Abstract

Development of the Microbiome and Obesity RiskKara 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

↑ EnergyHarvest

LPS

↑Inflammation

Weight Gain

Ente

rocy

tes

↑ Lipogenesis

Gpr41Gpr43

Fiaf

Translocation &Chylom

icrons

Altered Gene Function

Description Mechanism Research Study

IncreasedEnergy 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.2013.12.0447. 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.2014.12.0028. 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_Wong9. 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.100596310710. 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.300032211. 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 obesityPicture 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).3Obesity 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

GIMicrobiome 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