Today’s open access paper is interesting on two counts. Firstly as one of a number of studies in recent years examining the effects of age-related changes in the gut microbiome via fecal transplantation between young and old animals. Secondly, it suggests that negative effects on cognitive function resulting from these changes is mediated by chronic inflammation generated by the interaction of harmful gut microbes with the immune system.

There is a growing interest in the age-related shift in microbial populations in the gut. Researchers have identified some important metabolites that are generated at lower levels in older people as a result of loss of beneficial microbes. These include butyrate, propionate, and indole. Supplementation is a possibility, but this is by no means a comprehensive list, and that will not solve all of the other issues, such as growing populations of harmful microbes aggravating the immune system to generate chronic inflammation. Fixing the balance of populations is the more sensible path forward, and given sufficient funding for development and trials, the medical community might deploy fecal microbial transplantation from young to old as an intervention.

It is quite unclear as to why microbial populations change for the worse with age. The direction of causation between immune dysfunction and a worse gut microbiome might be in either direction. The earliest significant changes occur around age 35, which seems far too young for any of the obvious mechanisms of aging to be producing meaningful pathology. There are many potential contributing causes in later life, including the aforementioned immune dysfunction, dietary changes, lack of exercise, and declining tissue function of the intestines. Establishing which of these causes are actually important is very much a work in progress.

Age-related shifts in gut microbiota contribute to cognitive decline in aged rats

The human gastrointestinal tract harbors a complex and dynamic population of microorganisms, referred to as gut microbiota. The gut microbiota is very important for the development and homeostasis of the body; it regulates intestinal motility and gastrointestinal barrier, host energy metabolism and mitochondrial function, as well as immune responses and the central nervous system. In adulthood, the microbiota reaches a relative equilibrium, and does not significantly change under stable environmental and health conditions. Generally, the phyla Bacteroidetes and Firmicutes dominate the intestine for adulthood. However, with an increasing age, the gut microbiota undergoes a profound remodeling. Researchers have shown that the gut microbiota of the elderly is substantially different from the younger adults, and correlates with frailty. However, given our current inability to delineate the most significant effector mechanisms involved in the host-microbiota interactions over a lifetime, it is difficult to tease apart causality from correlation.

Although some animal studies indicated that the gut microbiota affects learning and memory, these reports were based on special animal models, such as germ-free (GF) mice, or on various artificial interventions that change the gut microbiota, such as pathogenic bacterial infection, probiotics, and antibiotics. Since the aging process and aging biological characteristics were not considered in these studies, they were not able to uncover the association between gut microbiota and cognitive function under normal aging process. Given these findings, we hypothesized that alterations in the gut microbiota contribute to cognitive decline in aging. In this study, we transplanted the gut microbiota from aged rats to young rats by using the fecal microbiota transplantation (FMT) technique, to observe whether the reshaped gut microbiota can cause a shift in cognitive behavior, brain structure, and functions in the young recipient rats. To our knowledge, this is the first study that investigates the effect of gut microbiota on cognitive decline in normal aging process.

Results showed that FMT impaired cognitive behavior in young recipient rats; decreased the regional homogeneity in medial prefrontal cortex and hippocampus; changed synaptic structures and decreased dendritic spines; reduced expression of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor NR1 subunit, and synaptophysin; increased expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE). All these behavioral, brain structural and functional alterations induced by FMT reflected cognitive decline. In addition, FMT increased levels of pro-inflammatory cytokines and oxidative stress in young rats, indicating that inflammation and oxidative stress may underlie gut-related cognitive decline in aging. This study provides direct evidence for the contribution of gut microbiota to the cognitive decline during normal aging and suggests that restoring microbiota homeostasis in the elderly may improve cognitive function.