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Page 10 of 35 Boyajian et al. Microbiome Res Rep 2024;3:29 https://dx.doi.org/10.20517/mrr.2024.05

hypothesis of LPS-induced metabolic endotoxemia, as the Bacteroidetes phylum is the main group of Gram-
[55]
negative bacteria in the gut microbiota . Enriched levels of Proteobacteria, another Gram-negative phylum
of which Escherichia coli is the dominant species, are reported in obese and aged individuals [50,76] . LPS
derived from E. coli elicits an immune response and inflammatory cytokine release and enables endotoxin
tolerance, whereas Bacteroidetes LPS inhibits immunogenicity by E. coli LPS . Thus, the characteristic
[77]
differences in LPS subtypes may explain metabolic endotoxemia observed in obese and aged patients,
despite the apparent decrease in Bacteroidetes species.

As a result of a HFD, mice exhibit a hyperpermeable gut, evidenced by a decrease in trans-epithelial
resistance and subsequent mucosal inflammation . The intestinal barrier is also disrupted via restructuring
[78]
[79]
of claudins, a family of tight junction (TJ) proteins, which can occur independent of diet . These changes
cause the intestinal barrier to become deregulated, contributing to systemic disruption and the obese
phenotype. Barrier dysfunction may also promote dysbiosis associated with obesity or aging. Dietary fats
may impair the gut mucosal layer through inhibition of Mucin 2 (Muc2) expression (i.e., the most
important component synthesized by intestinal goblet cells) , downregulation of TJ proteins, and
[80]
[81]
induction of colonic and systemic inflammation . Similarly, age-related decline involves localized loss of
the gut mucosal barrier . Mice deficient in Muc2 or Foxo1 develop gut dysbiosis, including an elevated F/B
[82]
ratio and abundance of Proteobacteria [83,84] . Such evidence suggests that intestinal barrier dysfunction
impacts gut homeostasis and may contribute to enriched levels of harmful, LPS-producing bacteria in the
host. However, direct investigation into the relationship between barrier impairment and subsequent
dysbiosis in obese or aged models is needed. Similar findings are reported in aged organisms; old baboons
exhibit increased colonic permeability and decreased TJ protein expression (i.e., ZO-1, occludin, JAM-A),
[85]
compared to young models . The data showed a slight increase in claudin-2 in the older models, although
not significant; an upregulation of claudin-2 enhances intestinal permeability . In addition, mRNA levels
[86]
of pro-inflammatory cytokines were increased (i.e., IFN-γ, IL-6, IL-1β) in the colon, indicating age-
associated inflammation . Beyond structural barrier changes, the function of gut microbes is altered in
[85]
obese and aged individuals. An imbalanced intestinal microbiota contributes to obesity through energy
harvest from short-chain fatty acids (SCFAs), inflammatory response driven by LPS translocation, and
hormonal mechanisms that regulate appetite control , among other factors. SCFAs also play a critical role
[87]
in healthy aging, wherein their decline is associated with unhealthy aging, as evident in neurodegenerative
disorders . SCFAs (e.g., acetate, propionate, butyrate) are the product of the fermentation process by
[43]
intestinal microbes on indigestible dietary fibers and are either reabsorbed by the colon to contribute to a
variety of physiological processes or excreted in feces. Notably, SCFAs activate G-protein-coupled receptors
41 and 43 (GPR41/43) on enteroendocrine cells, which promote PYY and GLP-1 secretion, respectively, and
increase insulin sensitivity . SCFA receptors are also present on adipocytes, namely GPR41/43 and
[88]
GPR109a, which stimulate leptin secretion upon activation, thereby suppressing insulin signaling and
adipogenesis. G protein-coupled receptors are also expressed on pancreatic β cells, which can be mediated
by SCFAs to modulate insulin secretion. The abundance of SCFA-producing bacteria, such as
Faecalibacterium prausnitzii, is reduced in obese and aged gut microbiota [82,89,90] . Research shows a
relationship between higher fecal SCFA concentrations and measures of obesity, gut permeability, metabolic
dysregulation, and hypertension , indicating a lack of absorption of SCFAs. Earlier reports also show a loss
[91]
of genes for SCFA production in aged humans, compared to younger adults, as well as lower microbiota
production of essential amino acids . These alterations could play a fundamental role in the overall
[92]
nutritional status of the elderly individual, leading to sarcopenia. Similarly, bile acids (BAs) are signaling
molecules synthesized in hepatocytes from cholesterol and released into the colon to facilitate metabolic
processes such as glucose, lipid, and energy homeostasis through the absorption of dietary lipids and
vitamins. The intestinal microbiota deconjugates primary BAs into secondary BAs via the enzyme bile salt
hydrolase (BSH). However, an obese gut is associated with a decrease in BSH-producing bacteria, leading to