Ketogenic Diet Alleviates Hypoglycemia‐Induced Neuroinflammation via Modulation the Gut Microbiota in Mice

Abstract

Scope: This study aims to investigate the role of gut microbiota regulation with ketogenic diet (KD) in hypoglycemia-induced neuroinflammation. Methods and results: Immunofluorescence staining and western blotting show that KD alleviates blood-brain barrier injury induced by hypoglycemia by increasing Podxl and zonula occludens-1 (ZO-1) levels. KD-fed mice show reduced brain edema by decreasing aquaporin-4 (AQP4) content and maintaining its polarized expression. 16S rRNA gene amplicon sequencing results show that KD reduces the Chao 1 index of gut microbiota 𝜶-diversity, and significant separation is detected in the 𝜷-diversity analysis between the control and KD-fed mice. KD increases the relative abundance of Firmicutes and Proteobacteria and decreases that of Bacteroidetes. Hypoglycemia can reduce SOD and GSH-PX levels while increasing TNF-𝜶, IL-1𝜷, and IL-6 mRNA levels in the brain tissues of mice. KD alleviates hypoglycemia-induced neuroinflammation by inhibiting microglia activation and TLR4/p38MAPK/NF-𝜿B signaling pathway. Importantly, antibiotic cocktail depletion of the gut microbiota weakens anti-inflammatory and antioxidation responses in KD-fed mice. Conclusion: Collectively, these findings suggest that KD alleviates hypoglycemia-induced brain injury via gut microbiota modulation, which may provide novel insights into the therapy for hypoglycemia.

Ketogenic diet attenuates cognitive dysfunctions induced by hypoglycemia via inhibiting endoplasmic reticulum stress-dependent pathways

“…Three hours after injection, all groups were administered 0.1 mL of 50% glucose by gavage for rescue, followed by resuming the same diet as before. 14…”

Effects of Calorie Restriction and Fasting on Macrophage: Potential Impact on Disease Outcomes?

“…Metabolic signaling pathways (such as mTOR, AMPK, and HIF-1 pathways) and metabolites (lactate, glutamine, arginine), such as the activation of the mTOR and AMPK pathways, have been shown to influence macrophage polarization. [10] As metabolic reprogramming towards other pathways might lead to the differentiation of diverse phenotypes and even dysfunction of macrophages in health and disease, [25] it has been suggested that reprogramming the metabolism of macrophages could represent a promising therapeutic strategy for several diseases. [26,27] Due to the ability to induce metabolic reprogramming, energy restriction is considered to have the potential to regulate macrophage function.…”

“…[7] These include alterations in energy metabolism, regulation of glucose and growth factor levels in the blood, [6] reduction of ROS production and related cell damage, [4] induction of autophagy [8] and DNA repair, [9] and modulation of the gut microbiota. [10] Given the reliance on immune cell function, maintenance, and clonal expansion on metabolism, energy restriction has the potential to shape and modulate the immune response. [11] It has become increasingly evident that macrophages, a type of innate immune cell distributed throughout the body, play critical roles in mediating the outcome of CR/fasting in various diseases.…”

“…[ 7 ] These include alterations in energy metabolism, regulation of glucose and growth factor levels in the blood, [ 6 ] reduction of ROS production and related cell damage, [ 4 ] induction of autophagy [ 8 ] and DNA repair, [ 9 ] and modulation of the gut microbiota. [ 10 ]…”

Biomaterial strategies for regulating the neuroinflammatory response

“…7,8 Since the 1960s, there have been 1200-3000 clinical studies investigating treatments for neuroinflammatory diseases. Combinations of anti-inflammatory drugs, [9][10][11] antioxidants, [12][13][14] corticosteroids, 15,16 exercise, [17][18][19] and tailored diets [20][21][22][23][24] have been implemented with limited long-term success. While these strategies can help manage disease symptoms, they fail to fully resolve inflammation within the CNS.…”