MicrObesity: to what extent do gut microbes contribute to obesity?

Obesity—morbid overweight—is usually defined by a body mass index (BMI) >30. The condition can develop into metabolic syndrome, a rapidly emerging global epidemic that is associated with the development of multiple gastrointestinal (GI) disorders, including GI cancer.

In one of the presentations now available for viewing from the "EAGEN Obesity Course—metabolic and nutritional problems in Western and Eastern Europe", which was held in October 2014, Professor Peter Malfertheiner dishes out quite a few disturbing facts.¹ In 2005, 1 billion people worldwide were overweight and 300 million were obese. Ten years on and the numbers have risen to 2.3 billion overweight people and 700 million obese. This means that 14% of the world’s population is now pre-obese (7%) or obese (7%).

One of the main concerns regarding obesity is the level of co-morbidity and reduction in life expectancy that is associated with it. Indeed, at the age of 40, the life expectancy of obese individuals is reduced by 7 years compared with that of non-obese individuals. However, it is not the actual BMI level per se, but the number of years living with obesity that is the stronger predictor of mortality, which is why strategies to delay the onset of obesity should be developed and implemented.

Distinctions are also made between ‘benign’ and ‘malign’ obesity, the latter being synonymous with ‘visceral obesity’ (or ‘central obesity’), which is linked to inflammatory processes and insulin resistance, and which is labelled metabolic syndrome. Professor Malfertheiner explains how an inappropriate diet may lead to dysbiosis, increased gut permeability and gut bacterial lipopolysaccharide-associated metabolic endotoxaemia, with deterioration in gut, liver and endocrine functions.

Professor Malfertheiner also discusses how obesity-associated non-alcoholic fatty liver disease (NAFLD) may develop into hepatocellular cancer (HCC) and underlines the fact that patients receiving insulin have a much higher risk of developing colorectal cancer (CRC). In general, the role of metabolic syndrome in cancer development is currently under intense scrutiny. In his talk ‘The link between obesity and lower GI tract diseases’, Dr Lazlo Herzeny mentions that 15% and 20% of cancer deaths in men and women, respectively, can be attributed to visceral/central obesity.² Allegedly, 40%, 30% and 10% cases of oesophageal carcinoma, HCC and CRC, respectively, are associated with this type of obesity. In their study, Kang et al.³ showed that visceral obesity and insulin resistance are risk factors of colorectal adenoma, and Rampal et al.⁴ found an association between metabolic syndrome and colorectal adenoma. Be sure to look up Dr Herzeny’s talk to learn more about the factors potentially involved in obesity-related tumour development and progression.

Incidentally, the EAGEN meeting included a pro-con debate on the role of obesity in GI cancers. Citing a study by Danaei et al.,⁵ Professor Borut Stabuc argues that obesity is on its way to outcompeting tobacco as the number one preventable cause of cancer.⁶ He talks us through reviews and meta-analyses that provide data evidencing links between metabolic syndrome and various types of cancer. However, gender differences are seen, and the relative risks associating metabolic syndrome with cancer are generally quite modest. As Professor Jaroslaw Regula points out in his talk,⁷ we are swamped with epidemiological data evidencing associations between metabolic syndrome and GI cancer, but these associations do not necessarily represent causal relationships. Professor Regula gives examples of some of the caveats when interpreting epidemiological data and calls into question the overall applicability of BMI in epidemiological studies, since BMI is not a direct indicator of visceral obesity. Moreover, there are few intervention studies and they do not necessarily show the same trends for men and women.⁸

The composition of the gut microbiota varies substantially among individuals, but within individuals it is also dynamic and susceptible to change by diet and administration of antimicrobial agents. The term ‘MicrObesity’ (microbes and obesity), coined by Drs Cani and Delzenne, is about deciphering the specific role of intestinal microbiota dysbiosis and its impact on host metabolism and energy storage.⁹ Microbes take up approximately 1 kg of our body weight, with most microbes being in the gut. Perturbations of the intestinal microbiota can have severe implications for our health, and several diseases appear to stem from intestinal dysbiosis.

According to Lopez-Legarrea et al.,¹⁰ the majority of the bacterial phylotypes found in the intestine are members of two phyla: the Firmicutes (e.g. Clostridium, Enterococcus, Lactobacillus, Ruminococcus), which make up 60% of the gut microbiota, and the Bacteroidetes (e.g. Bacteroides, Prevotella), which account for about 15%. Other phyla include Actinobacteria (e.g. Bifidobacterium) and Proteobacteria (Helicobacter, Escherichia). In her talk, Dr Darij Vranesic Bender points out that a Mediterranean diet, which is high in polyphenols and polyunsaturated fatty acids, leads to increases in Prevotella, Enterococcus, Bifidobacteria, Latobacillus and Bacteroides, while a decrease in obesity-associated Clostridium is seen.¹¹ Changes in the relative balance of bacterial groups may be directly associated with nutritional uptake, but the situation is complex and influenced by host factors such as genetics/co-evolution and physical activity. Also, one might ask how do changes in microbiota structure and function impact benign and malign (visceral/central) obesity? Data are still scarce, but a study recently published in Gut showed that cranberry extract administered to mice fed on a high-fat/high-sucrose (HFHS) diet reduced HFHS-induced weight gain and visceral obesity.¹² Cranberry extract treatment markedly increased the proportion of the mucin-degrading bacterium Akkermansia muciniphila, which has previously been shown to be decreased in obese individuals, and which may be a bacterium actively fighting obesity and diabetes.¹³

As pointed out by Professor Krznaric in his talk “The role of microbiota in the pathophysiology of obesity”, imbalances in the relative proportion of Bacteroides to Firmicutes may lead to obesity.¹⁴ Of particular interest is the recognition of obesity-associated gut microbiomes with increased capacity for energy harvest, since the human microbiota—in this rising era of microbiota transplantation—can be remodelled in different cohorts (obese vs underweight) with a view to optimising nutritional intake. Part of the mechanism underlying this is the role of short-chain fatty acids that are not only a source of energy for the intestinal epithelium, but also act as signalling molecules with implications for fat metabolism. Professor Krznaric also underlines the possibility that long-term exposure to low-dose antibiotics, for instance through foods, may lead to intestinal dysbiosis and obesity. Moreover, as pointed out by Professor Malfertheiner, non-caloric artificial sweeteners—quite paradoxically—drive the development of glucose intolerance, which is associated with insulin resistance, due to alterations of the structure and function of the intestinal microbiota.²

Given this complex situation it will be challenging to come up with one-size-fits-all strategies for combatting obesity in the future. Nonetheless, Professors Petr Díte and Tomica Milosavljevic both attempt to do this. To learn about their thoughts and to update yourself with much more news in the field interfacing obesity and GI diseases, please do listen to their talks.^15,16

Gut microbiota manipulation appears to be critical to future advances in preventing and treating obesity, and the effect of diet on gut microbiota structure and function is probably one of today’s hottest research areas.

The collection of talks from the EAGEN meeting includes a variety of other obesity-associated topics, including endoscopic approaches to obesity, an update on bariatric surgery and epidemiology, clinical presentation and management of non-alcoholic steatohepatitis (NASH), to mention just some. Why not sit down with a nice cup of coffee and have a browse yourself, though you may want to try the coffee without the sugar or sweetener … and skip the biscuits!

References

1. Malfertheiner, P. Epidemiological trends of metabolic syndrome affecting GI diseases. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
2. Herzeny, L. The link between obesity and lower GI tract diseases. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
3. Kang HW, et al. Visceral Obesity and Insulin Resistance as Risk Factors for Colorectal Adenoma: A Cross-Sectional, Case–Control Study. Am J Gastroenterol 2010; 105: 178–187. http://www.nature.com/ajg/journal/v105/n1/full/ajg2009541a.html
4. Rampal S, et al. Association Between Markers of Glucose Metabolism and Risk of Colorectal Adenoma. Gastroenterology 2014; 147: 78–87. http://www.gastrojournal.org/article/S0016-5085(14)00307-2/abstract?referrer=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpubmed%2F24632359
5. Danaei G, et al. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet 2005; 366: 1784–1793. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67725-2/abstract
6. Stabuc  B. Debate: Obesity and the risk of GI cancer – PRO. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
7. Regula J. Debate: Obesity and the risk of GI cancer – CONTRA. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe. 
8. Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trial - a prospective controlled intervention study of bariatric surgery. J Intern Med 2013; 273: 219–234. http://onlinelibrary.wiley.com/doi/10.1111/joim.12012/abstract;jsessionid=0F0E52EE795C85CC7F04ABCCB6A072F1.f04t04
9. Cani PD and Delzenne NM. The gut microbiome as therapeutic target. Pharmacol Ther 2011; 130: 202–212. http://www.sciencedirect.com/science/article/pii/S0163725811000362
10. Lopez-Legarrea P, et al. The influence of Mediterranean, carbohydrate and high protein diets on gut microbiota composition in the treatment of obesity and associated inflammatory state. Asia Pac J Clin Nutr 2014; 23: 360–368. http://www.ncbi.nlm.nih.gov/pubmed/25164445
11. Bender DV.  Protein, carbs and fats in personalised weight control - efficacy and safety. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe. 
12. Anhê FF et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut (Epub ahead of print 30 July 2014) doi:10.1136/gutjnl-2014-307142. http://gut.bmj.com/content/early/2014/07/30/gutjnl-2014-307142.abstract
13. Everarda, A et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci 2013; 110: 9066–9071. http://www.pnas.org/content/110/22/9066
14. Krznarik Z. The role of microbiota in the pathophysiology of obesity. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe. 
15. Díte P. Health strategies to manage the epidemics of metabolic syndrome. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe. 
16. Milosavljevic T. Health strategies to manage the epidemics of metabolic syndrome. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.