In today's open access paper, researchers attempt to throw a big tent over three distinct issues in the aging of the body and brain. Firstly, the intestinal barrier fails, allowing bacteria and bacterial metabolites into tissue and the circulation, where they can provoke dysfunction and inflammation. Secondly, blood vessels become leaky, harming surrounding tissues by allowing excessive fluid, inappropriate molecules and cells to escape. Lastly, the blood-brain barrier leaks; this is a more specialized barrier layer surrounding blood vessels in the brain, and when it leaks, the passage of unwanted cells and molecules into the brain again produces dysfunction and inflammation.
Can one really draw a circle around these three quite different phenomenon and talk about a unified "leaky syndrome", as the authors of today's paper do? Perhaps so if these issues largely begin with intestinal barrier dysfunction, allowing gut microbes and their inflammatory metabolites into the bloodstream to cause increased dysfunction in blood vessel walls. That this is the primary issue has yet to be determined, but given that we are entering an era in which the aged gut microbiome is both accurately measurable and can be rejuvenated via techniques such as fecal microbiota transplant, flagellin immunization, and so forth, I'd imagine much more will be known a decade from now.
Aging is a natural process associated with decreased physiologic function in all organs, i.e. it not only affects our immune system, but also affects all tissues and cells, resulting in increased risk of several chronic diseases and vulnerability to death. The gut microbiome is now recognized as one of the key elements to maintaining host health1 and contributing to disease progressions such as high abundance of pathogenic bacteria (such as Escherichia coli, Staphylococcus aureus, and Clostridium difficile) and low abundance of short-chain fatty acid producing bacteria such as Bifidobacterium, Faecalibacterium, Roseburia. Several studies over the past few years revealed that the gut microbiome and its composition changes with age which could have significant implications on overall health during aging, however, the mechanisms by which it impacts the biology of aging remain largely unknown.
The microbiome is composed of diverse microbes i.e., bacteria, archaea, viruses, eukaryotic microbes, and fungi, that have lived in and around our body since birth. The gut and skin are the most extensively colonized regions of our body, while other areas including the mouth, eyes, ears, and reproductive organs also harbor dense populations of specific microbes. These microbes establish a symbiotic relationship with the host, playing a crucial role in regulating essential functions such as protection against pathogens, immunomodulation, and maintaining the structural integrity of the gut mucosal barrier, indicating a strong association between abnormalities in gut microbiota and the development of a wide range of diseases including autoimmune disorders, depression, and neurodegenerative diseases such as Alzheimer's disease and metabolic disorders.
However, the mechanisms by which the microbiome contributes to the development of these diseases are unclear. There can be several mechanisms but inflammation is a key suspect. Low-grade inflammation is often higher in older adults but the source of inflammation remains largely elusive. Growing evidence indicates that gut dysbiosis, characterized by an imbalance in gut microbial composition, tends to escalate with age. This dysbiosis, in turn, contributes to increased gut permeability, often referred to as "leaky gut". This heightened permeability facilitates the passage of pro-inflammatory substances such as bacterial toxins and lipopolysaccharide (LPS) from the gut lumen into the bloodstream or mucosal immune system, thereby triggering inflammation. Elevated inflammation is also known to increase the permeability of other epithelial and endothelial barriers such as intestinal epithelia (leaky gut), blood vessel endothelia (leaky vessels), blood-brain barrier (BBB) (leaky brain), and others, and collectively called "leaky syndrome". The link between leaky syndrome with chronic inflammation and microbiome dysbiosis in aging biology remains poorly understood.