Obesity and the Human Microbiome

Ruth E. Ley


Curr Opin Gastroenterol. 2010;26(1):5-11. 

In This Article

Mechanisms Linking the Microbiota to Obesity

Obesity is associated with a number of chronic conditions, including inflammation, insulin resistance, type II diabetes, hepatic steatosis, and cardiovascular disease. A number of recent studies have focused on the mechanistic links between gut microbes and specific conditions associated with obesity (for more in-depth reviews see [25•,26]). Combining studies of host-microbial interactions relevant to obesity with studies of microbial diversity should lead to a more comprehensive understanding of which microbes, or microbial products, are the best targets for interventions (such as pharmaceutical mimicry) aimed at improving health, aiding weight loss, or preventing weight gain.

Gut Microbes and Host Metabolism

The microbiota can influence host adiposity through energy extraction from the diet, with variable efficiency depending on community composition; furthermore, the microbiota can also affect host adiposity by influencing metabolism throughout the body. Germ-free mice raised in asceptic isolators are significantly leaner than conventionally raised mice despite their considerably greater food intake, and, in addition, they are resistant to diet-induced obesity and insulin resistance.[27,28] Presence of a microbiota increases serum levels of glucose and SCFAs, which can induce triglyceride production in the liver, and is associated with greater adiposity and reduced glucose tolerance.[28]

Bäckhed et al.[27] showed that the gut microbiota regulates an important gut-derived regulator of host lipid metabolism, angiopoietin-like protein 4 (Angptl4), also known as Fiaf, or fasting-induced adipose factor. Angptl4 regulates fatty acid oxidation in both muscle and adipose tissue.[29] When a normal mouse microbiota is administered to germ-free mice, Angptl4 production is suppressed in the intestine and a greater proportion of triglycerides are deposited in adipose tissue. Furthermore, germ-free mice lacking Angptl4 are no longer protected against diet-induced obesity.[27] The relevance of these findings to human health is underscored by population genetic and metabolic studies in humans. Functional variants of the ANGPTL4 gene were found to be more prevalent in individuals with comparatively low triglyceride levels.[30] In addition, in a study of 108 participants, ANGPTL4 plasma levels correlated with fasting fatty acid levels and adipose tissue lypolysis.[31] Thus, ANGPTL4 may be an important regulator of lipid metabolism in humans as well, and research that investigates the role of the gut microbes in regulating its expression in the human intestine is warranted.

Gut Microbes, Inflammation, and Insulin Resistance

Low-grade metabolic inflammation is recognized as an important component of obesity and metabolic syndrome.[32] Metabolic systems are integrated functionally and molecularly with immune responses, for instance, the increase in pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), typical of obesity-related inflammation, has been shown to result in insulin resistance.[33] Recent work has shown that gut bacteria can initiate the inflammation and insulin resistance associated with obesity.

One of the ways bacteria can impact inflammation and insulin resistance is through the activity of lipopolysaccharide (LPS), an essential component of the cell walls of Gram-negative bacteria such as the Bacteroidetes. Cani et al.[34] have shown that subcutaneous infusion of LPS can cause weight gain and insulin resistance in mice without altering energy intake. In accordance with this, mice lacking Toll-like receptor 4 (TLR4), which recognizes LPS, are resistant to diet-induced obesity and insulin resistance.[35]

In addition to insulin resistance, Cani et al.[34] showed that LPS also induces inflammation in mice and that mice lacking CD14 (a co-receptor of TLR4) are resistant to the development of inflammation. One type of inflammatory molecule that appears to be induced by LPS are the serum amyloid A (SAA) proteins, which exhibit increased levels in the serum of obese persons.[36] The mouse isoform SAA3 is the most abundant in adipose tissue.[37] Reigstad et al.[38••] assessed the effects of the presence of microbes on SAA3 levels in germ-free, conventionally raised and Myd88−/− mice. Results showed that SAA3 is elevated in adipose tissue and colonic tissue in the presence of microbes. Decreased levels of SAA3 in Myd88-deficient mice compared with controls and increased levels of TNF-α in colonic tissue in conventionalized vs. germ-free mice indicate that microbiota can partially mediate SAA3 through LPS-mediated TLR/Myd88/NF-κB signaling.

Evidence suggests that a high-fat diet can trigger the steps that lead to metabolic inflammation by aiding transport of LPS out of the gut. A diet rich in energy can increase levels of plasma LPS in humans[39] and mice.[34] Furthermore, SAA3 is upregulated in the adipose tissue of mice fed a high-fat diet.[37] Myd88-deficient mice fed a high-fat diet are leaner than wild-type controls, further supporting the role of LPS-TLR signaling in SAA3 production.[38••] The link between a high-fat diet, LPS, and inflammation was made by Ghoshal et al.,[40] who showed that a high-fat diet can increase LPS absorption. Dietary fat is transported from the gut after its incorporation as triglycerides into chylomicrons, which also have a high affinity for LPS. Thus, triglycerides form chylomicrons that move LPS from gut cells into the circulation.

A high-fat diet may also modulate plasma LPS levels and inflammation through changes in the gut microbiota. A high-fat diet has been shown in mice to alter the proportion of Bacteroides-related bacteria both positively and negatively[19••,41••] (these studies used different enumeration methods), as well as to promote a bloom in Mollicutes (phylum Firmicutes[19••]), but perhaps most importantly to reduce the numbers of Bifidobacteria (Gram-positive, phylum Actinobacteria).[41••] The effect of a decrease in Bifidobacterial levels may be inferred by the inverse: augmenting levels of Bifidobacteria in the gut, either directly as an ingested probiotic or indirectly with bifidogenic prebiotics, has been shown to reduce inflammation and improve glucose tolerance.[42,43] Greater levels of Bifidobacteria have also been associated with reduced gut leakiness, allowing less LPS to translocate to the serum.[44] Thus, a high-fat diet is thought to modulate the composition of the gut bacteria (notably by reducing levels of Bifidobacteria), which increases gut permeability and allows higher LPS plasma levels.[26]

In humans, plasma LPS levels correlate positively with total energy intake in healthy individuals.[39] Plasma LPS levels are also higher in participants with type II diabetes.[45] At this time, the effect of energy intake and diabetes on the gut microbiota is not known in humans, but based on the results in mice, it is likely that a dysbiosis exists under these conditions.


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