Integrated Analyses of Microbiomics and Metabolomics Explore the Effect of Gut Microbiota Transplantation on Diabetes-Associated Cognitive Decline in Zucker Diabetic Fatty Rats

Abstract

Diabetes-associated cognitive decline (DACD), one of the complications of type 2 diabetes (T2DM), correlates significantly with the disorder in glycolipid metabolism, insulin/leptin resistance, and accumulation of β-amyloid (Aβ). Although gut microbiota transplantation (GMT), a novel non-invasive physiotherapy strategy, has been a promising intervention to alleviate the symptoms of T2DM, its protective effect on progressive cognitive decline remains elusive. Here, we transplanted the gut microbiota of healthy or cognitive decline donor rats into ZDF or LZ rats, and integrated microbiomics and metabolomics to evaluate the directional effect of the gut microbiota on the recipient rats. The basal metabolism phenotype changed in ZDF rats instead of in LZ rats. One possible mechanism is that the microbiota and metabolites alter the structure of the intestinal tract, stimulate the brain insulin and leptin signaling pathways, and regulate the deposition of Aβ in the brain. It is worth noting that 10 species of genera, such as Parabacteroides, Blautia, and Lactobacillus, can regulate 20 kinds of metabolites, such as propanoic acid, acetic acid, and citramalic acid, and having a significant improvement on the cognitive behavior of ZDF rats. In addition, the correlation analysis indicated the gut microbiota and metabolites are highly associated with host phenotypes affected by GMT. In summary, our study indicates that altering the microbiota-gut-brain axis by reshaping the composition of gut microbiota is a viable strategy that has great potential for improving cognitive function and combatting DACD.

Neuroactive Steroid–Gut Microbiota Interaction in T2DM Diabetic Encephalopathy

“…On the other hand, a strict interaction among brain functions, including memory, DM, and microbiota, is also well ascertained. Indeed, changes in microbiota composition in T2DM patients [ 84 , 85 ] and in ZDF rats have been already reported [ 86 , 87 , 88 , 89 , 90 ], and it has been proposed that these changes contribute to insulin resistance and metabolic syndrome-developing progress. However, whether they are related to memory alterations and/or to the steroid environment in T2DM, has not been yet reported.…”

Reduced SV2A and GABAAreceptor levels in the brains of type 2 diabetic rats revealed by [18F]SDM-8 and [18F]flumazenil PET

“…One possibility for the lack of differences in the levels of [ 18 F]florbetapir and [ 18 F]PM-PBB3 uptake could be that the accumulation levels of Aβ and tau deposits have not reached the threshold detectable by using PET or that the aggregates are not mature enough to harbor sufficient fibrillar structures that the β-sheet binding imaging tracers recognize [45,46]. This is reflected partly in previous studies using immunohistochemical staining showing relatively low insoluble Aβ, Aβ plaques, and tau deposits in the brains of T2DM rats [9][10][11] compared to those in animal models of amyloidosis [47,48] and tauopathy [49,50].…”

“…In addition, advanced glycation end products (AGEs)/RAGE signaling plays an important role in T2DM and is involved in multiple pathways [8]. In addition, increased levels of soluble/insoluble amyloid-beta (Aβ), Aβ plaques, phosphorylated tau, and tau deposits, which are pathological features in the brains of AD patients and animal models, have been shown in the brains of T2DM rats [9][10][11].…”

Untargeted Metabolomic Profiling Reveals Differentially Expressed Serum Metabolites and Pathways in Type 2 Diabetes Patients with and without Cognitive Decline: A Cross-Sectional Study

“…Numerous metabolomics investigations have explored DACD within animal models, employing various biological specimens including brain tissues, cerebrospinal fluid (CSF), blood, or urine samples [26][27][28][29][30]. However, the utilization of human brain tissue or CSF is fraught with impracticality due to the postmortem nature of brain tissue acquisition and the highly invasive procedure associated with CSF collection.…”