Obesity in the United States – Dysbiosis from Exposure to Low-Dose Antibiotics?

Research by Dr. Lee Riley, Eva Raphael, and Eduardo Faerstein

Presentation by Megha Majumder

WHAT HAPPENED TO US?

Background - Definitions

1. Obesity

Obesity has emerged as an epidemic, especially in the United States. It is a complex disorder that involves an excessive amount of fat in the body.

It is often accompanied by a variety of chronic medical problems, including diabetes, heart disease, hypertension (high blood pressure), and dyslipidemia (high cholesterol).

The study of microbiota is one that is paid a significantly lesser amount of attention in comparison to the topic of obesity in popular science, despite its equal and interrelated importance.

2. Microbiota/Microbiome

The microbiome is the totality of microbial population (culture-independent) in a particular ecological niche or community (ocean, soil, body site, etc).

If the human intestinal micro biome is disrupted, then you have dysbiosis - disruption of intestinal bacteria that have adverse effects on homeostasis and metabolism.

Background - The Microbiome

Hypothesis

Most reports attribute the obesity epidemic to factors such as excess food energy intake, changes in diet and eating behavior, and increasing sedentary life style. Undoubtedly, these factors contribute, they do not account for the rapid increase in obesity rates we’ve seen over the last two decades.

Recently, a series of studies have described the role of intestinal microbiota on body metabolism and energy balance, and how its disruption (known as dysbiosis) could adversely affect body physiology and health.

If this mechanism – disruption of the intestinal microbiota – occurred at the population level, it could actually explain the obesity epidemic.

It is important to note that the livestock use of antimicrobial agents has sharply increased in the USA over the same 20-year period of the obesity epidemic and its sharp rise.

HYPOTHESIS: the American human intestinal microbiota may have been disrupted by chronic, widespread exposures to low-residue antimicrobial drugs that have increasingly entered our food chain and the environment over the last 20 years. These exposures can be contributing to the obesity epidemic - they could be the missing link to our explanation of the epidemic.

Procedure

The hypothesis and conclusion is based on a review of relevant literature.

1. First, they searched PubMed by cross-referencing the word “obesity” with the following terms: epidemic, prevalence, diet, calorie intake, nutrients, physical activity, lifestyle, host factors, genetics, antibiotics/antimicrobial agents, antibiotic residues in food, antibiotics in plants, antibiotic growth promoters, environmental release of antibiotics, animal husbandry, animal feed, gut microbiome/microbiota, and metagenome.

2. Then they found more references by reviewing the cited references from the primary articles.

3. They excluded abstract reports or conference proceedings. Articles not available electronically were sought at the University of California library collections.

*The search was limited to publications in English up to August 2013.

Antibiotics in the Environment and Food

- One major potential source of antibiotics that enter the food chain in the US is the food animal reservoir.

- 1990s - intensification in livestock production and animal feeding operations expanded significantly, meaning that the use of antibiotics increased, too.

- 2011 - The Food and Drug Administration (FDA) reported that the sales of antimicrobial agents used in food-producing animals were 13,542,030  kg.

- 75% of antibiotics given to feedlot animals are not even absorbed by the body and thus, excreted in waste (manure and urine). That’s 780 million tons of manure.

- 780 million tons of antibiotics-infested manure that is converted into fertilizers and spread over crops.

- 7.5 – 18 million pounds of antimicrobial drugs are released into the environment annually.

- Regions of highest usage of these growth-promoting antibiotics for animal husbandry overlap with the regions that have the highest obesity prevalence in the USA. (Agricultural Atlas of the United States)

- The antibiotics can also accumulate in plant tissue; sulfamethazine in manure-based soil accumulated in corn, lettuce, and potato. So, we digest them through plants and vegetables. The concentrations are low, but still significant.

- We are chronically exposed to these drugs, whether it be from the soil our food grows in, spraying fruits and vegetables, discarded expired drugs, and other human activities.

*Note: exposure does not indicate a cause and effect relationship; more experiments and evidence is necessary to derive at such a conclusion.

Antibiotics as Growth Promoters

1946 - Moore et al. reported that the administration of low-dose streptomycin and sulfasuxidine (antibiotics) in chicken feed caused increased weight gain in chicks.

- Food animal industry gradually adopts practice of administering subtherapeutic doses of antibiotics as growth promoters.

- How do they gain weight anyway?

1. Suppression of subclinical infections and overt diseases which promotes general health of the animal and hence better nutrition.

2. Stimulation of growth of bacteria in the gut that synthesize essential nutrients.

3. Suppression of microbes that compete with the host for nutrients.

4. Improvement in intestinal absorption of nutrients.

- Thus, if humans are indeed chronically exposed to low-dose antibiotics from the environment, there is a good reason to believe that they, like the chicks, can gain weight.

Change in Intestinal Microbial Population Structure and Its Effect on Body Physiology

- A recent series of reports has shown that the structure of the total human intestinal microbial population (microbiota) has a significant influence on body physiology.

- The gut microbiota can even be considered as another vital human organ, based on its newfound functions:

a. Makes vitamins and other micronutrients.

b. B3, B

5, B

6, B

12, D, folate, cobalamin.

c. Protects host against pathogens by competitive exclusion.

d. Promotes healthy mucosa.

e. Digests polysaccharides to make short-chain fatty acids.

f. Produces anti-oxidants, anti-inflammatory agents.

g. Needed for the proper development of the intestinal immune system

- Evolution of Gut Microbiome:

Over a course of tens of thousands of years, the intestinal bacterial population evolved with the Homo sapiens body to share and compete for energy and nutrient supply and, in the process, has come to establish a stable equilibrium state. This intestinal microbial equilibrium state adds to homeostatic maintenance of body weight.

A disruption of this steady state (dysbiosis) could affect nutrient and energy utilization by the human body and thus, human physiology.

Experiment - Proving that the gut micro biome, if it’s disrupted, has adverse consequences.

- Conventionally reared (CONV-R) mice fed polysaccharide-rich diet weighed about 40% more than its germ-free (GF) counterpart fed the same diet.

- When the gut microflora from the CONV-R mice was transferred to the GF mice, the latter saw a 60% weight gain in 2  weeks.

- The increase in weight of the lean mice was attributed to the gut microflora that allowed energy to be salvaged from otherwise indigestible polysaccharide diet.

- The next relevant question would be, how does exposure to antibiotics contribute to alteration in intestinal microbial population?

Evidence of Antibiotic-Induced Changes in the Human Gut Microbiota and Body Physiology

• Trasande et al. examined the long-term effect of antibiotic exposures in the first 2 years of life of children born in Avon, United Kingdom between 1991 and 1992. They found that exposure to antibiotics during the first 6 months of life, but not during 6–14 or 15–23 months was consistently associated with a later increase in BMI.

• Blaser and Falkow have suggested that the accelerated disappearance of the normal human microbial community, such as Helicobacter pylori in the stomach, due in part to the human use of antibiotics to treat peptic ulcer disease, may be contributing to post-modern conditions, including obesity.

• In a 10-month prospective experimental study of three human subjects given two courses of ciprofloxacin, Dethlefsin and Relman showed that the gut microbiota was rapidly altered with the antimicrobial drug exposure.

• If a large proportion of Americans are exposed to low-residue antibiotics in the food they eat, chronic exposures to such sources could certainly disrupt the normal steady state gut microbiota, which should be reflected by changes in body physiology.

Future Research

What needs to be done:

1. The impact of antibiotic exposures on the gut microbiota ecology and body physiology needs to be examined at the population level.

2. There needs to be a comparison of gut microbiota of populations residing near farms or regions where animals are administered antibiotics versus those living away from those places to reveal microbiota population structures associated with differences in body physiology.

3. The practice and trend of use of antibiotics as growth promoters in animal husbandry needs to be assessed to examine the relevance of this hypothesis to the obesity epidemic in these other regions of the world.

4. A more systematic and comprehensive analysis of antimicrobial residues in food and the environment is needed.

Conclusion

- Today, the core gut microbiota of many Americans may be substantially different from that of most Americans living before the 1950s.

- Chronic exposures to low-residue antimicrobial drugs in food could disrupt the equilibrium state of intestinal microbiota and cause dysbiosis that can contribute to changes in body physiology.

- Thus, the obesity epidemic in the United States may be partly driven by the mass exposure of Americans to food containing low-residue antimicrobial agents.