You and Your Microbiome – Part 2

  • Global Obesity Epidemic is Linked to Gut Microbiome
  • DNA Sequence-Based Microbiomes Accurately Associate with Obesity
  • Blue Agave Margaritas Contain Beneficial Gut Microbes
  • Investments in Microbiome-based Therapies on the Rise, but is there Hype?

Last August, my post entitled Meet Your Microbiome: The Other Part of You dealt with growing recognition that trillions of microbes—mostly bacteria but also fungus—reside in and on each of us, and influence our health status. Moreover, the compositions of these microbiomes change with our diet, what we drink or breath, and who we contact—family, pets, and close friends.

Since then, I’ve collected a string of microbiome articles delving into the implications of this dynamic, symbiotic relationship, and selected some topics that I thought were “blogworthy.” This Part 2, as it were, focuses on overweight/obesity, microbiome therapy, and burgeoning business opportunities.

Overweight/Obesity Epidemic

A recent article in The Wall Street Journal highlights the obesity epidemic that much of the world is facing today. Since 1980, obesity rates have risen by 28% among adults and 47% among children. By 2013 approximately 29% of the world population was said to be overweight or obese. That equates to about 2.1 billion people, the majority of which live in developing countries.

This is a BIG problem—no pun intended—given the very serious consequences of these scary statistics. Policies and programs introduced years ago in countries like the USA have obviously not reversed the continual increase in obesity.

graph

From Wall Street Journal article by Betsy McCay, published May 29, 2014.

Dieting, Exercise and Microbiota

Obesity is considered by the World Health Organization to be preventable by limiting food-derived energy intake from total fats and sugars; increasing consumption of fruits, veggies, etc. and—of course—regular physical activity (60 minutes a day for children and 150 minutes per week for adults).

Some of the roughly 1,000 bacterial species in the human gut help make us fat, while others keep us lean. Centre for Infections/Public Health England/Science Photo Library (taken from Nature).

Some of the roughly 1,000 bacterial species in the human gut help make us fat, while others keep us lean. Centre for Infections/Public Health England/Science Photo Library (taken from Nature).

There could, however, also be links between obesity and bacteria living in our guts, according to Sarah DeWeerdt’s freely accessible article in venerable Nature magazine from which selected snippets are as follows.

Consider what Liping Zhao, a microbiologist at Shanghai Jiao Tong University in China, found after he put a severely obese man on a strict diet. Over the course of 6 months, the man shed ~100 pounds. As he lost weigh, a group of bacteria known as Enterobacter became undetectable in his stool samples, even though they had previously made up 35% of the microbes in his gut.

This dramatic change in human gut microbiota—estimated to be ~1,000 species of bacteria—might be coincident with weight loss, but Zhao and other researchers think otherwise, and believe that these bacteria actually play a key role in regulating body weight.

DeWeerdt quotes Fredrik Bäckhed—a researcher at the University of Gothenburg in Sweden who investigates the gut microbiota using mouse models—as noting that ‘There are a lot of studies in humans, but those are only associations. There are a lot of studies of causation, but those are only in animals.’

How to translate results from studies of lab mice into treatments for humans in the real world is no simple matter, and will likely be the subject of much continued experimentation and hot debate.

The Role of Prebiotics

We’ve all heard about probiotics, but when it comes to studying obesity it’s important to also understand prebiotics. Unlike probiotics which are live organisms, prebiotics are non-living substances (usually carbohydrates) that function as food sources for beneficial bacteria. Research indicates that both pro- and prebiotics are key to controlling obesity. Researchers have shown that in mice prebiotics, particularly oligofructose, can reverse certain gastric problems. DeWeerdt quotes Patrice Cani, a researcher of metabolism and nutrition at the Catholic University of Louvain in Belgium as saying ‘We found that mice fed with oligofructose had an improved gut barrier function.’ ‘The mice that were given prebiotics also had improved metabolic markers, reduced fat mass and reduced inflammation,’ Cani added.

Harvesting a Blue Agave plant in Mexico involves hard work before processing into Agave Tequila and Agave Nectar (taken from inari-hof.de via Bing Images). Blue Agave Margarita is a refreshing source of oligofructose prebiotic (taken from experience-it-island-thyme.blogspot.com via Bing Images).

Harvesting a Blue Agave plant in Mexico involves hard work before processing into Agave Tequila and Agave Nectar (taken from inari-hof.de via Bing Images).
Blue Agave Margarita is a refreshing source of oligofructose prebiotic (taken from experience-it-island-thyme.blogspot.com via Bing Images).

The most widely used prebiotic is oligofructose (aka fructo-oligosaccharides or FOS)—a type of soluble but indigestible carbohydrate fiber found in the Blue Agave plant, as well as fruits and vegetables such as bananas, onions, chicory root, garlic, asparagus, barley, wheat, jicama, leeks and the Jerusalem artichoke. Some grains and cereals, such as wheat, also contain oligofructose. The Jerusalem artichoke—and its relative yacón—together with the Blue Agave plant have been found to have the highest concentrations of oligofructose in cultured plants. Both yacón and Agave nectar are becoming popular substitutes for sugar—BTW, Agave Nectar Margaritas have a 5-Star rating at Food.com!

As the saying goes, “too much of a good thing can be bad.” One report cautions that 15 g or more of FOS can produce side effects such as gas, bloating and general intestinal discomfort, and doses higher than 40 g might cause diarrhea (taken from prebiotin.com via Bing Images).

As the saying goes, “too much of a good thing can be bad.” One report cautions that 15 g or more of FOS can produce side effects such as gas, bloating and general intestinal discomfort, and doses higher than 40 g might cause diarrhea (taken from prebiotin.com via Bing Images).

It’s not clear, however, if the benefits of prebiotics that were seen in mice studies translate to humans. In 2013, Cani and his team conducted a study giving obese women a daily supplement of oligofructose and inulin (a similar substance). After three months, the women ‘showed a slight decrease in fat mass and a reduction in blood levels of an inflammation-promoting molecule. But the results were not really equivalent to the ones we observed in mice,’ Cani told DeWeerdt.

As another caveat regarding studies of prebiotics, consider the results of a study conducted regarding the dietary regimen followed by the subject in his aforementioned obesity study. For 9 weeks, about 100 participants followed a diet that included whole grains, traditional Chinese medicinal foods and prebiotics. The participants all showed ‘improved markers of metabolic health and lower levels of potentially harmful bacteria, including Enterobacter, but they only achieved a modest weight loss of ~6 kg on average.’ Since this average weight loss is almost 10-times less than that achieved by Zhao’s severely obese patient, more factors need to be considered.

Microbiomes Sort “Lean from Obese” with 90% Accuracy!

The advent of fast and cheap DNA sequencing has enabled not only detection and quantification of the type of bacteria in the gut, but also the genes that these microorganisms are expressing, in addition to our own human genes. BTW, researchers in this field generally refer to the collection of bacterial species present in the gut as the microbiota (aka gut flora), and the collection of corresponding expressed genes as the microbiome. In this regard, I find it fascinating—and somewhat difficult to accept—that the ongoing Human Microbiome Project is extending the definition of what constitutes a human to include microbiome, so “it” is technically part of “you”!

The MetaHIT Consortium—a European effort to determine the associations between gut microbes and chronic diseases—sequenced the microbiomes of 169 obese and 123 non-obese individuals. They found that those with fewer bacterial expressed genes tended to have more body fat and other markers of poor metabolic health compared with people with a more diverse microbiome.

The stunning conclusion was that microbial genes are a much better readout of whether you’re likely to be obese or not than human genes are. I repeat—with emphasis—this remarkable conclusion:

…microbial genes are a much better readout of whether you’re likely to be obese or not than human genes…

At the Risk of Oversimplifying this Finding, Genes in your Microbiome Seemingly Influence your Tendency to be Obese or not more so than your own Human Genes!

DeWeerdt reports that other investigators have come to a similar conclusion, and on a quantitative basis claim that microbial genes sort the lean from the obese with 90% accuracy, whereas human genes do this with much less accuracy, i.e. only 58% of the time.

Cause or Effect?

So the really big question is whether these microbial changes are a cause or an effect of the obesity. A step toward deciphering this puzzle has been convincingly addressed by very clever—I think—experimentation wherein the microbiota of an obese mouse is transferred to a microbiota-free mouse.

Jeffrey Gordon, director of the Center for Genome Sciences & Systems Biology at Washington University in St. Louis, Missouri, found back in 2004 that when a microbiota-free mouse is colonized with gut microbes from a normal mouse, it experiences a 60% increase in body fat over the course of 2 weeks—despite eating less food than it did before the transfer.

The simplest interpretation—in my opinion—is that microbes in the gut of these mice increased the ability of mice to store fat. How this occurs biochemically is, of course, not at all clear and will require much more investigation.

BTW, in a variant of this line of research, it has been shown that germ-free mice that receive gut microbes from an obese human donor gain more weight than those that receive them from a lean person. While this might seem surprising, I think it’s actually somewhat expected based on functional biochemical similarity of mouse and human genes that may nevertheless be different genetically, i.e. at the level of DNA sequence.

In Hot Pursuit of Microbiome Therapies

Sarah Reardon reports in Nature magazine that roughly $500 million has been spent on microbiome research since 2008. However, the only major therapy resulting from this sizable investment has been the use of fecal transplants for treating life-threatening gut infections or inflammatory bowel disease—discussed in my earlier blog.

This seeming absence of clinical impact by investment dollars may change due to large pharmaceutical companies viewing this area as a new source of revenue. This past May, Pfizer announced plans to partner with Second Genome, a biotechnology firm in South San Francisco, California, to study the microbiomes of ~900 people comprising a group with metabolic disorders and, of course, a control group.

At virtually the same time, Paris-based Enterome revealed that it had raised $13.8 million in venture capital to develop tests that are intended to diagnose inflammatory and liver diseases based on measuring the composition of gut bacteria. Based on the aforementioned microbiota vs. microbiome issue, I’m somewhat skeptical of this approach by Enterome. Maybe they’ll find otherwise.

Reardon also reports that Joseph Murray—a gastroenterologist at the Mayo Clinic in Rochester, Minnesota—fed gut bacterium Prevotella histicola to transgenic mice with human-like immune systems, and found suppression of inflammation caused by multiple sclerosis and rheumatoid arthritis. He is hoping to develop this into a therapy with biotech firm Miomics in New York.

Similarly, Vedanta Biosciences in Boston, Massachusetts, is conducting preclinical trials of a pill containing microbes that suppress gut inflammation. I checked out Vedanta’s website, and it’s worth visiting to watch a video entitled Telling “Good” from “Bad,” which is about the immune system evolving to differentiate ‘good’ microbes from ‘bad’ microbes, as related to its microbe-based therapeutic approach.

And last June, Second Genome announced a deal with Janssen Pharmaceuticals of Beerse, Belgium, to study the microbial populations of people with ulcerative colitis, in the hope of identifying new drugs and drug targets. Already in the clinic, Microbiome Therapeutics, a biotechnology company in Broomfield, Colorado, is currently conducting trials with two small molecules that select for ‘good’ gut bacteria to help people with diabetes to take up insulin more easily.

From all of the above, there’s no doubt in my mind that microbiomes need to be factored into assessment, modulation, and maintenance of a person’s health, and much R&D is clearly moving in these directions. On the other hand, my sense is that progress will be slower than hoped for, partly because there’s much to be discovered, and partly because people aren’t like mice: we can choose to eat what we wish, indulge our cravings, and skip taking medications.

Chime in with your comments if you think I’m being too pessimistic about this.

BTW, for those of you who do want to change your diet so as to hopefully beneficially change your microbiomes, you can consider engaging with uBiome, which is a small start-up that offers DNA sequence-based microbiome analysis as part of ongoing research involving likeminded persons. An explanatory—and humorous video—can be accessed here.

Hyping the Microbiome?

“Maybe the microbiome is our puppet master” says Carl Zimmer in his NY Times article headlined above (Credit: Jonathan Rosen).

“Maybe the microbiome is our puppet master” says Carl Zimmer in his NY Times article headlined above (Credit: Jonathan Rosen).

Throughout all of the above, you’ll notice that weight-related conclusions derived from legitimate scientific inquiries are properly couched with caveats and the need for further investigations. By contrast, some reports may be pushing the envelope of credulity, as discussed in an engaging but anonymous article in GenomeWeb entitled “Hyping the Microbiome.” One notable quote is by William Hanage, an associate professor of epidemiology at the Harvard School of Public Health, who says that ‘Microbiomics risks being drowned in a tsunami of its own hype.’ He also points to a blog Jonathan Eisen, who gives awards for ‘overselling the microbiome,’ and provides an updated list of links to questionable claims.

Hanage partly blames the media for generating this hype. I agree with this finger pointing, and my personal favorite is this headline and accompanying visual in the NY Times.

Our Microbiome May Be Looking Out for Itself

Postscript

After writing this post, a publication in Nature reported “dynamics and associations” of microbial communities across the human body, based on detailed analysis of data from the Human Microbiome Project. Following is a portion of the abstract that draws three conclusions (see underlines), the first of which I find fascinating:

First, there were strong associations between whether individuals had been breastfed as an infant, their gender, and their level of education with their community types at several body sites. Second, although the specific taxonomic compositions of the oral and gut microbiomes were different, the community types observed at these sites were predictive of each other. Finally, over the course of the sampling period, the community types from sites within the oral cavity were the least stable, whereas those in the vagina and gut were the most stable. Our results demonstrate that even with the considerable intra- and interpersonal variation in the human microbiome, this variation can be partitioned into community types that are predictive of each other and are probably the result of life-history characteristics. Understanding the diversity of community types and the mechanisms that result in an individual having a particular type or changing types, will allow us to use their community types to assess disease risk and to personalize therapies.    

One thought on “You and Your Microbiome – Part 2

  1. Thank you for the overview of the microbiome field Jerry! its definitely one of the hot topics of research these days, tremendous potential. but a lot of hype as well. Biopharma Research Council is organizing a first webinar on this topic “An Introduction to the Microbiome” this coming Thursday, Dec 4th:
    http://www.biopharmaresearchcouncil.org/introduction-to-the-microbiome?utm_source=BRC+Microbiome+Webinar+Dec+4+2014+2&utm_campaign=Dec+4+Microbiome&utm_medium=email

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