To What Extent are Gut Bacteria Involved in the Benefits of Fasting?

Calorie restriction improves health and extends life in most species and lineages tested, while both Protein restriction and intermittent fasting can provide similar but usually lesser packages of benefits. Once delving into the details of the biochemistry involved, however, the picture becomes very complex, and is still quite uncertain. These strategies probably work through overlapping collections of mechanisms that in turn interact with one another. Intermittent fasting and protein restriction still provide some benefits even when calorie level is kept constant, for example, and assays of epigenetic changes look fairly different for each of these dietary strategies.

Part of the challenge inherent in investigating calorie restriction, protein restriction, and intermittent fasting lies in the fact that near everything in the operation of metabolism changes in response. To the degree that these approaches modestly slow aging, near every measure of aging is affected. How to pinpoint root causes, or important causes, or chains of cause and effect? It isn't easy, as demonstrated by the very slow progress on this front despite a great deal of investment in time and effort over the past three decades.

The scope of "near everything" certainly includes the behavior and distribution of gut bacteria, and in recent years researchers have devoted increasing attention to their role in health and aging. That may well turn out to be in the same ballpark of importance to life expectancy as, say, exercise, but the degree to which it is entirely secondary to dietary choice or other factors in aging - such as immune dysfunction - is an interesting question. Certainly in the case of calorie restriction there is strong evidence for the benefits to be near-completely a function of increased autophagy, and thus there is little room for gut bacteria in that picture.

What about intermittent fasting, however? Researchers here demonstrate the ability to replicate at least some measures observed in intermittent fasting in mice by transplanting gut microbiota from fasting mice into non-fasting mice. This is quite interesting as a point of comparison for what we think we know about how calorie restriction works. It suggests that intermittent fasting with overall calorie restriction is probably quite a different beast from intermittent fasting without overall calorie restriction.

Obesity and related metabolic disorders are growing health challenges; they mainly result from an imbalance between energy intake and energy expenditure. Emerging evidence suggests that non-shivering thermogenesis can re-establish energy balance and therefore counter the effects of elevated energy intake. This process is mediated primarily by the thermogenic activity of uncoupling protein 1 (UCP1), mainly in brown and beige fat cells. In this context, activating brown adipose tissue (BAT) or browning of white adipose tissue (WAT) could be a promising therapy for obesity and related metabolic diseases.

Recently, intermittent fasting was demonstrated to optimize energy metabolism and promote health. However, the mechanism for these benefits is unclear. Notably, one study found that time-restricted feeding can counteract obesity without reducing energy intake. Although perturbation of circadian rhythm was considered as a significant contributor to the increased energy expenditure, the possibility exists that white adipose browning would be a more direct mechanism. Therefore, in the current study, mice were placed on an every-other-day fasting (EODF) regimen to explore its effect on white adipose beiging and metabolic disorders. Evidence suggests that EODF selectively activates beige fat thermogenesis and ameliorates obesity-related metabolic diseases, probably via a microbiota-beige fat axis.

Gut microbiota play a critical role in energy metabolism and lipid homeostasis, and germfree or microbiota-depleted rodents have decreased susceptibility to diet-induced obesity and metabolic syndrome. Based on the above findings, EODF treatment could alter the microbiota compositions and prevent high-fat-diet-induced obesity and metabolic disorders. To further clarify the role of gut microbiota in mediating the beneficial effects of EODF regimen on metabolic diseases, the effect of EODF in control and microbiota-depleted high-fat-diet-induced obesity mice was compared. EODF treatment significantly reduced obesity and hepatic steatosis and improved insulin sensitivity in control mice, but not in microbiota-depleted mice, indicating that the effects of EODF depend on gut microbiota.

To examine whether gut microbiota are sufficient to replicate the effects of EODF, microbiota-depleted mice with high-fat-diet-induced obesity were transplanted with microbiota from ad libitum (AL) feeding and EODF mice, respectively. Compared with the AL microbiota-transplanted group, EODF microbiota transplantation did mimic all the beneficial effects of EODF treatment on metabolic dysfunctions.

In summary, the present work uncovered novel perspectives on beige-fat development in white adipose tissue. EODF was shown to selectively activate beige fat, probably by re-shaping the gut microbiota, which led to increases in the beiging stimuli acetate and lactate. EODF also dramatically ameliorated metabolic syndrome in a mouse model of obesity. This alternative beige fat activation by EODF offers new insights into the microbiotabeige fat axis and provides a novel therapeutic approach for the treatment of obesity-related metabolic disorders.


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