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Boyajian et al. Microbiome Res Rep 2024;3:29 https://dx.doi.org/10.20517/mrr.2024.05 Page 11 of 35

BA dysregulation. Research shows decreased microbial transformation of BA in obese mice compared to
[93]
[94]
lean mice . In addition, plasma concentrations of BA are significantly reduced with advancing age ,
[93]
which may be attributed to age-related dysbiosis . In sum, similar compositional and functional changes to
the gut microbiome are evident in obesity in aging. The gut microbiome may, therefore, act as a novel target
for the treatment and/or management of obesity and aging.
In summary, evidence of gut compositional and functional changes among obese and aged individuals is
expansive, although it remains elusive. Based on reported data, several trends are observed among obese
and aged populations that may be extrapolated for clinical use upon further investigation [Table 1].
Specifically, a higher abundance of the Proteobacteria genera may indicate an underlying state of metabolic
endotoxemia in metabolically compromised adults. Similarly, decreases in the Firmicutes class Clostridia or
the Akkermansia species of the Verrucomicrobia phyla might be evidence of an obese or accelerated aged
phenotype. Signature microbial metabolites may also act as biomarkers of obesity and aging, such as
increased serum LPS, fecal SCFAs, and BAs. The measurement of microbes and their metabolites depends
on relatively cost-effective, minimally invasive procedures and may help in the diagnosis and treatment
management of obesity, aging, and related metabolic disorders. Assessment of these microbes and
metabolites may also advance the diagnosis of sarcopenic obesity. However, significant additional research
is needed before the proposed biomarkers can be adopted for clinical use. Additional region-specific meta-
analyses on obese and aged cohorts would be beneficial in reaching a consensus on the distinct microbiota
alterations that occur with these diseases among diet and other external variables. Assessment of the gut
microbial composition in obese and aged comorbid patients would also be valuable.

Gut dysbiosis leads to adipocyte dysfunction
Microbial dysbiosis plays an evident role in obesity and aging, as does altered microbiota function. As
discussed, an impaired gut barrier is often associated with obesity and aging, as is the abundance of harmful
bacteria, such as pathogenic E. coli. LPS, an abundant lipoprotein in E. coli and other Gram-negative
bacteria, may transport across the permeable gut barrier and enter systemic circulation at high levels.
Bacterial LPS may then bind to circulating LPS binding protein (LBP), eliciting an immune response. In the
context of obesity or aging, macrophages may recruit LPS and infiltrate adipose tissue, especially large
[96]
adipocytes, prompting inflammatory cytokine production . Adipocytes express the required receptor for
[97]
bacterial LPS, TLR4, at increased levels in the context of obesity . Although TLR4 expression in aged and
young mice is comparable, TLR4-deficient aged mice are protected from adipose tissue inflammation with
[98]
aging, suggesting TLR4 to be a critical player in age-associated inflammation . With the help of LBP and
CD14, LPS eagerly binds to TLR4 receptors on adipocytes . Activation of TLR4 triggers the MyD88-
[96]
dependent pathway and subsequently NF-κB, leading to the expression of pro-inflammatory chemokines
and cytokines, as well as promoting immune cell recruitment and infiltration. This behavior creates a
positive feedback loop that furthers adipocyte inflammation and dysfunction, thereby promoting the obese
and aged phenotypes. Clinical evidence has shown an association between LBP and central adiposity, a
strong risk factor for obesity and type 2 diabetes, as well as BMI, fasting serum insulin, insulin resistance,
and metabolic syndrome components, specifically obesity status [99,100] . There is also an inverse relationship
between LBP and skeletal muscle density, potentially due to an increase in skeletal muscle adiposity .
[99]
Other reports state that obese individuals with or without comorbid diabetes have increased serum LPS
levels after high-fat dietary intake compared to healthy controls, indicating an exacerbated metabolic
response . Moreover, LBP is increased in obese and non-obese aged individuals and serves as a biomarker
[101]
of declining physical function and inflammation . Increased endotoxin levels are also evident in age-
[102]
related disorders and cognitive impairment, including AD and PD, among other brain pathologies .
[103]
Specifically, LPS is associated with brain amyloid uptake, suggesting it plays a mechanistic role in AD
pathology . Microbial dysbiosis and microbial translocation are therefore potential drivers of adipocyte
[104]