Fecal Microbiota Transplant from Old to Young Mice Produces Vascular Aging and Metabolic Dysfunction

Here are two interesting points about the gut microbiome that have become clear in recent years: (a) the composition of the gut microbiome, the relative sizes of microbial populations, changes with age in ways that contribute to inflammation and tissue dysfunction throughout the body; and (b) it is possible to produce lasting change in the composition of the gut microbiome through either engineering of an immune response against target microbes or the procedure of fecal microbiota transplantation from a donor with a very different microbiome.

A simple example of the immune engineering approach is to inject small amounts of flagellin, the protein making up bacterial flagellae, to rouse the immune system into greater efforts to destroy anything it can find equipped with a flagellum. In the gut, most such bacteria are undesirable. Like fecal microbiota transplantation from a younger donor, the effects are unknowable in advance, generally in the direction of producing benefit, but these are not precision approaches to therapy. One can't yet engineer the exact gut microbiome one desires. Unfortunately strategies involving oral probiotics, which seem the most obvious path towards obtaining more of the specific microbes desired in the gut, have yet to advance to the point at which they are capable of producing lasting change; their effects are very transient.

As today's open access paper illustrates, the aged gut microbiome is clearly harmful. It is harmful in ways that even a young body and immune system cannot escape from. Just as fecal microbiota transplantation from young to old animals produces a lasting change to a young-looking microbiome in an old body and consequent benefits to health, the reverse produces a lasting change to an old-looking microbiome in a young body and consequent damage and dysfunction to tissues throughout the body. This is a good argument for replacement of the microbiome to be the primary thrust of development when it comes to finding ways to remove this aspect of aging. It seems unlikely that rousing the aged immune system is going to solve enough of the problem if a young immune system cannot wrestle an aged gut microbiome into shape.

Aged Gut Microbiome Induces Metabolic Impairment and Hallmarks of Vascular and Intestinal Aging in Young Mice

The aging vasculature is associated with endothelial dysfunction, arterial stiffness, increased oxidative stress and chronic inflammation, contributory to higher risks of cardiovascular diseases, such as heart failure and coronary artery disease. 'Dysbiosis' is considered as a new integrative hallmark of aging. During aging, the microbial composition in intestine varies that the homeostatic relationship between the host and gut microbiome deteriorates, contributory to altered immune and inflammatory responses in the elderly. Age-associated dysbiosis also increases the risks of various diseases, particularly cancers, cardiovascular diseases (CVDs), and diabetes, potentially through shift in intestinal microbial composition from providing benefits to causing chronic inflammation, and through alterations in the production of gut-derived substances to influence host nutrient-sensing pathways. However, the comprehensive mechanism of how age-related dysbiosis promotes other recognized hallmarks of aging remains elusive.

Of note, the vasculature serves as the first-line barrier vulnerable to the changes in gut microbiome due to close proximity between the intestine and blood circulation. Besides, the increased intestinal permeability, known as 'leaky gut', during aging further aggravates the vulnerability of vasculature towards dysbiosis. However, whether age-associated dysbiosis promotes host premature aging remains unclear. Previous studies showed that gut microbiome suppression by antibiotics ameliorates endothelial dysfunction in aged mice, and age-associated hyperproduction of harmful gut-derived metabolite (e.g., trimethylamine-N-oxide) drives endothelial dysfunction. It is therefore reasonable to hypothesize that age-associated dysbiosis shall promote vascular aging by triggering aging hallmarks in the vasculature, such as telomere attrition, endothelial dysfunction, and vascular inflammation and oxidative stress.

In this study, we performed fecal microbiome transfer (FMT) from aged to young mice to (i) study whether age-associated dysbiosis causes premature vascular and intestinal dysfunction; (ii) unveil whether such transfer changes the metabolic profiles; (iii) uncover microbiome alterations and underlying mechanism that are potentially critical; and (iv) identify potential interventions that might partially reverse age-related harmful effects. We demonstrated that age-associated dysbiosis, achieved by aged-to-young FMT, caused endothelial dysfunction, telomere dysfunction, inflammation, and oxidative stress in vascular tissues, partially reflective of premature vascular aging. Moreover, aged-to-young FMT also caused metabolic impairment and altered gut microbial profiles in young mice, along with disrupted intestinal integrity. Interestingly, aged-to-young FMT caused telomere dysfunction in both intestinal and aortic tissues. These findings highlight the harmful effects of aged microbiome on intestine and vasculature, providing important insight that gut-vascular connection represents a potential intervention target against age-related cardiometabolic complications.

Comments

Even if their effects are very transient, if taken frequently enough might probiotics still be effective at reducing inflammation?

Posted by: Hal at November 7th, 2024 6:30 PM

I find it very interesting that these FMT procedures produce lasting changes compared to probiotics, and if an aging immune system is not the reason why, then what is the reason?

Posted by: William at November 17th, 2024 8:43 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.