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Page 12 of 35 Boyajian et al. Microbiome Res Rep 2024;3:29 https://dx.doi.org/10.20517/mrr.2024.05

Table 1. A summary of similar alterations to gut microbiota composition and function in obese and unhealthy aged populations
Increased abundance Decreased abundance Gut functional changes
Phylum: Phylum: • Decreased TJs and barrier integrity [78,85]
[54,70] [52,54] [82,90]
• Firmicutes • Bacteriodetes • Decreased SCFAs
[50,76] [79,85]
• Proteobacteria Family: • Inflamed colon
Genera: • Clostridiaceae [57,63] • Mucus degradation [52,76,82]
[52,56,82] [76,82]
• Enterobacteriaceae Genera: • Increased permeability
[57,70,82] [52,76,82] [79,82]
• Streptococcus • Prevotella • Bacterial translocation
• Enterococcus [76,82] Species:
Species: • Akkermansia muciniphila [52,54]
• Lactobacillus [56,95] • Faecalibacterium prausnitzii [82,89]
[76,82] [56,82]
• Escherichia coli • Bifidobacterium
[52,54]
• α-diversity
TJs: Tight junctions; SCFAs: short-chain fatty acids.
dysfunction, a hallmark of both obesity and aging [Figure 2]. Although this idea has been previously
discussed , further mechanistic studies to help clarify the exact pathway from gut dysbiosis to adipocyte
[96]
disruption would be beneficial. Such findings may identify novel therapeutic targets for obesity and aging,
among other diseases associated with adipocyte dysfunction.

The gut-brain axis: a key mediator between obesity and aging
The GBA is a complex network of neuro-immuno-endocrine mediators that connect the enteric and
nervous systems. Intestinal homeostasis is therefore critical for proper brain function. When dysbiotic, the
gut microbiota sends dysfunction signaling to the brain, promoting low-grade inflammation, increased
oxidative stress, unbalanced energy homeostasis, and increased cellular degradation. The GBA has been
implicated in several diseases involving the CNS, including mental health disorders, AD, dementia, and
premature aging . Although the exact mechanisms governing the GBA have yet to be fully identified, the
[105]
involvement of the nervous, endocrine, and immune systems, as well as microbial antigens, is well-
established. Briefly, the translocation of microbial antigens (e.g., LPS, SCFAs, BAs) from a permeable gut
barrier may enter the CNS and pass through the blood-brain barrier, activating microglia, the resident
immune cells of the CNS. As a result, neuro-inflammation is stimulated, causing a neurotoxic phenotype by
activation of A1-like reactive astrocytes. In the context of neurodegenerative disease, A1-like astrocytes
dominate the astrocyte population and even surround Aβ deposits in AD patients [106,107] . Another GBA-
related mechanism regards the hypothalamic-pituitary-adrenal (HPA) axis, which utilizes the nervous and
endocrine systems to regulate stress. Gut dysbiosis enables dysregulation of the HPA axis, which can
accelerate and progress cognitive defects and AD . Obesity also leads to hyperactivation and priming of
[108]
the HPA axis, according to a recent study , inferring that HPA dysfunction may link obesity and cognitive
[109]
impairment. Once activated, the HPA axis triggers the stress response and release of glucocorticoids (i.e.,
cortisol) from the intestine to the brain. The vagus nerve also regulates the neural signaling from the gut to
the brain, acting as a critical component of the GBA . Originating from the brainstem and extending
[110]
through the body, the vagus nerve innervates the GI tract with vagal afferent (80%) and efferent (20%) fibers
that communicate with the brain. As the main component of the parasympathetic nervous system, the
vagus nerve regulates internal organ functions, including digestion. For example, receptors of GI
neurohormones (e.g., CCK, ghrelin, etc.) are present on vagal afferent nerve endings and either initiate or
inhibit vagal afferent firing after food consumption, regulating digestive activity (e.g., gastric emptying).
Interestingly, altered vagal signaling is observed with obesity or exposure to a HFD, such as an orexigenic
phenotype, leading to reduced satiety or decreased sensitivity and excitability. A state of microbial dysbiosis
may also alter vagal activity. In mice fed a high-fat/high-sugar or low-fat/high-sugar diet, changes to the gut
microbiota (e.g., decrease in bacterial diversity, increase in F/B ratio) were observed, as well as reduced vagal
innervation . Additionally, an increase in the expression of pro-inflammatory cytokines, reduction in TJ
[111]