Blame the Biota

The role of gut microbiota in relation to the human body has grown in importance due to its implication with many diseases that are prevalent in the western world such as diabetes, inflammatory bowl disease, and obesity. Although obesity is on the rise, there are many strategies available for people to lose weight, however, one of the main problems is maintaining the weight loss; instead, almost 80% of individuals find themselves cycling between weight loss and weight gain. Gut microbiota has become a new target for investigating the causes of obesity, however most experiments that have been done quantify and identify the types of microbiota in the human body while the underlying metabolic pathways that drive post-diet weight gain remain unknown. Thaiss et al. has found that there were intestinal microbiome signatures that persisted even after successful dieting in obese mice that contributed to faster weight-regain and metabolic changes after re-exposure to obesity-promoting conditions.

Changes in metabolic homeostasis and the subsequent increase in risk for obesity have more recently been linked to changes in the gut microbiome. By using mouse models of weight loss and regain to mimic recurring obesity, the authors try to show that although obese mice can lose the weight, there is a change in the gut microbiota that persists over time and increases post-weight loss weight gain. In addition, the find that metabolites produced by the gut microbiota may be viable targets for treatment to prevent regain of weight.

The study used mouse models to study weight loss and recurring obesity to try and understand the mechanisms involved in repeated cycles of weight loss and gain. Mice were cycled on high-fat diets (HFD) and normal chow (NC), which promoted a cycle of weight loss and weight gain that would resemble a typical human’s weight loss and gain. Control mice were fed either all NC or HFD. They observed that the weight-loss, weight-gain cycle led mice to be susceptible to increased weight gain the second time, even if they returned to the original weight. In addition to increased weight gain, they found that there were metabolic difficulties such as enhanced glucose intolerance, and elevated levels of leptin and low-density lipoprotein (LDL) but not high-density lipoprotein (HDL). All three of which have been correlated to various inflammatory diseases. Second and third cycles of HFD-induced obesity further increased the weight regain. The authors suggest that repeated cycles of weight loss and gain may lead to accelerated weight regain, in addition to other metabolic damage.

Enhanced recurrent weight gain after treatment of obesity.

Figure 1. Shows the weight gain over time of control HFD (blue) and NC (black) mice along with mice subjected to weight cycling (red) and mice given a HFD once (green).

From these findings, the authors proposed that it was the initial obese state in the mice that caused the abnormalities that persisted, predisposing them to the metabolic disorders after the cycling occurred. They found that this was not the case but that it was the composition of the gut microbiota that changed after the first obesity state that never reverted back to its pre-obese state. Instead, it was in between the obese and pre-obese states. This is significant because although shifts in diet have the ability to change microbiota within days of beginning, the findings show that there are microbial changes that have long-lasting effects.

To further understand the long-term effects of obesity on gut microbiota, the authors performed a genomic sequencing on the gut microbiota and identified 733 bacterial genes whose abundance was altered by the HFD and did not return to the NC levels even after dieting. They also found that the microbiota composition only reverted back to the pre-obese state after 21 weeks, indicating that weight loss maintenance must be prolonged enough that the gut microbiota can revert back and even then, it is does not ensure the prevention of weight regain. Fecal transplants from previously obese and control mice to germ-free mice were also performed and mice were fed either HFD or NC diets. They found that NC fed mice who had not gone under the weight gain/loss cycle were similar to normal NC fed mice which the authors indicate means that the post-obese microbiome itself does not have obesogenic properties. However, when mice were fed HFD, there was enhanced weight gain and glucose intolerance even if the mice were not previous obese. This suggests that it is likely that the post-obese microbiota increases the likelihood of metabolic complications upon re-exposure to obesity-causing conditions.

The authors also suggested that the post-obese microbiome configuration might give a possible prediction as to how much weight would be regained upon introducing the mice to a HFD again. By using a DNA-based prediction, they found that it was the composition of the gut microbiota as a whole that may change the post-obese microbiome, rather than specific species. This means that targeting the entire biome may be a more effective treatment to prevent weight-regain than single-species targeting.

Although reversion of the post-obese microbiome took longer than expected, the authors found that modulating the microbiome during the post weight-loss period could prevent some of the secondary weight gain the associated metabolic complications. The authors tested this by subjecting weight-cycling mice to daily fecal transfers from mice that had either never gone under weigh-cycling or mice that were in a post-diet phase. Those that received the transplant from non-cycling found that there was less regain of weight once subjected to an obesity-inducing environment.

Given the increasing rates of obesity in the western world, finding and preventing the weight regain that is extremely common in obese people is one of the keys to stopping the cycle of weight gain and regain. Although the underlying metabolic pathways are not yet known exactly, the authors found that alterations in gut microbiota have lasting effects on subjects regardless of whether they return to their original weight or not. This provides for a new target that can be highly specified towards an individual which may promote decreased weight regain.

Reference

Thaiss, Christopher A., Itav, Shlomik., Rothschild, Daphna., et al. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature. February 2016, 544-551.

 

Powered by WPeMatico

One Reply to “Blame the Biota”

  1. Hi Eve, great article! I was especially intrigued by the authors’ representation of the pathways in Figure 2k. Looking at the general pattern of the KEGG pathways throughout the experiment, it seems that the microbiota’s functional pathways that were most affected during obesity were least affected after obesity. The author’s focused briefly on isoflavonoid and steroid biosynthesis and how these pathways were not recovered after obesity (see extended data figure 6). Other pathways seemed to recover slightly but not fully, why do you think these two pathways in particular did not recover at all and were completely lost?

Comments are closed.