1. Abstract
Development of the Microbiome and Obesity Risk
Kara Lechtenberg and Megan Osborne
Department of Food Science & Human Nutrition, Colorado State University, Fort Collins, CO
Spring 2016
Role of Microbiome in ObesityFactors of Microbiome Development
Applications/Conclusions
References
The colonization of the human microbiome occurs both before and after birth. There
are several environmental factors that have a significant impact on the development
of the microbiota composition over the first year of life. However, once diet is
introduced it plays the most significant role in cultivating the microbiome. These
bacteria are essential to human health and may impact the development of obesity
due to their contribution to energy regulation and inflammation. The research shows
a possible link between the composition of the infant microbiota and risk of
obesity/overweight.
Physiology
The human gut microbiome is cultivated during and after birth, and develops into an adult
microbiome by 19-36 months of life which is affected by the following factors5:
• Birth Mode: Vaginal delivery associated with higher Bacteriodetes and cesarean section
associated with initial risk of obesity (hygiene hypothesis)6
• Initial Feeding: Breastfeeding increases Bifidobacerium and Bacteriodetes via human
milk oligosaccharides7
• Antibiotic Usage: Alters the abundance and composition of bacteria (dysbiosis)7
• Diet:
• High fiber content foods such as plants  fermented by the gut microbiota more
abundant and diverse microbiome.8
• A study compared the gut microbiota between children from Europe (high fat, low
fiber diet) and rural Africa (low fat, high fiber diet).9
• The microbiome of the EU children had higher Firmicutes and
lower Bacteroidetes and displayed dysbiosis.9
• Sample groups had similar microbiome composition at young age.
However, the older children showed drastic differences in their microbiota
composition meaning diet plays the most dominant role in developing the
microbiome.9
• A study compared the effects of low fat/high plant diet and high fat/high sugar
diet on the microbiome composition in mice.10
• The high fat/high sugar diet resulted in higher Firmicutes and decrease in
Bacteroidetes.10
Objectives
1) Determine the environmental factors that impact the development of the infant
microbiome.
2) Determine the effect of the infant microbiome on obesity/overweight risk later in
life.
3) Determine the mechanisms involved in the altered microbiome composition and
obesity risk.
Factors:
•Mode of Delivery
•Antibiotics
•Initial feeding
method
•Maternal health
•Diet Altered Gut
Microbiome:
•High Firmicutes:
Bacteriodetes
•Dysbiosis
Mechanism
Pathways:
•↑ Energy Harvest
•↑ Lipogenesis
•↑ Inflammation
↑ Risk of Childhood
Obesity
Altered GI Microbiome
SCFAs
↑ Energy
Harvest
LPS
↑Inflammation
Weight Gain
Enterocytes
↑ Lipogenesis
Gpr41
Gpr43
Fiaf
Translocation&
Chylomicrons
Altered Gene
Function
Description Mechanism Research Study
Increased
Energy
Harvest
• Ferment nondigestable CHO’s
into SCFAs.
• SCFAs used as additional energy
source for coloncytes.3
• Mice transplanted with obese microbiota
had significantly greater percentage ↑ in
body fat than mice transplanted with lean
microbiota, when consuming same type &
amount of food. 11
Increased
Lipogenesis
• Gpr41/Gpr43 receptors bound
by SCFAs→ ↑ adipogenesis 3
• Component of microbiome
suppresses fasting induced
adipose factor (Fiaf)→
↑Lipoprotein lipase activity→
↑lipogenesis & ↓TG metabolism3
• Germ-free mice colonized with SCFAs
producing bacteria had ↑ in percentage
body fat and weight. 12
• In Gpr41-/-mice, ↑ in weight & adiposity
does not occur. 12
• Fiaf-/- mice have same amount body fat as
colonized mice 13
Increased
Host
Inflammation
• LPS from gram negative bacteria
translocates or is carried by
chylomicrons across enterocytes.
• LPS triggers innate immune
response via CD14 cells. 3
• Rats infused with low doses of LPS for 4
weeks and rats on a high-fat diet for 4
weeks displayed similar weight gain. 14
• CD14-/-rats infused with LPS displayed no
weight gain. 14
1. Fast Facts on the State of Obesity in America. The State of Obesity. Available at: http://stateofobesity.org/fastfacts/. Accessed April 7, 2016.
2. Pandita A. Sharma D, et al. Childhood obesity: prevention is better than cure. Diabetes Metab Syndr Obes. 2016; 9: 83-89. doi: 10.2147/DMSO.S90783
3. Graham C., Mullen A., Whelan K. Obesity and the gastrointestinal microbiota: a review of associations and mechanisms. Nutrition Reviews. 2015; 73: 376-385. Doi: 10.1093/nutrit/nuv004.
4. Bervoets L, Van Hoorenbeeck K, Kortleven I, et al. Differences in gut microbiota composition between obese and lean children: a cross-sectional study. Gut Pathog. 2013; 5: 10. doi: 10.1186/1757-4749-5-10.
5. Weir T. Probiotics, Prebiotics and Gut Health: Colorado Stat University; April 5, 2016; Fort Collins, CO.
6. Pei Z, Heinrich J, Fuertes E, et al. Cesarean Delivery and Risk of Childhood Obesity. Jrn of Ped. 2014; 164 (5): 1068-1073.e2.doi: 10.1016/j.jpeds.2013.12.044
7. Mueller N, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello M. The infant microbiome development: mom matters. Trends Mol Med. 2015 Feb; 21(2): 109–117. doi:10.1016/j.molmed.2014.12.002
8. Wong J, Esfahani A, Mirrahimi A, et al. Gut microbiota, diet and heart disease. Journal of AOAC. 2012; 95(1): 24-30. doi: 10.5740/jaoacint.SGE_Wong
9. Filippo C, Cavalieri D, Paola M, et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. PNAS. 2010; 107(33): 14691-14696. doi: 10.1073/pnas.1005963107
10. Turnbaugh P, Ridaura V, et al. The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice. Sci Transl Med. 2009; 1(6): 1-19. doi:10.1126/scitranslmed.3000322
11. Turnbaugh P, Ley R, Mahowald M, Magrini V, Mardis E, Gordon J. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006; 444(21): np. Doi:10.1038/nature05414.
12. Samuel B, Shaito A, Motoike T, et al. Effects of the gut microbiota on host adiposity are modulated by short-chain fatty-acid binding G protein coupled receptor, Gpr41. Proc Natl Acad Sci USA. 2008; 105: 16767-16772. doi:
10.1073/pnas.0808567105.
13. Backhed F, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101(44):15718–15723.
14. Cani P, Amar J, Iglesias MA, et al. Metabolic Endotoxemia Initiates Obesity and Insulin Resistance. Diabetes. 2007; 56 (7): 1761-1772. doi: 10.2337/db06-1491.
15. Luoto R, Collado M.C, Salminen S, Isolauri E. Reshaping the Gut Microbiota at an Early Age: Functional Impact on Obesity Risk? . Ann Nutr Metab. 2013; 63 (suppl 2) : 17-26. doi:10.1159/000354896.
Figure 2: Physiology of the altered GI microbiome and mechanisms linking it to the risk of obesity
Picture modified from: Koleva P, Bridgman S, Kozyrskyj A. The infant gut microbiome: evidence for obesity risk and dietary intervention. Nutrients. 2015; 7: 2237-2260. doi: 10.3390/nu70422371
Introduction
Obesity has become the most prevalent nutritional disorder among children. In only 30
years, the incidence of obesity among children nationwide has jumped from 5% to 17%.1
Children who are obese or overweight have an increased likelihood of being obese as
adults.2 Therefore obese and overweight children are at higher risk for developing severe
comorbidities later in life such as metabolic syndrome, type 2 diabetes and nonalcoholic
fatty liver disease which may decrease life expectancy.2 Currently the most accepted
strategies to combat obesity are lifestyle changes such as adjusting dietary and physical
activity habits. However, new research suggests that gut microbiota is involved in energy
regulation and inflammation, which indicates it could play a role in obesity (see Figure 1).3
Obesity has been associated with high intestinal concentration of Firmicutes and low
concentrations Bacteroidetes.4 While lean individuals showed higher intestinal
concentration of Bacteroidetes and low concentrations of Firmicutes paired with higher
diversity and abundance.4 However, there are several lifestyle factors that play a role in the
microbiome composition and development of obesity.
Diet
GI
Microbiome
Obesity
Figure 1: Interaction between dietary intake, GI microbiome
composition and potential risk of obesity development
With current understanding of the relationship between diet, the microbiome, and obesity
the following applications are possible:
• Modulate microbiome through prebiotics and probiotics15, fecal transplants, and diets
high in fiber, low in fat to prevent and treat weight gain/obesity.
• Educate healthcare providers on role of microbiome in obesity development and how to
prevent and treat obesity through modulating microbiome.
• Educate mothers on how to help develop their child’s microbiome in order to prevent and
treat obesity.
• Conduct further research into the underlying mechanisms that link diet and microbiome
to obesity.
As shown, the development of the microbiome is impacted by many factors from a young
age with dietary intake being the most pronounced. While the mechanisms are not yet fully
understood, the relationship between diet, the microbiome, and obesity is a promising area
for further research that could provide new methods for treating and preventing obesity. 3