming down the pipeline to examine how genetic variation in the human genome predicts bacterial composition.
To provide a foundation to answer some of these questions, the National Institutes of Health launched the Human Microbiome Project at the end of 2007. The project has targeted an estimated $115 million over five years to determine what parts of the microbiota are similar in all humans and what parts differ—and how those differences may relate to disease. The European Commission is funding a related effort, called Metagenomics of the Human Intestinal Tract, and in October 2008 scientists from around the globe formed the International Human Microbiome Consortium to share data on the human metagenome—comprising the genomes of all our microorganisms—among researchers around the world.

Being able to sequence thousands of microbes quickly and easily will likely lead to another field - the consideration of the individual's microbiota in the development of personalized medicine. The differences between each person's microbiota will influence not only their health risks but also how they respond to interventions including probiotic treatment and dietary changes. One should think about differences in microbiota being analogous to genetic differences that make our responses distinct.
According to Nita Salzman, assistant professor of Pediatrics at the Medical College of Wisconsin, simply knowing the constituents of our microbiota will not be enough to reach this goal. Even when we can determine the entire microbiota of a species and every gene of the metagenome, it's still hard to say which of those things is actually important in driving health or disease. Efforts to provide such an understanding are now focusing not on the genome sequences of resident bacteria but on the proteins they produce.

In The International Society of Medical Ecology Journal (Feb. 2009), Jansson's group released an analysis of the human bacterial proteome—the thousands of bacterial proteins that are expressed in our bodies. "The proteome [tells] you what's actually going on in the gut," she says. She and her colleagues found that proteins involved in carbohydrate metabolism and food utilization were very highly expressed, whereas other proteins, such as those involved in motility, were nearly absent. They are now working on analyzing the microbial proteomes in people with Crohn’s disease.

Another way of analyzing relevant microbial function is to examine the metabolites produced by the microbes, which reveals not just what the bacteria are expressing but what the body is actually absorbing. A study by William R. Wikoff et al., published in March 10th, 2009 Proceedings of the National Academy of Science, shows that many aspects of mammalian metabolism rely on the microbiota. In the absence of microbiota, the metabolites found in the blood of mice were significantly changed, suggesting that an animal's ability to metabolize drugs—and by extension, many other chemicals—likely relies in part on its community of microbes.

Combining genomic inventories of the microbial species that live inside us with functional analyses of the proteins they express and the metabolites we absorb will advance this field significantly in terms of understanding what's going on and how it relates to obesity and disease. Technological advances have profoundly pushed the field.

Consuming excess calories usually spurs what is called insulin resistance - when cells in the body that normally respond to the action of the hormone insulin fail to be stimulated by it. This greatly increases the risk of diabetes.

Now scientists at the Nestlé Research Centre, Lausanne, Switzerland, report in the FASEB Journal (Journal of the Federation of American Societies for Experimental Biology) that changing the make-up of gut microbiota reverses the insulin resistance that occurs progressively with obesity.
Obese, diabetic animals were given antibiotics to change the make up of microbes in the gut - their microbiota- in turn altering the way the body uses glucose, which is controlled by insulin. This lab experiment strongly supported the hypothesis that altering gut mirobiota could be beneficial in reducing insulin resistance.

Although there are many yoghurt and probiotic drinks on the market, more work would have to be done to determine which strains of probiotics would be most helpful for diabetes.

Prof Jeremy Nicholson of Imperial College London recently commented that this work adds to evidence that microbiota influence energy and fat use in the body "but we don't really know how much percentage wise it contributes to the obesity epidemic and how the bug influences varies between each person - that means for certain people- perhaps not all - that gut microbial engineering of some sort could be used as a future therapeutic route."

As for the hope of treating obesity this way, he stresses that "nothing will stop you getting fat if you overeat and exercise too little - that surpasses any host genetic or microbial variation”.
"But bugs do also respond to diet- if you get a high fat/calorie diet- you get a set of bugs that are better at making those calories available, a vicious circle."

Stay tuned for further news on the relationship of bugs in the gut to obesity and perhaps diabetes.

References:
1. Gordon.J and associates.Nature 2006;Volume 444:1022-1023
2. Ronaghi M and associates . Genome Research,2001;Volume ; 3–11
3. http://nihroadmap.nih.govt.hmp/
4. Salzman,N and associates, Proceedings National Academy Sciences. 2005;Volume 103:18129-181234
5. Verberkmoes N and associates. Shotgun Metaproteomics of the Human Gut Bacteria..ISMEJ;Vol 3:179-1896.
6. Wikoff W and associates.Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites.Proceedings of National Academy of Sciences, 2009.Vol 106:3698-36703-36703
 

Read past news stories on heart health