Life science
Medical & healthcare, Drug development

Elucidation of the mechanism of the disruption of the crosstalk
between host and gut microbiota with aging
Department of Molecular Microbiology, Research Institute for Microbial Diseases
Associate Professor Shimpei Kawamoto

https://researchmap.jp/kawamoto_shimpei?lang=en

Professor Eiji Hara							https://researchmap.jp/read0108962?lang=en▍ Background & Results
Aging is accompanied by a decline in biological functions andthe onset of age-related diseases, leading to an increasing number of unhealthy elderly people and causing a major problem thatthreatens the sustainable social systems in developed countries. Inrecent years, two age-associated phenomena, i.e., accumulation ofcells inducing cellular senescence (senescent cells) and disruptionof the gut microbiota, are likely to play a central role in the aging
process. Cellular senescence, which is irreversible cell-cycle arrest
induced by heavy DNA damage, acts as a cancer suppression
mechanism but causes chronic inflammation, thereby promoting
the development of age-related diseases. On the other hand, thegut microbiota plays an essential role in maintaining health but
becomes imbalanced with aging, leading to various age-relateddiseases. However, it has yet to be clarified whether there is a relationship between the two phenomena.
Therefore, we compared mice in which senescent cells could
be visualized by luminescence maintained under normal or sterile
conditions and found that senescent cells accumulated in the ileum
and that cellular senescence was induced, especially in germinal
center B cells in the ileum in a bacteria-dependent manner (Fig.1).
We also found that a decrease in the quantity and quality of IgA
and a disruption of the gut microbiota simultaneously occurred withaging. Furthermore, comparative analysis revealed that age-related changes in IgA and gut microbiota are caused by B cell senescence. Thus, we proved that the induction of cellular senescenceof germinal center B cells by the gut microbiota promotes the disruption of the gut microbiota with aging.

▍ Significance of the research and Future perspective
Although it has long been believed that there is a link between
age-related disruption of the gut microbiota and the progressionof aging, the cause of the disruption of the gut microbiota has remained unclear. This study revealed that long-term stimulation by
the gut microbiota accelerates gut aging and suggested that thereaNormal

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Aged

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We have demonstrated that one of the causes of age-related
disruption of the gut microbiota is cellular senescence of germinal
center B cells in the ileum induced by the gut microbiota (Fig.1).
Namely, long-term stimulation by the gut microbiota causes theinduction of cellular senescence in germinal center B cells of theileum, leading to a decrease in IgA production and diversity, which
in turn yields a disruption of the gut microbiota during aging. Furthermore, we found that lipopolysaccharide (LPS), a component ofGram-negative bacteria, is responsible for the induction of cellularsenescence of B cells. These findings indicate that a vicious cycle
is formed between host and gut microbiota via cellular senescenceof B cells, which leads to gut aging (Fig.2).

may be gut bacteria promoting disruption of the gut microbiota(Fig.2). In the future, we would like to confirm whether a similar
mechanism exists in humans, identify bacteria that have the potential to induce cellular senescence of B cells, and establish an
artificial control method for them, leading to the development of
new preventive methods against age-related disruption of the gut
microbiota.

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Life science

Abstract

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Fig. 1. Gut bacteria-dependet accumulation of senescent cells with aging(a)Mice in which senescent cells could be visualized with luminescence weremaintained under normal or sterile conditions and used for in vivo imaging at
young or old ages. Accumulation of senescent cells was observed in the abdomen with aging under normal conditions.
(b)Imaging images of the organs collected from each mouse. A significant accumulation of senescent cells was observed, especially in the ileum of the small
intestine (red dot box).

YoungAged

Gut lumen

Gut lumen

3 Reduction of IgAquantity and quality

4 Dysbiosis ofgut microbiota

Symbiosis between
host and gut microbiota

IgA
plasma cells

IgA
plasma cells
B

1 Induction of B cell senescenceby long-term stimulationof gut microbiota
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p16

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Germinal center
Isolated lymphoid follicles

Peyer’s patches

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INK4a2 Accumulation of senescent B cells

Fig.2. Age-associated changes of the interaction between host and gut microbiota
Left: In young age, IgA induced by the gut microbiota regulates the gut microbiota; thereby, a symbiotic regulatory loop between the host and gut microbiota
through IgA is formed.
Right: In old age, long-term stimulation of the gut microbiota induces cellularsenescence in ileal germinal center B cells, which leads to the reduction of IgAproduction and function, causing dysbiosis of gut microbiota through aging.

P a t e n t
Tr e a t i s e

Kawamoto, Shimpei; Uemura, Ken; Hori, Nozomi et al. Bacterial induction of B cell senescence promotes age-related changes in the gut microbiota.
Nature Cell Biology. 2023, 25(6), 865-876. doi: 10.1038/s41556-023-01145-5

URLK e y w o r d aging, gut microbiota, cellular senescence, B cell, IgA