Abnormalities in microbiota/butyrate/FFAR3 signaling in aging gut impair brain function
Sidharth P. Mishra, … , Sushil G. Rane, Hariom Yadav
Sidharth P. Mishra, … , Sushil G. Rane, Hariom Yadav
Published February 8, 2024
Citation Information: JCI Insight. 2024;9(3):e168443. https://doi.org/10.1172/jci.insight.168443.
View: Text | PDF
Research Article Aging Microbiology

Abnormalities in microbiota/butyrate/FFAR3 signaling in aging gut impair brain function

Abstract

Aging-related abnormalities in gut microbiota are associated with cognitive decline, depression, and anxiety, but underlying mechanisms remain unstudied. Here, our study demonstrated that transplanting old gut microbiota to young mice induced inflammation in the gut and brain coupled with cognitive decline, depression, and anxiety. We observed diminished mucin formation and increased gut permeability (“leaky gut”) with a reduction in beneficial metabolites like butyrate because of decline in butyrate-producing bacteria in the aged gut microbiota. This led to suppressed expression of butyrate receptors, free fatty acid receptors 2 and 3 (FFAR2/3). Administering butyrate alleviated inflammation, restored mucin expression and gut barriers, and corrected brain dysfunction. Furthermore, young mice with intestine-specific loss of FFAR2/3 exhibited gut and brain abnormalities akin to those in older mice. Our results demonstrate that reduced butyrate-producing bacteria in aged gut microbiota result in low butyrate levels and reduced FFAR2/3 signaling, leading to suppressed mucin formation that increases gut permeability, inflammation, and brain abnormalities. These findings underscore the significance of butyrate-FFAR2/3 agonism as a potential strategy to mitigate aged gut microbiota–induced detrimental effects on gut and brain health in older adults.

Authors

Sidharth P. Mishra, Shalini Jain, Bo Wang, Shaohua Wang, Brandi C. Miller, Jea Y. Lee, Cesar V. Borlongan, Lin Jiang, Julie Pollak, Subhash Taraphder, Brian T. Layden, Sushil G. Rane, Hariom Yadav

×

Figure 3

Old microbiota disrupts gut barrier functions by reducing mucin expression and goblet cells in recipient mouse gut.

Options: View larger image (or click on image) Download as PowerPoint
Old microbiota disrupts gut barrier functions by reducing mucin expressi...
(A) Differential abundance data on an intestinal epithelia-related gene array showing significantly reduced expression of mucin genes Muc2 and Muc6 and tight junction gene Zo1 and increased expression of inflammatory genes Il6 and Tnfa in the intestine (ileum) of mice receiving FMT from old mice compared with controls receiving young FMT. (B) Random forest analysis shows that Muc2 was most significantly affected by old FMT. The mean decrease in gini score respresents the importance of the variable in building the model; thus, the higher the value of the mean decrease in gini score, the higher the importance of the variable in the model. (C and D) Old FMT recipients have significantly fewer goblet cells (periodic acid–Schiff [PAS] staining; red arrows) in their intestinal villi than controls. (E) Fecal mucin content was also significantly lower in old FMT recipients than in controls. (F and G) Treatment with fecal conditioned media (FCM) made from the feces of old mice significantly reduced transepithelial electrical resistance (TEER) (F) and increased FITC-dextran permeability (G) in the monolayers of human HT29 cells compared with treatment with young FCM. (H–K) Muc2 and Muc6 expression was significantly reduced in goblet-like CMT93 cells (H) and enteroids (I) treated with old FCM; they resembled the intestines (ileum and colon) of old FMT recipient mice (J and K). All the values represent the mean of 5–10 animals or 3–4 independent replicates for each group in the cell and enteroid experiments repeated 2–3 times, and error bars represent the standard error of means. Statistical significance was determined using t test and/or ANOVA, as applicable, and P values *P < 0.05, **P < 0.01, and ***P < 0.001 are statistically significant.