A Book Review of Missing Microbes by Dr. Martin J. Blaser

by Kirke on November 30, 2014

Photo of the author by Troi Santos-NYULMC
Photo of the author by Troi Santos-NYULMC
Photo of the author by Troi Santos-NYULMC

 

If you take my recommendation and read Missing Microbes: How the overuse of antibiotics is fueling our modern plagues by Dr. Martin J. Blaser, it may alarm you enough to want to read my post entitled “Eat More Legumes and Feed Your Microbiota” to learn what to eat to promote your inner garden of microbes, and hopefully avoid any modern plagues. The current societal plagues Dr. Blaser is referring to in his title include: diabetes type II, obesity, food allergies, asthma, eczema, esophageal reflux, and the ever increasing virulence of antibiotic resistant pathogens.

Dr. Blaser’s thesis is that the over prescribing of antibiotics has so diminished our beneficial flora that we are left vulnerable to major health issues. In 2010, 258 million courses of antibiotics were prescribed in this country. That’s five doses for every six people. Rates of prescribing varied according to region. The average for the whole country was 833 per thousand people. In the West the number was 630 per thousand, and in the South 930 prescriptions were written per thousand people, a 50% difference. Dr. Blaser’s statistics prompted my memory of this map showing that rates of obesity in the South were much higher than rates in the West in 2010. Could this be epidemiological proof that the overuse of antibiotics is at least a contributing causative factor for higher rates of obesity in the South? In his book Blaser makes a persuasive argument that this may be the case.

 

The author first realized that antibiotic use might be an underlying cause of obesity when considering the fact that for more than 60 years farmers have been using them to fatten their livestock. The author and his colleagues performed multiple studies on mice using the same subtherapeutic antibiotic doses that farmers use. In humans and other animals, bacteria make available calories in the form of short-chain fatty acids (products of bacterial fermentation of indigestible plant fiber) from food that would otherwise pass unutilized. In one study on mice, Blaser found that small amounts of antibiotics changed their microbiota, making it more efficient at extracting those calories, which then go right to the liver to be turned into fat for storage. Mimicking the farm practice of feeding a high fat diet on top of the antibiotics, researchers found that male mice gained 25% more body fat, and amazingly, female mice increased their body fat by 100%; they had doubled their body weight.The effect of combining antibiotics with a high-fat diet was synergistic. Could it be that the increase in antibiotic use in humans coupled with the rise in availability of high calorie processed food is largely responsible for skyrocketing rates of obesity?

The effect of combining antibiotics with a high-fat diet was synergistic

But those studies were done on mice. What about the human animal? Blaser evaluated a large study called the Avon Longitudinal Study of Parents and Children (ALSPAC, also known as Children of the Nineties), which started in 1991 and involved over 14,500 pregnant women. The subjects and their children were followed for the next 15 years. In Blaser’s paper “Infant antibiotic exposures and early-life body mass” they evaluated the question asked at six, fifteen, and twenty-four months: were their kids given antibiotics during the previous period? About a third was given antibiotics in the first six months of their lives, and by two years, three-quarters of the children had received the therapy. After controlling for the child’s birth weight, the mother’s weight, and other possibly confounding variables, they found that the children who received antibiotics in the first six months of life became fatter. In both mouse and human studies, they had determined that it was the disruption of the microbiota early in life that led to a continuing, long term change in gut metabolism, precipitating in greater fat weight gain.

ALSPAC also was used to compare obesity outcomes with method of birth. It was found that Cesarean section births were associated with obesity of offspring later in life, which is just one of the negative outcomes becoming associated with the procedure. Blaser’s wife, Dr. Maria Gloria Dominguez-Bello has been concentrating on the missing microbe issues that stem from the great increase of Cesarean sections around the world. Rates of C-sections performed in this country are rising for a few reasons. One is the very real fear of the pain of natural childbirth. Many choose the option for the convenience of choosing when to give birth, or to be sure their chosen doctor is available. Dr. Blaser also points to the unpleasant fact that C-sections are more convenient for the doctor’s schedule and more lucrative for the physician and the hospital. The result is that C-section rates have risen from 1 in 5 births in 1996 to 1 in 3 in 2011, a fifty percent increase in 15 years.

Cesarean section births were associated with obesity of offspring later in life

Dr. Dominguez-Bello’s studies revealed that the first bowel movements of babies born naturally were populated by their mother’s vaginal microbes, while C-section delivered babies showed populations mainly of skin and airborne microbes. Newborns delivered by C-section will not benefit from the mother’s lactobacilli or other bacteria that have been selected by hundreds of thousands of years of evolution, and as a result the infant’s immune system may fail to develop properly. Studies have shown that C-section born babies tend to have increased risk of developing asthma, allergies, obesity, diabetes type II, and other health problems. Dr. Dominguez-Bello is currently conducting research on inoculating C-section newborns with gauze swabs from the mother’s vaginal canal. But she has found that even after doubling the number of mom’s bacteria the babies are exposed to, vaginally born babies still were inoculated with 6 times as many organisms due the prolonged time and tight contact a fetus experiences during a natural birth. Dominguez-Bello believes that this may also be due to the antibiotics all C-section mothers are given during a birthing operation.

A mother’s microbes and her first milk expressed called colostrum, have long been known to help a newborn’s digestive and immune system by providing a diverse population of commensal (good guy) bacteria and protective antibodies. A more recent revelation was solving the mystery of why breast milk contained carbohydrates known as oligosaccharides that babies cannot digest. Researchers found that fledging microbes, such as Bifidobacterium infantis, use the sugar as an energy source, thus thriving and crowding out possibly pathogenic bacteria. And urea, a waste product in urine, also found in breast milk, was proved to provide beneficial bacteria a source of nitrogen for the making of proteins. These mechanisms benefiting a newborn’s young colony of microbiota are no accident. Having evolved along with mammals, the good guy bacteria are given a boost up, so that they gain a foothold before the competing bad guy bacteria bloom, which would strain the child’s immature immunity system. Dr. Blaser proposes it is the strain on an infant’s immune system resulting from early doses of antibiotics that leads to increased risk later in life of allergic disease like asthma, skin allergies, and possibly diabetes.

early doses of antibiotics leads to increased risk later in life of allergic disease

Another fascinating position stemming from Dr. Blaser’s thesis is his advocacy for saving from extinction the stomach bacteria thought to cause peptic ulcers. The scientists who discovered Helicobacter pylori, a bacterium that surprised everyone because it thrived in the highly acidic environment of the stomach, won the Nobel Prize for showing its link to peptic disease. Although Dr. Blaser concedes that rates of ulcers and stomach cancer have been going down along with the decreasing prevalence of H. pylori, he contends that there have been unforeseen consequences. He points out that H. pylori has not been linked directly to ulcers as a causative factor, even though its elimination reduces risk of recurrence. He notes that as the presence of H. pylori has diminished, other stomach related diseases have been increasing at alarming rates, diseases like gastroesophageal reflux disease, and cancer of the esophagus, the fastest rising cancer in the US. Blaser’s own research as well as research by others has found that H. pylori are also protective against allergic asthma and other allergen related illnesses.

There are many functions of our microbiota that have become accepted as fact by the scientific community, such as their ability to synthesize vitamin K, aiding in the metabolizing of drugs, the breaking down of fiber and starch to supply otherwise lost calories, helping maintain blood pressure, and they evolve to help us survive on limited diets. There are many more known benefits of having a diverse microbiome and more is being learned every year. It is postulated that the bacteria in our gut may influence our eating behavior. Scientists have observed that bacteria make exact replicas of neurochemical hormones produced by our central nervous system, opening the possibility that they may be influencing our mood and behavior through this microbial endocrinology pathway It is more than a little unnerving that not only are there far more bacteria cells in our bodies than our own cells, but that they may also be controlling our behavior for their own benefit.

Most will concede that it is plain that the overuse of antibiotics, human use as well as use in agriculture, is a serious problem for our well being and needs to be addressed. What are our alternatives? Dr. Blaser recommends radically reducing the use of antibiotics, only applying them when absolutely necessary. But what do we do as more pathogenic bacteria become resistant?

Looking beyond the scope of Missing Microbes

One alternative is currently being utilized in Russia and its former satellite countries in humans, and on farms in the US. It is the use of bacteriophages (meaning: eater of bacteria). If you felt creepy when you learned about how bacterial cells (100 trillion) outnumber our own (30 trillion), think about the fact that there are 10 times as many bacteriophages as bacteria in our bodies! The good news is that every two days, bacteriophages kill half the bacteria in the world, including those trying to take over our colon. These tiny viruses that look like a lunar lander your kid made from tinker toys line our mucus membranes by the millions , fighting off evil bacteria that would like to send endotoxin through our colon walls and into our blood streams. Here is what they look like, really:

Enterobacteria phage T4
Enterobacteria phage T4
Enterobacteria phage T4

 

Phages were named by Frenchman Felix d’Herelle in 1916 after he observed their antibacterial properties after isolating the tiny organisms in the stool of World War I soldiers suffering from bacteria caused dysentery. He eventually developed bacteriophage products to be used as therapy for infectious diseases, sold by a company called The Safe Hair Dye Company of France, now known as L’Oréal. The American drug manufacturer Eli Lilly marketed phage products targeting different infections, topical and internal, with mixed results. But the development of Sulfa drugs in the thirties, and the discovery of antibiotics in the forties quashed the development of bacteriophage therapy in the West.

However, today new uses of our viral friends are being implemented. The company Epibiome is working on finding the right phage to attack bacteria that cause an infection of cows’ udders called mastitis, that costs the dairy industry $2 billion every year. Unlike antibiotics, which attack good as well as bad bacteria, phages target specific bacteria, injecting their own DNA, creating hundreds of copies of themselves. They then rupture the bacterium cell so the newly created phages can go on to kill more target bacteria. Here is an animation of the phage T4 attacking an E.coli bacterium:

 

Governmental agencies are getting on the phage bandwagon, including The National Institute of Allergy and Infectious Diseases, hoping for a new weapon to fight antibiotic resistance, and the European Union is spending $5.2 million to develop a phage treatment for infected burns. The FDA has approved phage products for use in food processing like EcoShield by Intralyix, which can be used to treat ground meat products, and LISTEX P100 from Micreos Food Safety, which is being used to prevent Listeria contamination in food and food processing plants.

There are problems with using bacteriophages as a bacteria fighter. One is that phages reproduce and mutate quickly, making their effectiveness unstable. Bacteria also mutate and develop resistance against the phages. Another issue is that there are almost no studies of bacteriophages properly performed using scientific method on animals or humans. As antibiotics become more resistant, and the issues Dr. Martin J. Blaser has thoughtfully presented in his book Missing Microbes gain further credence, perhaps we will invest in more research into our relationship with both the bacteria and the viruses that appear to be so essential to our well being.

 

References for Missing Microbes Review

Alcock, J., Maley, C. C., & Aktipis, C. A. (2014). Is eating behavior manipulated by the  gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. Bioessays, 36(10), 940-949. http://dx.doi.org/10.1002/bies.201400071

Azad, M. B., Konya, T., Maughan, H., Guttman, D. S., Field, C. J., Chari, R. S., & Kozyrskyj, A. L.(2013). Gut microbiota of healthy Canadian infants: Profiles by mode of delivery and infant diet by 4 months. Canadian Medical Association Journal, 185(5), 385-394. http://dx.doi.org/CMAJ2013.DOI:10.1503/cmaj.121189

Barr, J. J., Auro, R., Furlan, M., Whiteson, K. L., Erb, M. L., & Rohwer, F. (2013, April 18). Bacteriophage adhering to mucus provide a non-host-derived immunity. Retrieved from Proceedings of the National Academy of Sciences website: http://www.pnas.org/content/110/26/10771

Blustein, J., Attina, T., Liu, M., Ryan, A. M., Blaser, M. J., & Trasande, L. (2013, April 8). Association of caesarean delivery with child adiposity from age 6 weeks to 15 years. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23670220

Deresinski, S. (2009). Bacteriophage therapy: Exploiting smaller fleas. Clinical Infectious Diseases, 1096-1101. http://dx.doi.org/10.1086/597405

Enterobacteria phage T4. (2014, September 10). In Wikipedia, The Free Encyclopedia. Retrieved 22:01, November 29, 2014, fromhttp://en.wikipedia.org/w/index.php?title=Enterobacteria_phage_T4&oldid=624973089

Gross, T. (Producer). (2014, April 14). Interview: Martin Blaser. Fresh air. Podcast retrieved from http://www.npr.org/2014/04/14/302899093/modern-medicine-may-not-be-doing-your-microbiome-any-favors

Holt, H. (2014, April 8). Dr. Martin Blaser introduces ‘Missing Microbes’ [Video file]. Retrieved from https://www.youtube.com/watch?v=3ew37rxAhjg&feature=youtu.be

Hope, J. (2013, February 11). Babies delivered by caesarean section at higher risk of asthma and allergies. Retrieved from http://www.dailymail.co.uk/health/article-2277046/Babies-delivered-Caesarean-section-higher-risk-asthma-allergies.html

Kaul, G. (2014, September 10). Bacteria-killing viruses seen as an alternative to antibiotics. San Francisco Chronicle, Health, pp. D1-D5.

Lyte, M. (2013). Microbial endocrinology in the microbiome-gut-brain axis. Plos Pathogens, 9(11), 1-3. http://dx.doi.org/10.1371/journal.ppat.1003726

National Public Radio. (2013, November 5). The invisible universe of the human microbiome [Video file]. Retrieved from https://www.youtube.com/watch?v=5DTrENdWvvM&feature=youtu.be

Obesity prevalence maps [PowerPoint slides]. (2010). Retrieved from http://www.cdc.gov/obesity/data/prevalence-maps.html

Pollan, M. (2013, May 15). Some of my best friends are germs. New York Times, Sunday magazine.

Reibman, J., Marmor, M., Finer, J., Fernandez-Beros, M.-E., Rogers, L., & Blaser, M. J. (2008, December 29). Asthma is inversely associated with Helicobacter pylori status in an urban population. Retrieved from http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004060

Salama, N. R., Hartung, M. L., & Anne Müller. (2013). H.pylori mediated protection against allergic and chronic inflammatory disorders. Retrieved from http://www.nature.com/nrmicro/journal/v11/n6/box/nrmicro3016_BX3.html

Sillankorva, S. M., Oliveira, H., & Azeredo, J. (n.d.). Bacteriophages and their role in food safety. International Journal of Microbiology, 2012. http://dx.doi.org/10.1155/2012/863945

Sulakvelidze, A., Alavidze, Z., & Morris, J. G. (2001). Bacteriophage Therapy. American Society for Microbiology. http://dx.doi.org/10.1128/AAC.45.3.649-659.2001

Trasande, L., Blustein, J., Liu, M., Corwin, E., Cox, L. M., & Blaser, M. J. (2013). Infant antibiotic exposures and early-life body mass. International Journal of Obesity, 37(1), 16-23. http://dx.doi.org/10.1038/ijo.2012.132

Zimmer, C. (2013, May 20). Meet you new symbionts: Trillions of viruses. Retrieved from http://phenomena.nationalgeographic.com/2013/05/20/meet-your-new-symbionts-several-trillion-viruses/

Zimmer, C. (2014, August 14). Our microbiome may be looking out for itself. Retrieved from http://www.nytimes.com/2014/08/14/science/our-microbiome-may-be-looking-out-for-itself.html

 

 

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