Biomolecular Actions by Intestinal Endotoxemia in Metabolic Syndrome

Abstract

Metabolic syndrome (MetS) is a combination of metabolic disorders that concurrently act as factors promoting systemic pathologies such as atherosclerosis or diabetes mellitus. It is now believed to encompass six main interacting conditions: visceral fat, imbalance of lipids (dyslipidemia), hypertension, insulin resistance (with or without impairing both glucose tolerance and fasting blood sugar), and inflammation. In the last 10 years, there has been a progressive interest through scientific research investigations conducted in the field of metabolomics, confirming a trend to evaluate the role of the metabolome, particularly the intestinal one. The intestinal microbiota (IM) is crucial due to the diversity of microorganisms and their abundance. Consequently, IM dysbiosis and its derivate toxic metabolites have been correlated with MetS. By intervening in these two factors (dysbiosis and consequently the metabolome), we can potentially prevent or slow down the clinical effects of the MetS process. This, in turn, may mitigate dysregulations of intestinal microbiota axes, such as the lung axis, thereby potentially alleviating the negative impact on respiratory pathology, such as the chronic obstructive pulmonary disease. However, the biomolecular mechanisms through which the IM influences the host's metabolism via a dysbiosis metabolome in both normal and pathological conditions are still unclear. In this study, we seek to provide a description of the knowledge to date of the IM and its metabolome and the factors that influence it. Furthermore, we analyze the interactions between the functions of the IM and the pathophysiology of major metabolic diseases via local and systemic metabolome's relate endotoxemia.

Keywords: biochemistry; chronic obstructive pulmonary disease (COPD); human microbiota; immunity; metabolic syndrome (MetS); metabolome; microbiota’s crosstalk axis; molecular biology; prebiotics; probiotics; respiratory rehabilitation.

Figure 1

The consequence for the host of achieving a “good balance” (eubiosis) of quantitative and qualitative microorganisms in the IM is significant. This condition can establish a “healthy main functions cycle” that promotes balance in the crosstalk axes, thereby helping to prevent MetS. (Original figure by I.A. Charitos).

Figure 2

The main key factors involving the IM metabolome and MetS include dysbiosis in bacteria populations. In subjects affected by MetS, the Lactobacillaceae family, Sutterella, and Methanobrevibacter spp. Were observed, while Akkermansia, Odoribacter, and Bifidobacterium spp. were associated with healthy individuals. Endotoxic metabolome throughout the metabolism of SBAs, the production of SCFAs with the metabolic endotoxemia, can lead to the disruption of lipids, altered glucose homeostasis, affect satiety, and create an inflammatory chronic condition. All this can lead to MetS, which in turn further alters the IM dysbiosis. (Original figure by I.A. Charitos).

Figure 3

The importance of the Enteric Nervous System (ENS) in the interaction with the IM is significant. The connections between the IM and ENS can manifest through both direct and indirect mechanisms. Bacterial components from Gram-negative bacteria (such as LPS or polysaccharide A) or Gram-positive bacteria (such as peptidoglycan), known as microbe-associated molecular patterns (MAMPs) are detected by receptors expressed in myenteric neurons, enteric glial cells, and innate immune cells. This recognition occurs via surface transmembrane pattern (PRR) or Toll-like endosomes (TLR). Furthermore, neuronal signaling and metabolic products of the IM, such as SCFAs, which are involved in maintaining ENS homeostasis, stimulate various G protein-coupled receptors (GPCRs), PNS, and block the action of histone deacetylases (HDACs). Some bacteria within the IM can release neurotransmitters produced (such as dopamine, serotonin, etc.) that modulate intestinal secretion and motility, thus establishing an axis of interaction between bacteria, neurons, the ENS, PNS, and CNS. (Original figure by I.A. Charitos).

Figure 4

Some key bacteria phyla and species found during pregnancy influence fetal intestinal microbiota. In the early stages of life, the qualitative and quantitative composition of microbial populations depends on the mode of delivery. Individuals delivered via cesarean section have exhibited a heightened susceptibility to allergic conditions and a greater inclination toward developing various diseases overall. (Original figure by I.A. Charitos).

Figure 5

Metabolites produced by the IM, including those associated with favorable body health (highlighted in green) and those correlated with organic and mental ailments (highlighted in azure), play a pivotal role in regulating various aspects of host metabolism and physiology. Microbial products, like short-chain fatty acids (SCFAs), interact with G-protein-coupled receptors (GPCRs) on intestinal epithelial cells (e.g., Gpr41 and Gpr43), influencing energy balance and modulating the release of the gut hormone PYY, as well as regulating the host’s inflammatory response. Activation of TLR5 (e.g., via bacterial flagellum) potentially impacts the composition of the intestinal microbiota, thereby influencing appetite, weight gain, and insulin sensitivity through mechanisms that are not yet fully understood. Bacterial signals also regulate the release of fasting-induced adipose factor (FIAF) from intestinal epithelial cells, which inhibits LPL and thus controls peripheral fat storage. Moreover, the intestinal microbiota modulates energy homeostasis in the liver and muscles, possibly through the phosphorylation of AMP-activated protein kinase (AMPK), although the exact mechanisms remain unknown. GLP-2 supports epithelial barrier function, and a compromised barrier may expose and activate myeloid cells in response to microbial signals such as the endotoxin ligand TLR4. (Original figure by I.A. Charitos).

Figure 6

Short chain fatty acids-SCFAs beneficially affect the health of the host in the various modality. (Original figure by I.A. Charitos).

Figure 7

The hypothesis suggests that the IM can modulate the immunological activity of the lung: Lipopolysaccharides (LPS) bind to Toll-Like Receptor (TLR) on the intestinal mucosa, activating dendritic cells that promote the activation of various T cells, particularly T-reg, T-h17, and Th1, which later migrate to the lung through the circulatory stream. Bacterial metabolites (such as SCFAs) directly act on the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), reducing the production of Tumor Necrosis factor (TNF-α) and downregulating pattern recognition receptors (PRRs), resulting in reduced production of inflammatory cytokines: IL-1, IL-12, IL-18, TNF-α, interferon gamma (IFNγ), and granulocyte-macrophage colony-stimulating factor (GM-CSF). (Original figure by I.A. Charitos).

Figure 8

Proposed mechanism for the role of the IM in energy production and fatty storage in the host. After fatty acid oxidation, the biomolecular connection with the IM causes the deposition of fat through three mechanisms: (a) stimulation of lipogenesis in the liver, (b) via the bacteria metabolite SCFAs, and (c) via fasting-induced steatosis factors. (Original figure by I.A. Charitos).

Figure 9

The hypothesis regarding the mechanisms involved in the occurrence of metabolic systemic endotoxemia suggest that IM dysbiosis initiates local immune interactions, leading to intestinal endotoxemia, which triggers a cascade of local and systemic reactions. This IM dysbiosis can affect some or all communication axes of the IM, resulting in generalized endotoxemia, further perpetuating the local and systemic imbalance. (Original figure by I.A. Charitos).

Figure 10

Initially, dysbiosis increases the population of some TMA-producing bacteria (such as those of Prevotella spp.), which contain flavonoids type 3 (FOM3). Subsequently, TMAO occurs in the liver, facilitating the formation of atheromasia plaques, resulting in local alterations that lead to endothelial sclerosis and damage to its functions. Furthermore, this inflammation and other reaction of the vessels will lead to a greater downregulation of immune, endocrine, and immune cycle homeostasis, worsening the state of cardiovascular alterations. (Original figure by I.A. Charitos).

Figure 11

The figure illustrates the two endocannabinoids along with their receptors distributed throughout the body. Each of these endocannabinoids is found in varying quantities in the gastrointestinal organs, lungs, peripheral and central nerve system, bone marrow, and muscles. Numerous investigations utilizing specific antagonists and agonists have revealed that the endocannabinoid system governs not only intestinal permeability, but also plasma lipopolysaccharide (LPS) levels and adipogenesis. Endocannabinoids have been observed to boost occludin-1 protein mRNA expression, indicating a possible involvement in regulating intestinal permeability. (Original figure by I.A. Charitos).