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Boyajian et al. Microbiome Res Rep 2024;3:29 https://dx.doi.org/10.20517/mrr.2024.05 Page 9 of 35

observed in patients with mild cognitive impairment, and further pronounced in AD patients. Moreover,
AD patients exhibit a mild, although not significant, increase in Firmicutes and Actinobacteria, a decrease in
Bacteroidetes, and no change in Proteobacteria. Geographical differences were also found, including an
increase in Bacteroidetes phylum in US AD cohorts, compared to Chinese AD cohorts. Another study
analyzed reports of the gut microbiota of frail and non-frail older adults (i.e., ≥ 60 years) across several
[64]
countries . Compared to non-frail elders, the frail group had a lower abundance of phyla Firmicutes and
Verrucomicrobia, Bacteroides and Prevotella genera, and Faecalibacterium prausnitzii species, as well as a
higher relative abundance of genera Bifidobacterium, Eubacterium, and Lactobacillus. Interestingly,
α-diversity did not differ between frail and non-frail individuals, nor did the abundance of the Akkermansia
genus.

To understand the microbiota composition of healthy aged individuals, the microbial profiles of
centenarians (i.e., individuals 100 years or older), a model of healthy aging, have been studied. Findings
from different populations reveal healthy centenarians to have increased levels of health-associated bacterial
species such as Akkermansia muciniphila, a mucin-degrading bacterium that increases mucus thickness and
thus promotes intestinal integrity, compared to younger individuals or dying centenarians [65-67] . The
Bifidobacterium genus is enriched in European centenarian populations, including those of Estonia and
semi-supercentenarians (i.e., aged 105-109) of Italy [66,68] . Specifically, the B. bifidum species is highly
[65]
abundant in Sardinian centenarians, as well as α-diversity . Bifidobacterium dominates in the gut
[45]
microbiota of healthy infants yet declines with age , inferring a potential role in longevity. However, a
study on Chinese centenarians revealed that the Bifidobacterium longum strain increases before death
compared to their healthy counterparts, suggesting a negative association with lifespan . Pang et al.
[67]
reported similar findings on a Chinese cohort, concluding that the gut microbiota of centenarians harbors a
youth-associated microbial community, including a decreasing abundance of Proteobacteria and an
[69]
enriched abundance of Bacteroides . Another study of Chinese nonagenarians (i.e., individuals aged 90-99)
reported a lower F/B ratio, decreased abundance of Streptococcus genus, and increased levels of Clostridiales
[70]
species in healthy long-living individuals, compared to non-healthy controls . However, a US-based study
identified Bacteroides depletion as a marker of healthy aging, suggesting its dominance in predicting
decreased survival in older individuals (i.e., aged 85 and older) . Different gut microbiota composition
[71]
among separate centenarian and healthy elder populations may be due to differences in epigenetics, regional
dietary habits, and other external factors that lead to region-specific microbiota profiles. Nevertheless, the
gut microbial communities found in centenarians of various origins seemingly oppose those of unhealthy
aged or obese cohorts.

Alterations to gut function in obesity and aging
Along with compositional changes, the gut environment undergoes functional alterations during obesity
and unhealthy aging. Physiological changes resulting from microbial dysbiosis can lead to systemic immune
dysregulation. For example, a dysbiotic gut may cause an increased abundance of Gram-negative
peptidoglycan bacteria, such as pathogenic Escherichia coli, which contain endotoxin LPS in the outer
membrane. LPS can impair the intestinal epithelial lining and increase gut permeability, leading to a “leaky
gut” and subsequently entering the bloodstream. Upon translocation, LPS binds to Toll-like receptor 4
(TLR4) and activates a pro-inflammatory signaling cascade via the nuclear factor-κB (NF-κB) pathway .
[72]
The resulting state of metabolic endotoxemia promotes chronic, low-grade inflammation. Translocation of
LPS and other bacterial products have been associated with obesity and aging, as well as type 2 diabetes,
psoriasis, and other immune-mediated diseases [73,74] . The gut microbiota plays a central role in both
inflammaging and metaflammation through the release of LPS and other inflammatory products,
contributing to crosstalk with other organs and systems . Many studies suggest the F/B ratio increases with
[75]
obesity and aging, as discussed above. However, a relative decrease in Bacteroidetes challenges the