Written by: Jasmin Kumar
Edited by: Ryan Lee
Edited by: Ryan Lee
Aging leads to declining cell, tissue, and organ function and an increased risk to chronic and debilitating conditions. The most vulnerable tissues are those of the central nervous system, eye, and epithelial barrier of the intestinal lining (Blazes and Lee 2023) . When someone is aging, there are changes in the epithelial barrier that lead to different proportions of the bacteria that play important roles in the immune system and the epithelial barrier of the digestive tract. Changes that occur in the epithelial barrier due to aging usually lead to cardiovascular, autoimmune, metabolic, and neurodegenerative disease (Boulange et al. 2016). Microbiota transplants have been done in fish and flies, in which these studies suggest that there is a direct role of the microbiota in age-associated diseases and in regulating lifespan.
In the paper by Parker et al. the researchers conducted experiments that investigated the effects of age-associated microbiota composition and the impact this has on the gut, brain, and retina. Microbiota fecal transplantations were used between young (3 months), old (18 months), and aged (24 months) mice. The experimental groups consisted of the mice that received fecal matter transplants (FMT) from other age groups, while the control groups consisted of mice that received fecal transplants from mice that were in the same age group. Biomarkers of inflammation and function in the brain, retina, intestinal epithelial barrier, circulating inflammatory markers, and behavioral impacts were the factors that were measured for the results of the study.
In the first experiment, immunohistochemistry was used to mark microglial cells in the brain, and it showed that there was an increased amount in old and aged mice. Young mice that received fecal microbiota from aged mice showed an increase in microglial marked cells. Also, aged and old mice that received young mice microbiota had a significant decrease in the amount of marked microglial cells in the corpus callosum. Microglia are involved in the immune response within the brain, which is more common to see in older mice than in younger mice because younger mice have less immune activation within the brain. The data suggest that intestinal microbiota strongly influence microglia activation (Parker et al 2022). To test if there is relationship between cognition and microbiota, the researchers had mice do a novel object recognition test to measure recognition memory, but there was no significant difference between any of the groups during fecal microbiota transfer. This suggests that there is no impact of microbiota on spatial and recognition memory (Parker et al 2022).
The next set of experiments investigated the retina, as researchers focused on protein C3 expression, which corresponds to retinal degeneration. Young mice that received aged donor microbiota had an increase in C3 levels, and aged mice that received young donor microbiota had a reduction in C3 expression. Retinal pigment epithelial protein RPE65 was also measured between groups since it is critical for retinal regeneration of photoreceptors (Balaratnasingam et al. 2016). This was decreased when young mice received aged donor microbiota, and it was increased in aged mice that received young microbiota. This suggests a causal role of the gut microbiota for retina inflammation regulation (Parker et al 2022).
Next, experimenters looked at the intestinal epithelial cells by measuring serum levels of intestinal fatty acid-binding protein (I-FABP), which is a key indicator of microbiota-related epithelial cell damage and disruption. I-FABP increased in young mice that received aged donor microbiota. I-FABP, conversely, was decreased in aged mice receiving young mice donor microbiota. Lipopolysaccharide (LPS) binding protein (LBP), which is secreted in response to leakage of LPS, was two times higher in aged mice than in young mice. This increased in young mice that received donor microbiota from aged mice. Conversely, aged mice that received young mice donor microbiota had a decrease in these levels. From this data, it was concluded that aged microbiota promote the breakdown of the epithelial barrier within the intestines (Parker et al 2022).
Microbiota composition also proved to be an important factor for determining how age plays a role in the inflammation of the body. The researchers used metagenomic analysis to detect any shifts in microbiota after donor transplantation. In young mice that received aged donor microbiota, there was a dramatic shift in composition, and the microbiota more closely resembled that of the aged mice. This same result was also seen in aged mice receiving young mice microbiota. The researchers also examined specific bacteria that are found within young and aged mice. Aged mice have the bacteria oscillibacter, prevotella, and lactobacillus johnsonii. In young mice, bifidobacterium, akkermansia, parabacteroides, clostridium, and enterococcus were found to be the most prominent. Also, bacteria such as bifidobacteriaceae, akkermansiaceae, and eubacteriaceae, which are associated with beneficial effects of intestinal health, were more prominent in young mice and in aged mice that received young donor microbiota. These results indicate FMT resulted in significant alteration of microbiota composition. Also, donor and recipient microbiota were influential in altering the resulting microbiota composition after FMT (Parker et al 2022).
The last experiment used H-NMR spectroscopy-based metabolomics to assess amino acids, sugars, short chain fatty acids, and alcohols. There were no significant differences between aged and young mice groups for any of these categories. However, the researchers also examined metabolic pathway abundance in metagenomic data. For aged mice that received young mice donor microbiota, there was a significant enrichment of pathways that involved lipid synthesis, specifically long and medium chain fatty acids. Also, young mice that received aged donor microbiota had some of the lipid pathways depleted. From these results, the researchers concluded that there is a shift in vitamin and lipid metabolic pathways with a change in the age of microbiota (Parker et al 2022).
Overall, the paper provides multiple pieces of evidence suggesting that the gut microbiota plays a large role in aging of the gut, brain, and retina. Aging microbiota leads to inflammation of the gut and damage to the intestinal epithelial barrier. This also leads to inflammation of the retina and the brain as microbiota age increases. These changes can be reversed, however, with the replacement of aged microbiota with young microbiota. Future research can focus on how modification of the gut microbiome may lead to changes in the gut-brain axis. This can create new therapy approaches that may reduce inflammation due to age and decline in other organs (Parker et al 2022). There also needs to be more research on whether or not FMT can promote long-term health benefits and reverse age-associated deterioration of the body.
References
Balaratnasingam C, Yannuzzi LA, Curcio CA, Morgan WH, Querques G, Capuano V, Souied E, Jung J, Freund KB. 2016. Associations Between Retinal Pigment Epithelium and Drusen Volume Changes During the Lifecycle of Large Drusenoid Pigment Epithelial Detachments. IOVS, 57: 13, 5479-5489, doi: 10.1167/iovs.16-19816
Blazes M, Lee CS. 2023. Understanding the brain through aging eyes. Adv Geriatr Med Res, 3:2, doi: 10.20900/AGMR20210008
Boulange CL, Neves Luisa A, Chilloux J, Nicholson JK, Dumas M. 2016. Impact of the Gut Microbiota on Inflammation, Obesity, and Metabolic Disease. Genome Medicine, 8: 42, doi: 0.1186/s13073-016-0303-2
Parker A, Romano S, Ansorge R, Aboelnour A, Le Gall G, Savva GM, Pontifex MG, Telatin A, Baker D, Jones, E, et al. 2022. Fecal Microbiota Transfer Between Young and Aged Mice Reverses Hallmarks of the Aging Gut, Eye, and Brain. Microbiome, 10:1, 68, doi: 10.1186/s40168-022-01243-w
Image: https://pixabay.com/photos/koli-bacteria-escherichia-coli-123081/
In the paper by Parker et al. the researchers conducted experiments that investigated the effects of age-associated microbiota composition and the impact this has on the gut, brain, and retina. Microbiota fecal transplantations were used between young (3 months), old (18 months), and aged (24 months) mice. The experimental groups consisted of the mice that received fecal matter transplants (FMT) from other age groups, while the control groups consisted of mice that received fecal transplants from mice that were in the same age group. Biomarkers of inflammation and function in the brain, retina, intestinal epithelial barrier, circulating inflammatory markers, and behavioral impacts were the factors that were measured for the results of the study.
In the first experiment, immunohistochemistry was used to mark microglial cells in the brain, and it showed that there was an increased amount in old and aged mice. Young mice that received fecal microbiota from aged mice showed an increase in microglial marked cells. Also, aged and old mice that received young mice microbiota had a significant decrease in the amount of marked microglial cells in the corpus callosum. Microglia are involved in the immune response within the brain, which is more common to see in older mice than in younger mice because younger mice have less immune activation within the brain. The data suggest that intestinal microbiota strongly influence microglia activation (Parker et al 2022). To test if there is relationship between cognition and microbiota, the researchers had mice do a novel object recognition test to measure recognition memory, but there was no significant difference between any of the groups during fecal microbiota transfer. This suggests that there is no impact of microbiota on spatial and recognition memory (Parker et al 2022).
The next set of experiments investigated the retina, as researchers focused on protein C3 expression, which corresponds to retinal degeneration. Young mice that received aged donor microbiota had an increase in C3 levels, and aged mice that received young donor microbiota had a reduction in C3 expression. Retinal pigment epithelial protein RPE65 was also measured between groups since it is critical for retinal regeneration of photoreceptors (Balaratnasingam et al. 2016). This was decreased when young mice received aged donor microbiota, and it was increased in aged mice that received young microbiota. This suggests a causal role of the gut microbiota for retina inflammation regulation (Parker et al 2022).
Next, experimenters looked at the intestinal epithelial cells by measuring serum levels of intestinal fatty acid-binding protein (I-FABP), which is a key indicator of microbiota-related epithelial cell damage and disruption. I-FABP increased in young mice that received aged donor microbiota. I-FABP, conversely, was decreased in aged mice receiving young mice donor microbiota. Lipopolysaccharide (LPS) binding protein (LBP), which is secreted in response to leakage of LPS, was two times higher in aged mice than in young mice. This increased in young mice that received donor microbiota from aged mice. Conversely, aged mice that received young mice donor microbiota had a decrease in these levels. From this data, it was concluded that aged microbiota promote the breakdown of the epithelial barrier within the intestines (Parker et al 2022).
Microbiota composition also proved to be an important factor for determining how age plays a role in the inflammation of the body. The researchers used metagenomic analysis to detect any shifts in microbiota after donor transplantation. In young mice that received aged donor microbiota, there was a dramatic shift in composition, and the microbiota more closely resembled that of the aged mice. This same result was also seen in aged mice receiving young mice microbiota. The researchers also examined specific bacteria that are found within young and aged mice. Aged mice have the bacteria oscillibacter, prevotella, and lactobacillus johnsonii. In young mice, bifidobacterium, akkermansia, parabacteroides, clostridium, and enterococcus were found to be the most prominent. Also, bacteria such as bifidobacteriaceae, akkermansiaceae, and eubacteriaceae, which are associated with beneficial effects of intestinal health, were more prominent in young mice and in aged mice that received young donor microbiota. These results indicate FMT resulted in significant alteration of microbiota composition. Also, donor and recipient microbiota were influential in altering the resulting microbiota composition after FMT (Parker et al 2022).
The last experiment used H-NMR spectroscopy-based metabolomics to assess amino acids, sugars, short chain fatty acids, and alcohols. There were no significant differences between aged and young mice groups for any of these categories. However, the researchers also examined metabolic pathway abundance in metagenomic data. For aged mice that received young mice donor microbiota, there was a significant enrichment of pathways that involved lipid synthesis, specifically long and medium chain fatty acids. Also, young mice that received aged donor microbiota had some of the lipid pathways depleted. From these results, the researchers concluded that there is a shift in vitamin and lipid metabolic pathways with a change in the age of microbiota (Parker et al 2022).
Overall, the paper provides multiple pieces of evidence suggesting that the gut microbiota plays a large role in aging of the gut, brain, and retina. Aging microbiota leads to inflammation of the gut and damage to the intestinal epithelial barrier. This also leads to inflammation of the retina and the brain as microbiota age increases. These changes can be reversed, however, with the replacement of aged microbiota with young microbiota. Future research can focus on how modification of the gut microbiome may lead to changes in the gut-brain axis. This can create new therapy approaches that may reduce inflammation due to age and decline in other organs (Parker et al 2022). There also needs to be more research on whether or not FMT can promote long-term health benefits and reverse age-associated deterioration of the body.
References
Balaratnasingam C, Yannuzzi LA, Curcio CA, Morgan WH, Querques G, Capuano V, Souied E, Jung J, Freund KB. 2016. Associations Between Retinal Pigment Epithelium and Drusen Volume Changes During the Lifecycle of Large Drusenoid Pigment Epithelial Detachments. IOVS, 57: 13, 5479-5489, doi: 10.1167/iovs.16-19816
Blazes M, Lee CS. 2023. Understanding the brain through aging eyes. Adv Geriatr Med Res, 3:2, doi: 10.20900/AGMR20210008
Boulange CL, Neves Luisa A, Chilloux J, Nicholson JK, Dumas M. 2016. Impact of the Gut Microbiota on Inflammation, Obesity, and Metabolic Disease. Genome Medicine, 8: 42, doi: 0.1186/s13073-016-0303-2
Parker A, Romano S, Ansorge R, Aboelnour A, Le Gall G, Savva GM, Pontifex MG, Telatin A, Baker D, Jones, E, et al. 2022. Fecal Microbiota Transfer Between Young and Aged Mice Reverses Hallmarks of the Aging Gut, Eye, and Brain. Microbiome, 10:1, 68, doi: 10.1186/s40168-022-01243-w
Image: https://pixabay.com/photos/koli-bacteria-escherichia-coli-123081/
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