A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites

Abstract

Background Cognitive impairment, an increasing mental health issue, is a core feature of the aging brain and neurodegenerative diseases. Industrialized nations especially, have experienced a marked decrease in dietary fiber intake, but the potential mechanism linking low fiber intake and cognitive impairment is poorly understood. Emerging research reported that the diversity of gut microbiota in Western populations is significantly reduced. However, it is unknown whether a fiber-deficient diet (which alters gut microbiota) could impair cognition and brain functional elements through the gut-brain axis. Results In this study, a mouse model of long-term (15 weeks) dietary fiber deficiency (FD) was used to mimic a sustained low fiber intake in humans. We found that FD mice showed impaired cognition, including deficits in object location memory, temporal order memory, and the ability to perform daily living activities. The hippocampal synaptic ultrastructure was damaged in FD mice, characterized by widened synaptic clefts and thinned postsynaptic densities. A hippocampal proteomic analysis further identified a deficit of CaMKIId and its associated synaptic proteins (including GAP43 and SV2C) in the FD mice, along with neuroinflammation and microglial engulfment of synapses. The FD mice also exhibited gut microbiota dysbiosis (decreased Bacteroidetes and increased Proteobacteria), which was significantly associated with the cognitive deficits. Of note, a rapid differentiating microbiota change was observed in the mice with a short-term FD diet (7 days) before cognitive impairment, highlighting a possible causal impact of the gut microbiota profile on cognitive outcomes. Moreover, the FD diet compromised the intestinal barrier and reduced short-chain fatty acid (SCFA) production. We exploit these findings for SCFA receptor knockout mice and oral SCFA supplementation that verified SCFA playing a critical role linking the altered gut microbiota and cognitive impairment. Conclusions This study, for the first time, reports that a fiber-deprived diet leads to cognitive impairment through altering the gut microbiota-hippocampal axis, which is pathologically distinct from normal brain aging. These findings alert the adverse impact of dietary fiber deficiency on brain function, and highlight an increase in fiber intake as a nutritional strategy to reduce the risk of developing diet-associated cognitive decline and neurodegenerative diseases.

Polydextrose Alleviates Adipose Tissue Inflammation and Modulates the Gut Microbiota in High-Fat Diet-Fed Mice

“…FMT from the obesity-associated human gut microbiota to mice can induce vascular dysfunction and glucose intolerance, and FMT from lean donors to patients with obesity can promote metabolic benefits (Mocanu et al, 2021;Russo et al, 2021). Recent studies over the past decade have revealed that many environmental factors, including diet, antibiotic exposure, energy intake and exercise, can dramatically influence the gut microbiota (Du et al, 2021;Giordan et al, 2021;Shi et al, 2021). Dietary fiber has been shown to improve obesity and is considered a potential therapy because it increases microbial fermentation of SCFAs (Schäfer et al, 2021;Thomson et al, 2021).…”

Dietary Fiber Intake is Associated with Cognitive Function in Older Adults: Data from the National Health and Nutrition Examination Survey

“…6 In this regard, emerging evidence suggests that diets low in dietary fiber content are associated with cognitive impairments. 7 Dietary fiber is associated with a reduced cardiovascular disease and all cancer risk, highlighting its importance as part of a healthy diet. 8,9 In the United States, more than 90% of women and 97% of men among adults do not meet current recommends for dietary fiber intake.…”

In Utero Exposure to Caffeine and Acetaminophen, the Gut Microbiome, and Neurodevelopmental Outcomes: A Prospective Birth Cohort Study

“…Proteobacteria includes many notorious pathogens, including Escherichia, Shigella , and Salmonella , all in the Gammaproteobacteria. An elevated relative abundance of the phylum is associated with worse cognitive performance or impairment in clinical [ 48 , 49 ], population-based [ 50 , 51 ], and animal studies [ 52 ], in addition to being considered a marker of gut dysbiosis [ 53 ]. Our findings suggest that in addition to the direct negative relationship between Proteobacteria relative abundance and cognitive scores observed in prior studies, it may modify the associations of caffeine and acetaminophen with cognition in an adverse manner.…”