16s rRNA sequencing allows the microbial populations resident in the gut to be catalogued in detail: which species are present, and relative numbers by species. In the years since this assay became cheap, reliable, and readily available, researchers have built increasingly large human gut microbiome databases from samples obtained over the course of epidemiological studies. The research community has found that the gut microbiome exhibits characteristic differences in older people, marked by a growth in populations of inflammatory microbes and a loss of those species that produce beneficial metabolites. Further, some age-related conditions appear to be strongly correlated with an altered gut microbiome, particularly with the presence of increased numbers of inflammatory microbes.
Alzheimer's disease is one of the conditions for which a growing body of evidence indicates that an altered gut microbiome plays a role in the onset and progression of pathology. The most likely mechanism by which the gut microbiome can contribute to disease is via provoking an increase level of chronic inflammatory signaling. Unresolved, continual inflammation is a characteristic of aging. It is disruptive of cell and tissue function, and contributes to many different age-related conditions. This doesn't rule out other possibilities, as biology is complex, and the gut microbiome can generate harmful metabolites as well as beneficial ones, but as today's open access paper indicates, inflammation is the first place to look.
Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer's disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity.
Multiple regression with maximum likelihood estimation and Satorra-Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using 11C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants.
Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.