A great diversity of microbial life dwells inside us all, largely in the gut, and these microbes interact with our tissues and immune system in ways that the research community has only recently started to map in earnest. There are a handful of obvious and sometimes very serious medical conditions caused by the presence and inappropriate behavior of forms of microbe in the gut, but beyond this even the more common species are clearly an important component of the body as a whole. They play as great a role as many individual organs in determining health and pace of aging, one slice of the myriad complex interactions that take place constantly between the surrounding environment and various bodily systems.
One of the more direct paths by which the microbiome of the gut can affect long-term health is via its interactions with the immune system. The degree to which the immune system declines with age is in part a function of its exposure to pathogens and other, similar circumstances, and the more of that taking place the worse off you'll be by the time old age rolls around. It is also a matter of the degree to which the immune system is constantly active, however, due to the rising levels of chronic inflammation that accompany old age. Gut microbes can certainly trigger greater inflammation at any age, to some degree, and over time that is thought to add up. Most age-related conditions are accelerated in their progression by inflammation, both via its impact on immune function and via other mechanisms. Among these is Alzheimer's disease and its association with misfolded protein aggregates in the brain: amyloid and tau. Levels of amyloid and tau in the brain are at least somewhat determined by the efficiency with which the immune system can dispose of the unwanted excess, but other links with the inflammatory state of the brain's immune system are also well demonstrated.
So all that said, the open access paper linked below fits into the bigger picture fairly well. Working with mice, the authors provide evidence for differing constituents of the gut microbiome to contribute to the progression of Alzheimer's disease, or at least to the observed levels of amyloid in the brain. While interesting, I think that the likely outcome of applying this knowledge to human medicine is probably incremental at best, let us say along the lines of the impact of excess fat tissue, or poor diet, and probably overlapping with both of those in the mechanisms involved. Tinkering with gut microbes isn't the path to a cure for Alzheimer's disease or other conditions involving the accumulation of damaged proteins in the brain. A cure must, by necessity, involve clearing out the damage comprehensively, which will require a more sophisticated approach to therapies.
According to the amyloid cascade hypothesis of Alzheimer's disease (AD) pathogenesis, the aggregation and cerebral deposition of amyloid-β (Aβ) peptides into extracellular amyloid plaques is an early and critical event triggering a cascade of pathological incidents that finally lead to dementia. Thus, arguing in favor of this hypothesis, the most rational strategy for an AD therapy would be to retard, halt and even reverse Aβ aggregation. However, despite all research efforts there is currently no treatment for AD, and currently approved therapies only provide symptomatic treatments for this disease.
Numerous studies indicate that microbial communities represent an essential factor for many physiological processes including nutrition, inflammation, and protection against pathogens. The microbial community is largely composed of bacteria that colonize all mucosal surfaces, with the highest bacterial densities found in the gastrointestinal tract. Increasing evidence suggests the gastro-intestinal tract is the bridge between microbiota and the central nervous system. Clinical and experimental evidence suggests that gut microbiota may contribute to aging and influence brain disorders. Recently, a study revealed an association of brain amyloidosis with pro-inflammatory gut bacteria of cognitively impaired patients. Furthermore, a recent study showed that antibiotic-mediated perturbations in the gut microbiome modulates amyloid deposition in an AD mouse model. While such findings strongly suggest that the gut microbiota may impact a wide range of brain disorders including AD, the impact of complete depletion of intestinal microbes on AD pathogenesis is unknown.
Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer's disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.
Our results showing reduced microgliosis and changes in the brain cytokine profile are in line with a recent publication demonstrating that germ-free mice show immature microglia and reduced pro-inflammatory cytokine production. Importantly, caspase-1 knockout (which prevents the production of IL-1β) has been shown to be sufficient to strongly reduce plaque load in APPPS1 animals through altering the microglial activation state and enhancing microglial phagocytosis of Aβ plaques. Therefore, a change in microglial responses in germ-free APPPS1 animals could contribute to the reduction of amyloid load observed in germ-free animals. Several in vitro and in vivo studies have shown that neprilysin (NPE) and insulin degrading enzymes (IDE) can degrade Aβ. Most notably, NPE and IDE levels were increased in germ free APPPS1 mice, indicating that increased levels of these Aβ degrading enzymes may contribute to decreased cerebral Aβ amyloidosis in germ free animals. Altogether, these results indicate that Aß degrading enzymes may partially play a role in decreasing Aβ levels and cerebral Aß amyloidosis in germ free animals.