Whilst the life extending effects of calorie restriction (CR) are known in many mammalian groups (including humans), the mechanisms of this phenomenon are not. Changes in urinary bacterial metabolites have been associated with CR in monkeys and dogs, flagging gut microbiome changes as a potential suspect and inspiring this study.
The trial fed mice either low-fat diet (LFD) or a high-fat diet (HFD) and sub-grouped into calorie restricted (CR) with/without exercise and calorie unrestricted (CU) with/without exercise. Faecal and serum sampling tested for changes in endotoxin load from the gut microbiota and for associations of improved lifespan with certain microbial community compositions. All CR mice were significantly longer lived and healthier than controls, most dramatically in LFD mice; exercise had no significant effect on longevity.
Of 34 distinct microbial phylotypes, 16 increased and 18 decreased in abundance between LFD and LFD + CR mice; Lactococcus phylotype abundances were lower in CR mice, whereas Lactobacillus dominated CR communities, but was almost absent in non-CR mice. As the mice aged, their gut communities developed distinctly, with the familiar probiotic Bifidobacterium thriving in CR mice and the obesity/inflammation-associated Desulfovibrionaceae being more populous in non-CR mice.
HFD and LFD microbial shifts were different; CR was associated with fewer phylotype differences in HFD than in LFD mice. Most differences were unique to each diet; only 3 phylotypes showed the same response to CR in HFD and LFD mice.
In LFD mice Lactobacillus members showed the strongest correlation with increased longevity and the 30 phylotypes associated with lower lifespan were from the Phyla of Bacteroidetes, Firmicutes, Proteobacteria, Actinobacteria and TM7. In HFD mice, more similar numbers of phylotypes were correlated either positively or negatively with lifespan and most were from Bacteroidetes or Firmicutes.
Additionally, lipopolysaccharide-binding proteins (LBP) were lower in CR mice, indicating a lower antigen load from the gut microbiome, suggesting that the benefits of calorie restriction may be related to altered interactions between the host's immune system and gut microbiota, for example, CR gut communities may be better at excluding opportunistic pathogens, thereby reducing antigen load.
Gender is known to affect lifespan and there are known gender associated gut microbiota in mammals, which is why this study used only male mice; a replica of this study using female mice could provide another insight into the relationship between gut microbes and longevity.
The study proposes that calorie restriction allows the host to extract more fat and protein from food, leaving proportionately more indigestible polysaccharides (dietary fibre) for gut microbes to digest, favouring the growth of beneficial phylotypes; perhaps you are what your microbes eat.
Clearly mammals, and probably all animals, have a dynamic, complex and obligatory relationship with their gut microbiota, one which we should increase our understanding of, as it will likely provide powerful new tools for improving human and animal health. The implications of this study extend to marine mammals and probably all marine animals; it also could impact aquaculture probiotic techniques and algae cultures, since edible algae contain diverse lipopolysaccharides, which could likely be beneficial for the microbe communities of humans and grazers.
Zhang, C., Li, S., Yang, L., Huang, P., Li, W., Wang, S., ... & Zhao, L. (2013). Structural modulation of gut microbiota in life-long calorie-restricted mice. Nature communications, 4.