Intestinal microflora and low grade metabolic inflammation

1 February 2011. Related: Conference reports, Lipodystrophy and metabolic complications.

Simon Collins, HIV i-Base

Remy Burcelin discussed metabolic outcomes as dependent not only on genetic and nutritional background but from the perspective of a more recent hypothesis based on the metagenome (of an individuals prokiaryotic microflora). [1]

With an estimated 10 x 10¹³ present in any individual, the balance in diversity between the major families (actinobacteria, proteobacteria, firmicutes and bacteroidetes) have been associated with metabolic disease. From a research perspective, these bacteria have broadly similar genomes across species (E-coli in humans is similar to in mice). Studies in ob/ob mice (genetically altered in their leptin receptor as a model for diabetes and other research because they become obese on a regular diet) showed that it is possible to identify the extent of obesity by the balance of gut microflora and these observations have been supported in human studies. [2, 3] Similarly, analysis of microflora clusters in humans show sufficiently distinct patterns to be able to diagnose broad insulin sensitivity.

Of note, some bacteria have a greater propensity to metabolise energy from food and bacterial diversity having the potential not only to reflect the metabolic phenotype but to play a causal role. Body weight increased significantly more in germ-free mice given obese rather than lean-associated gut flora.

Metabolic diseases, including diabetes, are associated with low grade (2-3 fold higher) inflammation which can be induced by a high fat diet, in adipose tissue (although this is a mild increase compared to the >50-fold increase induced by HIV) . Lipopolysacharides (LPS), are increased in HIV-positive people despite HAART and have been proposed as contributing to HIV-related increased immune inflammation. They are potential molecules from microflora that both induce inflammation and cause metabolic complications, for example, by inducing cytiokine pathways responsible for insulin resistance. Human and animal studies have confirmed that dietary fat is associated with elevated LPS compared to low fat diets (whether protein or carbohydrate based) and mice that have been genetically altered to have LPS receptors are protected from fat gain when fed a high fat diet. These mice also retain insulin sensitivity, avoid glucose intolerance and maintain low triglycerides (ie they are protected against high fat diet induced diseases). [4] Similarly, normal mice, infused with LPS over one month were shown to develop a metabolic disease phenotype which can be at least partly revered if LPS is reduced by antibiotic treatment.

On a cellular level, LPS is sufficient to increase lipocyte differentiation in vitro and dietary modification results in bacteria levels significantly increasing in adipose tissue, but also reducing lipid accumulation in adipocytes.

This led the presenter to the question of the potential benefit from strategies to control bacterial translocation, for example using dietary probiotic yogurt. Patients and mice fed a high fat diet had reduced bacterial translocation following probiotic yoghurt. In mouse studies, this intriguingly also reduced fasting insulin, improved insulin sensitivity and improved glucose intolerance.

In conclusion, dietary fat was suggested as having a direct role in changing intestinal microflora levels and subsequent microbial translocation increases LPS levels in adipose tissue. In addition to directly impacting on adipogenesis, this can release cytokines that trigger insulin resistance and other metabolic diseases.

In a separate presentation, Blodget and colleagues presented analyses from two brachial arterial flow mediated studies that identified an association between higher LPS levels with endothelial dysfunction in one study but not another. [5]

Kenneth Feingold from San Francisco VA Medical Centre in another plenary lecture discussed the complicated association between LPS and dislipidaemia (in this talk focussing on increased triglycerides and decreased HDL) as factors linking inflammation to the risk of atherosclerosis, including the possibility that lipid changes may be playing a protective role. [6]

References:

1. Burcelin R. Intestinal microbiota inflammation and metabolic diseases: new paradigms for the control of insulin resistance and adipose tissue plasticity. Plenary talk webcast for day one.
2. Turnbaugh PT, Gordon JI et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027-1031 (December 2006) | doi:10.1038/nature05414.
   http://www.nature.com/nature/journal/v444/n7122/abs/nature05414.html
3. Ley RE, Gordon  JI et al. Microbial ecology: Human gut microbes associated with obesity. Nature 444, 1022-1023 (21 December 2006) doi:10.1038/4441022a.
   http://www.nature.com/nature/journal/v444/n7122/full/4441022a.html
4. Cani PD et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–1772 (July 2007). 56:e20; doi:10.2337/db07-1181.
   http://diabetes.diabetesjournals.org/content/56/7/1761.ful
5. Blodget E et al. Relationship between microbial translocation and endothelial function in HIV infected patients. 12th Lipodystrophy Workshop, 3–6 November 2010, London. Oral abstract O_1. Antiviral therapy 2010; Suppl 4: A3.
6. Feingold K. The effect of inflammation anon lipid and lipoprotein metabolism. Session II plenary. 12th International Workshop on Adverse Drug Reactions and Co-morbidities in HIV Infection, 3—6 November 2011, London. Webcast online.