Extracellular Matrix and Oxidative Phosphorylation: Important Role in the Regulation of Hypothalamic Function by Gut Microbiota

Abstract

Background: In previous studies, our team examined the gut microbiota of healthy individuals and depressed patients using fecal microbiota transplantation of germfree (GF) mice. Our results showed that depression-like and anxiety-like behavioral phenotypes of host mice were increased, but the molecular mechanism by which gut microbiota regulate host behavioral phenotypes is still unclear. Methods: To investigate the molecular mechanism by which gut microbiota regulate host brain function, adult GF mice were colonized with fecal samples derived from healthy control (HC) individuals or patients with major depressive disorder (MDD). Transcriptomic profiling of hypothalamus samples was performed to detect differentially expressed genes (DEGs). qRT-PCR was used for validation experiments. Results: Colonization germ-free (CGF) mice had 243 DEGs compared with GF mice. The most enriched KEGG pathways associated with upregulated genes were "protein digestion and absorption," "extracellular matrix (ECM)-receptor interaction," and "focal adhesion." MDD mice had 642 DEGs compared with HC mice. The most enriched KEGG pathways associated with upregulated genes in MDD mice were also "protein digestion and absorption," "ECM-receptor interaction," and "focal adhesion." Meanwhile, the most enriched KEGG pathway associated with downregulated genes in these mice was "oxidative phosphorylation," and genes related to this pathway were found to be highly correlated in PPI network analysis.

Proteomic Profiling of Lysine Acetylation Indicates Mitochondrial Dysfunction in the Hippocampus of Gut Microbiota-Absent Mice

“…Previous study has confirmed that lysine acetylation is a prevalent modification in enzymes that catalyze intermediate metabolism ( Zhao et al, 2010 ), such as the seven TCA cycle-related dehydrogenases, and oxidative phosphorylation complexes I, II, III, and V. In this study, we revealed that various enzymes involved in ATP production are highly acetylated in mitochondria, suggesting the increase in the mitochondrial function for energy production in GF mice, which exhibit antianxiety- and antidepressive-like behaviors compared with SPF mice ( Zheng et al, 2016 ; Luo et al, 2018 ). Consistently, our previous studies showed the inhibition of the expression of genes related to oxidative phosphorylation pathway in gut microbiota-remodeled mice with depressive-like behaviors ( Qi et al, 2020 ), and studies have also revealed a low cerebral bioenergetic metabolism in different brain regions, including prefrontal cortex and basal ganglia of patients with MDD ( Drevets et al, 1997 ; Mayberg et al, 1999 ; Videbech, 2000 ; Moretti et al, 2003 ), which means decrease in mitochondrial function in depression. Taken together, these results indicated that mitochondrial dysfunction may be involved in the mechanisms by which gut microbiota regulates the host brain function.…”

Integrative proteomic and phosphoproteomic analysis in the female goat hypothalamus to study the onset of puberty

“…The formation of a speci c structure at the point of contact between the cell and extracellular matrix is called a focal adhesion [40,41]. In this structure, actin is anchored to transmembrane receptors of the integrin family by a multi-molecular complex, thereby forming a structural connection between membrane receptors and the actin cytoskeleton [42]. Local adhesion of relevant components changes cell shape and gene expression by regulating the actin cytoskeleton [43,44].…”

“…During brain development, the role of β-catenin in cell adhesions is essential for proper cell migration whereas the WNT signaling pathway regulates cell proliferation and cell fate determination [48][49][50]. More recently, Elizabeth et al [42] reported in the journal Developmental Biology that a central and multifaceted role for canonical WNT signaling in regulating growth, patterning, differentiation and nucleogenesis in multiple diencephalic regions. In summary, the above results provide a reliable theoretical basis for CTNNB1 as a new regulated target for the puberty onset of goat.…”

Roles for the gut microbiota in regulating neuronal feeding circuits

“…Proteomic analysis of the hypothalamus revealed differences in neuropeptide levels between CONV-R and GF mice, and differential abundance of proteins related to the regulation of transmitter release, signaling pathways, and synapses (49). In addition, GF mice conventionalized with microbiotas from CONV-R mice exhibit upregulation of hypothalamic genes related to extracellular matrix (ECM) function compared with GF mice, suggesting that ECM modification may contribute to gut microbial effects on the hypothalamus (50).…”