Next Article in Journal
MECP2 Dysfunction in Rett Syndrome: Molecular Mechanisms, Multisystem Pathology, and Emerging Therapeutic Strategies
Next Article in Special Issue
A Plant-Based Strategy for MASLD: Desmodium caudatum (Thunb.) DC. Extract Reduces Hepatic Lipid Accumulation and Improves Glycogen Storage In Vitro and In Vivo
Previous Article in Journal
2-Styrylquinolines with Push-Pull Architectures as Sensors for β-Amyloid Aggregation with Theranostic Properties
Previous Article in Special Issue
Deciphering the Diagnostic Potential of Small Non-Coding RNAs for the Detection of Pancreatic Ductal Adenocarcinoma Through Liquid Biopsies
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 26
Issue 17
10.3390/ijms26178276
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Are an Aging Gut and a Decrease in Butyrate Production the Reasons for Atherosclerosis?

by
Leon M. T. Dicks
Department of Microbiology, Stellenbosch University, Stellenbosch 7600, South Africa
Int. J. Mol. Sci. 2025, 26(17), 8276; https://doi.org/10.3390/ijms26178276
Submission received: 16 July 2025 / Revised: 16 August 2025 / Accepted: 25 August 2025 / Published: 26 August 2025
(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)
Browse Figures
Versions Notes

Abstract

Atherosclerosis (AS) is directly linked to the aging and damage of endothelial cells (ECs). As ECs and vascular smooth muscle cells (VSMCs) age, more autocrine and paracrine signals are released, extending a vicious cycle of tissue aging and physiological dysfunction. The recruitment of immune cells to inflamed arteries, including coronary arteries, and an increase in the uptake of oxidised low-density lipoprotein (ox-LDL) by macrophages (foam cells) onto the tunica intima (intima) of coronary arteries restrict blood flow. The inability of aging and damaged ECs to accommodate vast changes in signalling molecules, many produced by gut microbiota, leads to a range of anatomical and physiological arterial anomalies. These include degradation of cardiovascular membranes, fibrosis, calcification, plaque formation, and an increasingly dysfunctional immune system. Changes in the gut microbiome of the elderly have a direct effect on the immune response, as the signalling molecules produced by gut microbiota target specific receptors on inflamed arteries. This review summarizes the anatomical and physiological changes associated with the aging of coronary arteries and emphasizes the conditions leading to AS. The importance of butyrate-producing gut microbiota in preventing AS, especially in the elderly, is discussed.

1. Introduction

Aging may be defined as a progressive change in biological processes, driven by genomic instability and a decline in cellular communication. Modulation in the sensing of nutrients by a changing gut microbiome, variations in inflammatory reactions, the uncontrolled migration of macrophages, loss of enzymatic activities, and a decline in mitochondrial functions are some of the anomalies associated with aging [1]. These changes are key drivers of illnesses such as atherosclerosis (AS), associated with, but not limited to, the elderly [2], metabolic disease, neurodegenerative disorders, and cancer [3,4,5,6]. The gradual decline in physiological activities of intestinal epithelial cells (IECs) and the disappearance of signal-specific membrane receptors lead to an imbalance in the expression of pro- and anti-inflammatory cytokines, and drastic changes in the gut microbiome [3,7].
The inability of endothelial cells (ECs) in the intima of coronary arteries to accommodate vast changes in signalling molecules, many produced by gut microbiota, leads to a range of anatomical and physiological anomalies, e.g., calcification, immune infiltration, degradation of cardiovascular membranes, deposition of lipid-rich macrophages (foam cells), plaque formation, and fibrosis, as summarized in Figure 1 [8]. Apart from plaque formation, blood flow is disrupted, or arteries are completely clogged, which may lead to thrombosis and myocardial infarction (MI) (Figure 1). Prolonged inflammation leads to irreversible tissue failure, which is often difficult to correct with conventional therapies [9].
Arterial inflammation is characterized by the translocation of nuclear and mitochondrial DNA (mtDNA) into the cytosol [10]. This stimulates pro-inflammatory DNA sensors, exaggerated by ineffective autophagy (the degradation and recycling of cellular components), inadequate gene regulations, the incorrect folding of proteins, and malfunctioning of enzymes [3]. Damaged ECs stimulate the release of inflammatory cytokines, e.g., interleukin (IL)-1a, IL-1b, IL6, and interferon y (INF-y), chemokines, e.g., IL-8, monocyte chemoattractant protein 2 (MCP-2), and MCP-4, and matrix metalloproteinases (MMPs); and growth regulators, such as the urokinase plasminogen activator receptor (uPAR). These are listed in Figure 1 [11]. These relapses of membrane structure stimulate the release of damage-associated molecular patterns (DAMPs), free radicals, and reactive oxygen species (ROS), which enhance inflammation (Figure 1) [12]. Damaged blood vessels are repaired by platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) released from platelets (Figure 1) [13]. Leukocytes, such as IL-1, are recruited (Figure 1) and trigger the expression of protein tissue factor (PTF), which acts as a procoagulant [14].
In a previous review [8], the production of butyrate by gut microbiota, the uptake of butyrate by colonic endothelial cells, transport across arterial and myocardial endothelia, and interactions with G-protein-coupled receptors (GPCRs) were discussed. This review summarizes the anatomical, physiological, and molecular changes associated with the aging of coronary arteries. Cellular abnormalities and the role that gut microbiota play in the development of AS are discussed. The review is not a detailed discussion of changes in the gut microbiome at different ages. The focus is on microbial signals generated by gut microbiota, especially those produced by an “aging gut microbiome”. The importance of butyrate-producing gut microbiota in preventing AS is discussed.

2. Changes in the Vessel Wall

One of the hallmarks of AS and other forms of cardiovascular diseases (CVDs) is the dysfunction of ECs [15]. Persistent inflammation triggers genomic instability and somatic mutations, which may lead to an increase in the production of a specific clone of blood cells, referred to as clonal haematopoiesis (CH). This initiates AS and may cause certain blood cancers, e.g., myeloid leukaemia, myelodysplastic syndrome, and myeloproliferative neoplasms [16]. The destruction of coronary arteries by persistent inflammation leads to a decline in the density of capillaries and arterioles, a response typical of arteriosclerotic arteries and a precursor of atherothrombosis [17]. These changes coincide with an increase in coronary collagen and endothelin, loss of membrane elasticity, a decrease in nitric oxide (NO) production, and thickening of the medial layer (media) in coronary arteries (Figure 1) [17].
The surface of the intima of healthy coronary arteries is covered with receptors for LDL and thrombin, prostacyclin PGI2 (an antithrombotic agent), von Willebrand’s factor (a prothrombotic agent), interleukin-1 (IL-1), and plasminogen activator (a fibrinolytic agent) (Figure 1) [18]. Damaged blood vessels are repaired by platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) released from platelets (Figure 1) [19]. Leukocytes, such as IL-1, are recruited (Figure 1) and trigger the expression of protein tissue factor (PTF), which acts as a procoagulant [14]. A combination of these factors maintains blood flow in damaged arteries, prevents the formation of blood clots, and protects the intima from plaque buildup. Short-chain fatty acids (SCFAs), e.g., butyrate, and reactive oxygen species (ROS) produced by gut bacteria interact with signaling pathways and cell membrane receptors, e.g., Toll-like receptor 4 (TLR4), platelet glycoprotein 4 (CD36), and G protein-coupled receptors (GPCRs), as shown in Figure 2 [18]. Trimethylamine-N-oxide (TMAO), produced by gut microbiota, activates Nod-like receptor protein 3 (NLRP3) and triggers platelet formation (Figure 2) [18]. Gut bacteria such as Escherichia and Klebsiella are known to increase TMAO levels [19].
The decline of vascular homeostasis destabilizes membrane permeability, increases Nod-like receptor protein 3 (NLRP3), stimulates the nuclear factor kappa B (NF-κB) pathway, and induces apoptosis (Figure 2). An increase in NLRP3 activates NF-κB and mitogen-activated protein kinase (MAPK) pathways, which in turn lead to an increase in the expression of cytokines and chemokines (Figure 2) [18,20]. As a result of these changes, the levels of AGEs (advanced glycation end products) and ROS increase (Figure 2) [21,22]. An increase in oxidative stress leads to the production of ox-LDL, which is taken up by macrophages and transformed into lipid-rich foam cells (Figure 2). The latter accumulate on the intima and participate in plaque formation (Figure 2) [18]. T- and B-lymphocytes are also involved in the development of AS [23]. The main T cells in atherosclerotic plaques are CD4+ (Figure 2) [24]. Upon activation, CD4+ differentiate into helper T (Th) cells. Th1 cells express interferon-γ (INF-γ) to promote AS, whilst Th2 cells produce IL-4, IL-5, and IL-13, which neutralize INF-γ (Figure 2) [25]. Vascular smooth muscle cells (VSMCs) are maintained by Notch 3, which regulates gene transcriptions, intracellular communication, neural development, and the binding of epidermal growth factor (EGF) to EGF receptors (EGFRs) [26]. Arteries prone to AS are penetrated by foam cells, accumulate ROS, and are more prone to fibrosis (Figure 2) [27].
In ageing endothelial membranes with AS, the intima is covered by proteoglycans (Figure 3). Their negatively charged side chains (biglycan, versican, perlecan, and lumican) are linked to positively charged lipoproteins, specifically apolipoprotein B, which attaches to ox-LDL (Figure 3) [28]. Aging VSMCs release senescence-associated secretory phenotype (SASP) factors, e.g., matrix metalloproteinase 9 (MMP-9), and upregulate the inflammasome, preparing adjacent healthy endothelial cells and smooth muscle cells to produce pro-inflammatory cytokines (Figure 3) [21,29]. This stimulates the infiltration of foam cells (Figure 3) [30]. With the increase in MMP production, collagen is lysed and elastin degraded, destabilizing the fibrous cap of plaques, risking rupture, the release of plaque contents, and thrombosis (Figure 3) [21,30]. An aging immune system with impaired function may fail to eliminate dead cells and support the release of SASP [7]. Senescent immune cells infiltrate vessel walls, leading to an increase in the production of pro-inflammatory mediators and chemokines [7]. TET methylcytosine dioxygenase 2 (TET2)-deficient macrophages, prevalent in ageing blood cells, increase the release of NLRP3 inflammasome-mediated interleukin-1β (IL-1β) (Figure 3 and Figure 4) [21]. This results in the formation of larger aortic plaques (Figure 3 and Figure 4) [31].
Ox-LDL accelerates the degradation of macrophages, promotes the release of pro-inflammatory cytokines, and prevents macrophage migration [32]. A degradation of CD4+ and CD8+ T cells, correlated with a decline in IFN-γ and TNF-α and an increase in plaque infiltration, leads to the expression of perforin and granzymes, which damage surrounding ECs and VSMCs [24]. Further research is required to determine whether the accumulation of senescent T cells in peripheral blood cells and atherosclerotic plaques is the cause or consequence of atherogenesis.

3. Changes in the Gut Microbiome

The adult human gut hosts approximately 4 trillion microorganisms, equivalent to the estimated 3.0 × 1013 human cells in a 70 kg body [33]. The human gut hosts six prominent phyla, i.e., Bacillota (previously Firmicutes), Bacteroidota (previously Bacteroidetes), Pseudomonadota (previously Proteobacteria), Fusobacteriota (previously Fusobacteria), Verrucomicrobiota (previously Verrucomicrobia), Cyanobacteriota (previously Cyanobacteria), and Actinomycetota (previously Actinobacteria) [34]. Bacillota and Bacteroidota are predominant [34]. Fungi are less diverse, with Candida, Saccharomyces, Malassezia, and Cladosporium being the best represented. [34]. Less is known about the virome of the human gut, except for pathogenic viruses, such as Enterovirus from the family Picornaviridae [35], and Rotavirus [36] and Norovirus [37], from the families Reoviridae and Caliciviridae, respectively. Other members of the human gut virome are from the families Picobirnaviridae, Astroviridae, Adenoviridae, Anelloviridae, Cycloviridae, and Parvoviridae [38]. The diversity of bacteria within the human gut was reviewed by Rosenberg [39].
At birth, the infant is exposed to the mother’s microbiome. The exchange of microbiota is highly dependent on the delivery of the newborn [40]. The gastrointestinal tract (GIT) of infants born by Caesarean (C)-section is invaded by Enterobacter hormaechei, Enterobacter cancerogenus, Haemophilus parainfluenzae, Haemophilus aegyptius, Haemophilus influenza, Haemophilus haemolyticus, Staphylococcus saprophyticus, Staphylococcus lugdunensis, Staphylococcus aureus, Streptococcus australis, Veillonella dispar, Veillonella parvula, and a few Bacteroides spp. [41]. A comparative study conducted on same-age infants vaginally delivered showed less bacterial diversity, with dominance by Bacteroides, Bifidobacterium, Parabacteroides, Escherichia, and Shigella [42]. The core group of gut microbiota develops within the first 5 years [43]. Later in life, closer to puberty, the gut microbiome adapts to dietary preferences, external factors, and treatments of illnesses [44].
A diet rich in fat and carbohydrates (Western-style diet, WD) supports the growth of Bacillota (e.g., Streptococcus and Oscillibacter), Pseudomonadota, and Fusobacteriota, but suppresses the growth of Lactobacillus [45]. In general, individuals following an imbalanced WD are more obese and harbour more Bacillota and Bacteroidota compared to individuals on a Mediterranean diet (MD) [43,46]. Reports are not always consistent. According to Severino et al. [45], a WD is less supportive of Bacteroidota (e.g., Bacteroides, Parabacteroides Prevotella, Barnesiella, and Alistipes) and Actinomycetota (e.g., Bifidobacterium, Streptomyces, and Actinoplanes). According to Desai et al. [47], a WD promotes the growth of mucus-degrading Akkermansia muciniphila and Bacteroides caccae. The destruction of the mucus layer may render IECs vulnerable to pathogens such as Helicobacter pylori. Since H. pylori regulates the NLRP3 inflammasome [48], infection may initiate AS. Other bacteria associated with AS are Escherichia coli [49] and Acidaminococcus [50]. Diets with a high fiber content support the growth of Bifidobacterium, Lactobacillus, Enterococcus, Lachnospiraceae, Ruthenibacterium, Flavonifractor, Ruminococcus [51], Faecalibacterium, Roseburia, Eubacterium, Anaerostipes, Coprococcus, Subdoligranulum, Anaerobutyricum, and Oscillospira [52].
A comprehensive study conducted by Odamaki et al. [53], based on the sequencing of the 16S rRNA genes (V3-V4 regions) of more than 1.8 million bacteria isolated from individuals of various age groups (newborn infants to individuals 104 years old), has shown an increase in Bacteriodota and Pseudomonadota, and a decline in Bacillota in individuals older than 70 years. The dominant Bacillota were Eubacterium, Clostridium, Megamonas, Peptoniphilus, Lachnospiraceae, Blautia, Coprococcus, Roseburia, and Faecalibacterium [54]. According to Salazar et al. [55], centenarians harbour less Bacillota and more Bacteroidota and Proteus spp. This may be due to an increase in inflammation as the immune system becomes compromised with changes in diet [56]. The gut microbiota of the elderly is more adapted to proteolytic activities than glycolysis [56]. This promotes the growth of pathogenic bacteria and aggravates inflammatory responses, e.g., an increase in ROS. An increase in ROS inactivates strict anaerobic bacteria (i.e., Bacillota) and promotes facultative aerobes [57]. With an increase in the expression of inflammatory cytokines, the expression of tight junction proteins is reduced, and the gut wall becomes more permeable. This further increases inflammation [58].
A reduction in Bifidobacterium in the elderly [53] is influenced by diet [59]. Bifidobacteria downregulate pro-inflammatory responses in the gut epithelium [60] and produce acetate, which stimulates the growth of butyrate-producing bacteria [61]. It is interesting to note that individuals diagnosed with AS have less butyrate-producing Bifidobacterium, Bacteroides, Alistipes, Parabacteroides, and Prevotella [62]. Instead, they have significantly more Bacillota, especially members of the genera Megamonas, Streptococcus, and Veillonella [62]. Megamonas is associated with obesity, several metabolic diseases, and inflammation [63]. Veillonella is associated with insulin resistance [64]. Streptococcus has been isolated from atherosclerotic plaques [65]. Bifidobacteria strengthen gut barrier integrity and reduce systemic inflammation [66,67,68]. A decline in bifidobactera may explain why these individuals are more prone to developing AS.

4. Molecular Changes Driven by Gut Microbiota

With age and deterioration of renal function, TMAO levels increase [69], the population of SCFA-producing bacteria decreases [70], and the composition of bile acid changes [71]. Trimethylamine N-oxide (TMAO), produced by gut microbiota, activates nitric oxide dismutase leucine-rich repeats and pyrin 3 (NLRP3) inflammatory bodies, increases the release of intracellular calcium ions [72], accelerates the formation of aortic lesions by activating Farnesoid X receptors (FXRs) [73], and activates the protein kinase C/NF-kB (canonical NF-kB)/vascular cell adhesion molecule-1 pathway. At the same time, TMAO inhibits the ROS-thioredoxin interactive protein axis [74]. All these reactions promote AS [75]. TMAO also upregulates CD36 expression and the ATP-binding cassette transporter A1 in macrophages, resulting in the accumulation of cholesterol [76], and alters the electrophysiology in arteries [77].
Mucin production generally decreases with age as goblet cells become inactive [78]. Drastic changes in the expression of mucin may lead to an imbalance in microbiota, overgrowth of pathogens, changes in anti-inflammatory regulatory networks, and, ultimately, intestinal disease [79]. Sialic acid Neu5AC, produced by IECs, regulates the texture of mucus and is thus indirectly responsible for the adhesion of microorganisms [80]. Commensal gut bacteria stimulate mucin glycan production and the formation of new goblet cells. Apart from keeping the GIT in a homeostatic state, mucus also prevents the apoptosis of IECs and helps to maintain the integrity of the gut wall [80]. Other changes that occur with an aging gut are the loss of interstitial cells of Cajal [81], a reduction in cholinergic motor nerve functions [82], loss of enteric glial cells [83], an increase in senescence-like activity within myenteric nerve cell bodies [84], and an increase in total collagen content within muscles and the submucosal plexus [85].
Toll-like receptors and C-type lectin receptors on cell surfaces and the cytosolic nucleotide-binding oligomerisation domain, also known as NLRs, play a role in compartmentalisation and segregation of the commensal microbiota [86]. NLRs sense microbial infection through the recognition of MAMPs, which leads to activation of the innate immune response and the upregulation of key pro-inflammatory pathways, including interleukin (IL)-1β production and translocation of nuclear factor-κB (NF-κB) to the nucleus [87]. Activation of NF-κB leads to an increase in the expression of genes that regulate inflammatory and immune responses. Typical examples are the production of IL-8 and the pro-inflammatory mediator tumour necrosis factor α (TNF-α), which in turn results in the recruitment and activation of neutrophils [87]. TNF-α is synthesised by Paneth cells, located adjacent to the stem cell zone in the base of the crypts of Lieberkühn in the small intestine. Paneth cells also secrete microbicidal peptides (predominantly cryptdins) when in contact with Gram-negative or Gram-positive bacteria, lipopolysaccharide (LPS), lipoteichoic acid (LTA), lipid A, and muramyl dipeptide (MDP), a peptidoglycan fragment [88]. MDP activates NOD2, which in turn induces Paneth cells to produce defensins, i.e., small cysteine-rich cationic antimicrobial proteins [89]. Activation of NOD1 receptors by peptidoglycan stimulates lymphoid follicles and activates neutrophils [89,90]. The importance of NOD in the regulation of the gut microbiome is evident from studies that showed a deficiency in NOD2 correlated with increased numbers of Bacteroidota and Bacillota [90].
Antigens that cross the epithelial barrier interact with immune cells in the lymphoid tissue, induce an immune response, and are then transported from the intestinal lumen across the epithelial cell layer using enterocytes, M-cells, and DC pathways [91]. Antigen-presenting DCs are in direct contact with commensal microbiota and respond by the expression of TLRs and NLRs, activating naïve T-cells into effector T-cells (TH1, TH2, and TH17) or Treg [92]. An increase in lipopolysaccharide (LPS)-producing bacteria in the elderly activates TLRs and increases the degradation of mucous layers. Failure to maintain the defence against pathogens leads to changes in the permeability of IECs, which may lead to the development of bacteraemia and inflammation of the gut wall [93]. Paneth cells are induced by commensal strains, such as Bacteroides thetaiotaomicron, to produce angiogenin-4 (Ang4), which has antibacterial activity [94]. A decline in Bacteriodota, as observed in individuals with AS, may compromise the production of Ang4.
Production of IL-18 is crucial to repair epithelial cells and maintain the epithelial cell barrier [95]. The inflammasome is activated by SCFA-producing bacteria and activates CASPASE-1, a protease responsible for processing pro-IL-1β and pro-IL-18 [80]. Immune and epithelial cells express NLRP3 and NLRP6 inflammasomes, respectively. The NLRP6 epithelial inflammasome prevents microbial dysbiosis and development of inflammatory diseases such as ulcerative colitis by the production of IL-18. Pro-inflammatory cytokines induce TH1 and TH17 immune responses and activate neutrophils and macrophages to prevent infection. The activation of CASPASE-1 may also lead to pyroptosis, which is cell death with combined characteristics of necrosis and apoptosis. However, stimuli causing the activation of inflammasomes, and subsequently CASPASE-1, do not necessarily lead to CASPASE-1-associated epithelial cell death [96].
Early stages of blood clotting are initiated by the interaction between plasma kallikrein and factor XII, resulting in the release of the nanopeptide bradykinin. This increases the permeability of arterial walls, leading to leakage and inflammation, as reviewed by Dicks [18]. Intestinal health and lipid oxidation play critical roles in CVD [18]. Plasminogen activator inhibitor (PAI)-1, produced by endothelial cells (ECs), VSMCs, adipocytes, and platelets, decreases fibrinolysis and promotes clot formation. Urokinase plasminogen activator (uPA), a serine protease, converts inactive plasminogen into active plasmin. The protein epidermal growth factor receptor (EGFR) is involved in cell signaling pathways, cell division, and survival. Paraoxonases (PONs), especially PON1, protect LDL and outer cell membranes against oxidative modifications. PON2 lowers ROS, represses apoptosis, and protects mitochondria against oxidative stress [18]. PON3 interacts with apolipoprotein A-1(apoA1)-HDL, in a similar process to that described for PON1, and is strongly associated with microbial diversity and their metabolic pathways, especially the biosynthesis of antioxidant vitamin B1 [18].
Epithelial cellular adhesion molecule (Ep-CAM) and trefoil factor 3 (TFF3), a small peptide, secreted by intestinal goblet cells, keep intestinal epithelial cells (IECs) fused, prevent mucosal infections [97], and help repair the intestinal mucosa [98]. However, more recent research has linked TFF3 to cancer, colitis, gastric ulcers, diabetes mellitus, non-alcoholic fatty liver disease (NAFLD), and abnormalities of the CNS [98]. We do know that changes in Ep-CAM levels have an impact on the production of alpha-1,2-fucosyltransferase 2 (FUT2) and influence the composition of the gut microbiome [99].
A recent study [100] has shown that imidazole propionate (ImP), produced by gut microbiota, induced AS without altering lipid compositions. Supplementation of diets with ImP increased the development of AS in the aorta and aortic root without affecting circulating cholesterol or glucose concentrations. The binding of AS to the imidazoline-1 receptor (I1R, also known as nischarin), present in myeloid cells, induced phosphorylation of ribosomal protein S6 (pS6), a downstream target of the mammalian target of the Rapamycin (mTOR) pathway. mTOR, a protein kinase, is involved in regulating cellular metabolism and growth, and survival of macrophages [101,102]. The activation of mTORC1 in macrophages increases inflammation, apoptosis (programmed cell death), and impaired autophagy (cellular recycling), leading to the initiation of AS [103]. mTORC2, on the other hand, plays a protective role in AS by regulating cell survival and restraining the activity of MST1, a serine/threonine kinase and a key component of the Hippo signaling pathway, which contributes to cell death [103]. Furthermore, ImP activated systemic and local innate and adaptive immunity and inflammation [100]. Single-cell RNA-sequencing (scRNA-seq) of aortas from mice treated with ImP for eight weeks showed an increase in fibroblasts, endothelial cells, and immune cells [100]. The increase in immune cells was confirmed by flow cytometry and histological analysis of the aortic root [100]. In mice treated with ImP, clear signs of T cell infiltration in the intima–media layer and an increase in inflammatory macrophages were observed in plaque [100]. In vitro studies on mouse embryonic fibroblasts (MEFs) indicated that ImP activated embryonic fibroblasts by increasing the levels of monocyte chemoattractant protein-1 (MCP-1). The latter recruits monocytes associated with atherogenesis [104]. An increase in bone marrow-derived macrophages (BMDMs) and MEFs suggested that macrophages and fibroblasts are the main targets of ImP [102]. In another study [105], an increase in Clostridium leptum and pathogenic Enterobactericeae was noted in the gut microbiome of elderly people diagnosed with AS. The same study also reported an increase in pathogenic Streptococcus spp. in coronary plaques from the same group of individuals. Earlier studies [106,107] reported the presence of Pseudomonadota (e.g., Enterobacter spp.), Cryseomonas spp., Veillonella spp., Staphylococcus spp., Propionibacterium spp., and Chlamydia spp. in plaques from AS patients. Since these species are endemic to the human gastrointestinal tract [105], these findings suggest that the bacteria translocate to coronary arteries and accumulate in plaque. This may lead to the production of endotoxins in plaque [105]. This is troublesome, as Pseudomonadota and Escherichia coli levels are known to increase in the gastrointestinal tracts (GITs) of the elderly.

5. Immunosenescence in Aging and Atherosclerosis

Immunosenescence refers to the ageing of the immune system. This process is characterized by a decline in adaptive immunity and regulation of antigen-specific processes, specifically a reduction in B- and T cells, as well as changes in antibody production [23]. Aging of the immune system causes an imbalance in hematopoietic stem cells (HSCs), leading to myelopoiesis and a diminished lymphoid cell pool [108]. With aging, fewer naïve T and B cells are produced from bone marrow, and the production of lymphoid progenitor cells declines [109]. Although a reduction in the range of B-cell receptors (BCRs) was reported in the peripheral blood and lymph nodes of elderly individuals, an increase in BCR diversity was noted in spleens of the elderly [110,111,112]. These conflicting results may be due to variations in the ability of aged B cells to respond to IL-7, which they require for survival [113,114]. Adaptation to the SASP leads to the release of MMP-9 by ASMCs and an upregulation of the inflammasome [21,29]. Smooth muscle cells and healthy ECs increase the release of pro-inflammatory cytokines, which results in chronic low-level inflammation, referred to as “inflammaging” [115].
AS, normally associated with the elderly, is a lipid-driven chronic inflammatory process [114]. Damaged endothelia are infiltrated by lipids and immune cells, leading to plaque formation [8,18], a disruption in blood flow, thrombosis, and myocardial infarction (MI) [9]. CD4+ cells differentiate into helper T (Th) cells, with Th1 cells expressing interferon-γ (INF-γ) [25]. Th2 cells produce IL-4, IL-5, and IL-13, which neutralize INF-γ, as summarized in Figure 2 [25]. TET-2-deficient macrophages release NLRP3 inflammasome-mediated IL-1β, which increases the size of plaques [116]. Changes in the gut microbiome, which are inevitable with aging, change the expression of TLRs and NLRs by DCs in direct contact with gut microbiota. Naïve T-cells transgress to effector T-cells (TH1, TH2, and TH17) or Treg [92]. Regulatory T cells (Tregs) produce IL-10 and TGF-β, which inhibit pro-atherogenic effector T cells and stimulate efferocytosis by macrophages [117]. In ageing endothelial membranes, as with AS, negatively charged side chains (biglycan, versican, perlecan, and lumican) are linked to positively charged lipoproteins, specifically apolipoprotein B, which attaches to ox-LDL (Figure 3) [28]. Tregs may act autoreactively to apolipoprotein B and help suppress inflammation, thus preventing AS. With the progression of AS, the protective role of Tregs may decline, and they may produce pro-inflammatory cytokines, which stimulate immune responses against apolipoprotein and aggravate plaque formation [118]. AS is also associated with the accumulation of damaged DNA, as specifically noted in peripheral blood lymphocytes. This correlates with diabetes and hypercholesterolemia [119]. For further information on adaptive immunity, immunosenescence, and AS, the reader is referred to the comprehensive reviews by Snijckers and Foks [114] and Liu et al. [120].

6. The Link Between Butyrate and Atherosclerosis (AS)

An increase in Bacillota (associated with high caloric intake) and a decrease in Bacteroidota (associated with anti-inflammatory effects) may stimulate the production of proinflammatory cytokines and increase cholesterol levels, both of which are risk factors for AS [46,121]. Several studies have shown that butyrate-producing bacteria such as Bifidobacterium, Lactobacillus, Enterococcus, Lachnospiraceae, Ruthenibacterium, Flavonifractor, Ruminococcus, Faecalibacterium, Roseburia, Eubacterium, Anaerostipes, Coprococcus, Subdoligranulum, Anaerobutyricum, and Oscillospira activate the TLR4 pathway, increase nicotinamide adenine dinucleotide phosphate (NADPH), and activate NF-κB and MAPK pathways, as summarised in Figure 4 [52,54,122]. Bacteria associated with AS are listed in Table 1. Bacterial DNA may also trigger macrophages and activate the innate immune system via TLR2 and TLR4 [123,124]. The upregulation of these pathways leads to an increase in proinflammatory cytokines, and the formation of plaques (Figure 4) [125]. By increasing NF-κB, endothelial nitric oxide synthase (eNOS) is activated, and NO levels increase (Figure 4). NO relaxes VSMCs and may ease the restriction of arteries [126].
Butyrate prevents the infiltration of macrophages into VSMCs (Figure 4) [23,127] and decreases the production of pro-inflammatory cytokines, which suppresses plaque formation (Figure 4) [8,128]. Depending on the inflammatory stimuli, butyrate may inactivate NF-κB, suppress proinflammatory cytokines, and stimulate anti-inflammatory cytokines (Figure 4). Butyrate may regulate MAPK to suppress inflammation, muscle cell growth, apoptosis, and the uptake of ox-LDL by macrophages [8,129]. Binding of butyrate to peroxisome proliferator-activated receptor γ (PPARγ) increases the activity of IkBα, thereby inhibiting the production of NF-κB (Figure 4) [8]. This, along with the ligation of PPARγ with p65, degrades the NF κB/p65 complex [8], resulting in downregulation of the NF-κB pathway [8], the suppression of pro-inflammatory cytokines, and an increase in anti-inflammatory cytokines (Figure 4) [8,128]. Butyrate may also exert anti-inflammatory activities by inhibiting interferon γ (IFN-γ) signalling (Figure 4). This suppresses the activity of CD36 and decreases the uptake of ox-LDL by macrophages (Figure 4) [8,128,129]. Furthermore, butyrate suppresses the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, which alleviates inflammation and scar tissue formation (Figure 4) [8]. The opposite is true for TET-2-deficient macrophages. They increase the release of NLRP3 inflammasome-mediated IL-1β, resulting in the formation of larger plaques (Figure 4).
Table 1. Evidence supporting the link between gut microbiota and atherosclerosis a.
Table 1. Evidence supporting the link between gut microbiota and atherosclerosis a.
BacteriaSourceMethodologyReferences
Collinsella spp., Enterobacteriaceae, Streptococcaceae, Klebsiella spp.
(Eubacterium spp., Roseburia spp., Ruminococcaceae)		HumanMetagenome sequencing[130]
(Bacteroides xylanisolvens, Odoribacter splanchnicus, Eubacterium eligens, Roseburia inulinivorans, Roseburia intestinalis)HumanMetagenome sequencing[131]
Firmicutes phylum
(Bacteroidetes)		Human16S rRNA sequencing[132]
Streptococcus spp., Escherichia coli, Lactobacillus salivarius, Solobacterium moorei, Atopobium parvulum, Ruminococcus gnavus, Eggerthella lenta
(Bacteroides spp., Prevotella spp., Roseburia intestinalis, Faecalibacterium prausnitzii, Bacteroides spp., Prevotella copri, Alistipes shahii)		HumanMetagenome sequencing[133]
Escherichia coli, Shigella spp., Enterococcus spp.
(Faecalibacterium spp., Subdoligranulum spp., Roseburia spp., Eubacterium rectale)		Human16S rRNA sequencing[134]
Clostridium sp. HGF2, Streptococcus sp. M334, Streptococcus sp. M143HumanMetagenome sequencing[135]
Faecalibacterium prausnitzii, Prevotella copri
(Bacteroides vulgatus, Bacteroides dorei)		Human16S rRNA sequencing[136]
(Bacteroides xylanisolvens, Odoribacter splanchnicus, Eubacterium eligens, Roseburia inulinivorans, Roseburia intestinalis)Human16S rRNA sequencing[137]
Enterorhabdus spp., Romboutsia spp., Proteus spp., Eubacterium nodatum, Escherichia spp., Shigella spp., Eubacterium coprostanoligenes, Parasutterella spp., Muribaculum spp., Enterococcus spp.
(Bifidobacterium spp., Alistipes spp.)		Mice16S rRNA sequencing[138]
Proteobacteria, Firmicutes, Romboutsia spp., Lactococcus spp.
(Bacteroidetes, Actinobacteria, Faecalibaculum spp., Bifidobacterium spp., Bacteroides spp., Parabacteroides spp., Alloprevotella spp., Alistipes spp., Odoribacter spp., Allobaculum spp.)		Mice16S rRNA sequencing[139]
Firmicutes, Faecalibaculum spp., Oscillibacter spp., Eubacterium coprostanoligenes-group, Blautia spp.
(Muribaculaceae, Lactobacillus spp., Ileibacterium spp., Bifidobacterium spp.)		Mice16S rRNA sequencing[140]
Firmicutes, Bacteroidota, Lactobacillaceae, Lactobacillus spp., Helicobacter spp.
(Lachnospiraceae, Roseburia spp.)		Mice16S rRNA sequencing[141]
Firmicutes, Bacteroidota, Verrucomicrobia, Ruminococcaceae, Bacteroidaceae, Bacteroides spp., Akkermansia spp.
(Rikenellaceae)		Mice16S rRNA sequencing[142]
Firmicutes, Lactobacillus spp.
(Bacteroidetes; Bifidobacterium spp.)		Mice16S rRNA sequencing[143]
a Names in brackets refer to less dominant microbiota.

7. Limitations in Studies Linking Gut Microbiota to Atherosclerosis

Adequate evidence exists linking the gut microbiome to AS. However, the inconsistency in species identifications, mainly due to variations in identification techniques, makes it difficult to ascribe AS and aging to a specific group of gut microbiota. The discrepancies in data are also due to differences in diets and the influence of external factors such as stress and genetic background. Many studies rely on 16S rRNA sequencing to compare species and strain variations. Although useful in some studies, this technique has a poor discriminatory ability for some genera and does not identify variations amongst strains in the same taxon. The inability to identify small genetic variations in strains associated with AS renders it difficult, if not impossible, to understand intercellular interactions and develop a drug that would suppress the growth of atherosclerogenic gut bacteria. Most gut microbiome studies are performed on a small group of individuals, often from the same geographic region, following a specific diet. Findings are seldom followed up over extended periods and do not provide data on changes in the gut microbiome, e.g., the adaptation of gut microbiota to specific treatments. This is important to understand the bidirectional relationship between gut microbiota, aging, and cardiovascular health. Longitudinal follow-up studies will also determine whether changes in the gut microbiome are due to interventions or due to age-related changes, e.g., the development of AS. A typical example is changes observed in TMAO levels and the clarification of the findings. Is an increase in TMAO causing AS, or is it a marker pointing to other underlying medical conditions? Do we have a solid understanding of conditions leading to intestinal inflammation, an aging epithelium, and the translocation of bacteria and their products into the bloodstream that may exacerbate AS? By addressing these and other limitations in study designs, we may have a more comprehensive understanding of the complex interplay between gut microbiota and atherosclerosis, potentially leading to more effective prevention and treatment strategies.

8. Future Directions

More research is required on the aging gut wall and metabolites that cause AS. Changes in gut microbiota need to be studied using metagenomics, metabolomics, and proteomics. We need to understand how age-related changes in immune responses (immunosenescence) relate to dysfunctional ECs and the development of AS. Research needs to focus on conducting more targeted interventions aimed at drug design, slowing immunosenescence, and AS. The focus should be on selectively eliminating or modulating “senescent” T and B cells associated with chronic inflammation and vascular damage. We need to identify specific inflammatory markers and signalling pathways involved in these processes. The role of NAD+ (specifically its decline with age) in AS must be studied. Further studies need to be performed on cyclin-dependent kinase inhibitors, senescence-associated β-galactosidase, the proteins p53, p21cip1, ataxia-telangiectasia mutated protein, ataxia telangiectasia, and Rad3-related protein, and phosphorylated histone H2AX as markers of cellular senescence. We need to determine why cells lose their ability to grow when in a senescent state.

9. Conclusions

Accumulating evidence from preclinical and clinical studies has shown that the gut microbiome plays an important role in host health and disease. The more we learn about microbial interactions with intestinal epithelial cells and endothelial cells (ECs) in arteries, the closer we become to developing reporter systems to identify atherosclerosis at an earlier stage and develop drugs to treat cardiovascular diseases (CVDs). Microbial-derived biomarkers such as lipopolysaccharides (LPS) and trimethylamine-N-oxide (TMAO) are indicators of atherosclerosis (AS), but other reporters need to be developed. The elderly are more prone to developing AS. The reason for this may be attributed to a changing gut microbiome, associated with a decline in butyrate-producing bacteria. Binding of butyrate to peroxisome proliferator-activated receptor γ (PPARγ) increases the activity of IkBα (nuclear factor kappa-B, NF-κB, inhibitor). This suppresses the production of pro-inflammatory cytokines that cause AS and activates endothelial nitric oxide synthase (eNOS), leading to an increase in nitric oxide (NO), which dilates arteries. Butyrate may regulate mitogen-activated protein kinase (MAPK) to suppress inflammation, muscle cell growth, apoptosis, and the uptake of oxidised low-density lipoprotein (ox-LDL) by macrophages. Butyrate suppresses inflammation by inhibiting interferon γ (IFN-γ), Toll-like receptor 2 (TLR2), and platelet glycoprotein (CD36) signalling. By suppressing CD36, the uptake of ox-LDL by macrophages is prevented, and plaque formation is repressed. Furthermore, butyrate suppresses the NOD-, LRR-, and Nod-like receptor protein 3 (NLRP3) inflammasome, which alleviates inflammation and scar tissue formation. TET methylcytosine dioxygenase 2 (TET-2)-deficient macrophages increase the release of NLRP3 inflammasome-mediated IL-1β, resulting in the formation of larger plaques. The inhibition of interferon gamma (INF-γ) and NLRP3 prevents plaque formation. The elderly are more prone to chronic inflammation, including the recruitment of immune cells to damaged ECs, the deposition of foam cells on the intima, and plaque formation. Furthermore, the release of senescence-associated secretory phenotype (SASP) factors from aged vascular smooth muscle cells (VSMCs) induces the production of pro-inflammatory cytokines and stimulates foam cells to infiltrate arteries. Elevated levels of SASP and matrix metalloproteinase-9 (MMP-9) stimulate the lysis of collagen and the degradation of elastin, potentially causing plaque rupture and thrombosis. The release of damage-associated molecular patterns (DAMPs), free radicals, and reactive oxygen species (ROS) enhances inflammation and deprives the myocardium of O2, potentially causing myocardial infarction (MI). As butyrate levels decline, the growth of VSMCs is less controlled, and the uptake of ox-LDL by VSMCs is not prevented. Maintaining butyrate-producing bacteria in the gastrointestinal tract may suppress AS.

Funding

This research received no external funding.

Conflicts of Interest

The author declares no conflicts of interest.

References

  1. Wong, J.J.; Hong, R.; Teo, L.L.Y.; Tan, R.-S.; Koh, A.S. Atherosclerotic cardiovascular disease in aging and the role of advanced cardiovascular imaging. npj Cardiovasc. Health 2024, 1, 11. [Google Scholar] [CrossRef]
  2. Afzaal, M.; Saeed, F.; Shah, Y.A.; Hussain, M.; Rabail, R.; Socol, C.T.; Hassoun, A.; Pateiro, M.; Lorenzo, J.M.; Rusu, A.V.; et al. Human gut microbiota in health and disease: Unveiling the relationship. Front. Microbiol. 2022, 13, 999001. [Google Scholar] [CrossRef]
  3. López-Otín, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. Hallmarks of aging: An expanding universe. Cell 2023, 186, 243–278. [Google Scholar] [CrossRef]
  4. Lu, A.T.; Fei, Z.; Haghani, A.; Robeck, T.R.; Zoller, J.A.; Li, C.Z.; Lowe, R.; Yan, Q.; Zhang, J.; Vu, H.; et al. Universal DNA methylation age across mammalian tissues. Nat. Aging 2023, 3, 1144–1166, Correct in Nat. Aging 2023, 3, 1462. [Google Scholar] [CrossRef]
  5. Li, A.; Koch, Z.; Ideker, T. Epigenetic aging: Biological age prediction and informing a mechanistic theory of aging. J. Intern. Med. 2022, 292, 733–744. [Google Scholar] [CrossRef]
  6. Tenchov, R.; Sasso, J.M.; Wang, X.; Zhou, Q.A. Aging hallmarks and progression and age-related diseases: A landscape view of research advancement. ACS Chem. Neurosci. 2024, 15, 1–30. [Google Scholar] [CrossRef]
  7. Vellasamy, D.M.; Lee, S.J.; Goh, K.W.; Goh, B.H.; Tang, Y.Q.; Ming, L.C.; Yap, W.H. Targeting immune senescence in atherosclerosis. Int. J. Mol. Sci. 2022, 23, 13059. [Google Scholar] [CrossRef]
  8. Dicks, L.M.T. Butyrate produced by gut microbiota regulates atherosclerosis: A narrative review of the latest findings. Int. J. Mol. Sci. 2025, 26, 6744. [Google Scholar] [CrossRef]
  9. Pahwa, R.; Goyal, A.; Jialal, I. Chronic Inflammation. In StatPearls; Updated 7 August 2023; StatPearls Publishing: Treasure Island, FL, USA, 2025. Available online: https://www.ncbi.nlm.nih.gov/books/NBK493173/ (accessed on 4 July 2025).
  10. Ding, W.; Chen, J.; Zhao, L.; Wu, S.; Chen, X.; Chen, H. Mitochondrial DNA leakage triggers inflammation in age-related cardiovascular diseases. Front. Cell Dev. Biol. 2024, 12, 1287447. [Google Scholar] [CrossRef] [PubMed]
  11. Xia, T.; Yu, J.; Du, M.; Chen, X.; Wang, C.; Li, R. Vascular endothelial cell injury: Causes, molecular mechanisms, and treatments. MedComm 2025, 6, e70057. [Google Scholar] [CrossRef] [PubMed]
  12. Bleve, A.; Motta, F.; Durante, B.; Pandolfo, C.; Selmi, C.; Sica, A. Immunosenescence, inflammaging, and frailty: Role of myeloid cells in age-related diseases. Clin. Rev. Allergy Immunol. 2023, 64, 123–144. [Google Scholar] [CrossRef]
  13. Farooq, M.; Khan, A.W.; Kim, M.S.; Choi, S. The role of fibroblast growth factor (FGF) signaling in tissue repair and regeneration. Cells 2021, 10, 3242. [Google Scholar] [CrossRef]
  14. Eichhorn, T.; Weiss, R.; Huber, S.; Ebeyer-Masotta, M.; Mostageer, M.; Emprechtinger, R.; Knabl, L., Sr.; Knabl, L.; Würzner, R.; Weber, V. Expression of tissue factor and platelet/leukocyte markers on extracellular vesicles reflect platelet-leukocyte interaction in severe COVID-19. Int. J. Mol. Sci. 2023, 24, 16886. [Google Scholar] [CrossRef]
  15. Manetti, M.; Kahaleh, B. Mechanisms of vascular disease. In Scleroderma; Allanore, Y., Varga, J., Denton, C.P., Kuwana, M., Chung, L., Shah, A.A., Eds.; Springer: Cham, Switzerland, 2024. [Google Scholar] [CrossRef]
  16. Dunn, W.G.; McLoughlin, M.A.; Vassiliou, G.S. Clonal hematopoiesis and hematological malignancy. J. Clin. Investig. 2024, 134, e180065. [Google Scholar] [CrossRef] [PubMed]
  17. Barbu, E.; Popescu, M.R.; Popescu, A.C.; Balanescu, S.M. Inflammation as a precursor of atherothrombosis, diabetes and early vascular aging. Int. J. Mol. Sci. 2022, 23, 963. [Google Scholar] [CrossRef] [PubMed]
  18. Dicks, L.M.T. Cardiovascular disease may be triggered by gut microbiota, microbial metabolites, gut wall reactions, and inflammation. Int. J. Mol. Sci. 2024, 25, 10634. [Google Scholar] [CrossRef] [PubMed]
  19. Tacconi, E.; Palma, G.; De Biase, D.; Luciano, A.; Barbieri, M.; de Nigris, F.; Bruzzese, F. Microbiota effect on trimethylamine N-oxide production: From cancer to fitness—A practical preventing recommendation and therapies. Nutrients 2023, 15, 563. [Google Scholar] [CrossRef]
  20. Ramachandran, R.; Manan, A.; Kim, J.; Choi, S. NLRP3 inflammasome: A key player in the pathogenesis of life-style disorders. Exp. Mol. Med. 2024, 56, 1488–1500. [Google Scholar] [CrossRef]
  21. Puspitasari, Y.M.; Ministrini, S.; Schwarz, L.; Karch, C.; Liberale, L.; Camici, G.G. Modern concepts in cardiovascular disease: Inflamm-Aging. Front. Cell Dev. Biol. 2022, 10, 882211. [Google Scholar] [CrossRef]
  22. Pal, R.; Bhadada, S.L. AGEs accumulation with vascular complications, glycemic control and metabolic syndrome: A narrative review. Bone 2023, 176, 116884. [Google Scholar] [CrossRef]
  23. Booth, J.S.; Toapanta, F.R. B and T Cell Immunity in Tissues and Across the Ages. Vaccines 2021, 9, 24. [Google Scholar] [CrossRef] [PubMed]
  24. Taleb, S. Inflammation in atherosclerosis. Arch. Cardiovasc. Dis. 2016, 109, 708–715. [Google Scholar] [CrossRef]
  25. He, C.; Kim, H.I.; Park, J.; Guo, J.; Huang, W. The role of immune cells in different stages of atherosclerosis. Int. J. Med. Sci. 2024, 21, 1129–1143. [Google Scholar] [CrossRef]
  26. Zhou, B.; Lin, W.; Long, Y. Notch signaling pathway: Architecture, disease, and therapeutics. Signal Transduct. Target. Ther. 2022, 7, 95. [Google Scholar] [CrossRef]
  27. Qian, C.; You, X.; Gao, B.; Sun, Y.; Liu, C. The role of ROS in atherosclerosis and ROS-based nanotherapeutics for atherosclerosis: Atherosclerotic lesion targeting, ROS scavenging, and ROS-responsive activity. ACS Omega 2025, 10, 22366–22381. [Google Scholar] [CrossRef]
  28. Galimberti, F.; Casula, M.; Olmastrini, E. Apolipoprotein B compared with low-density lipoprotein cholesterol in the atherosclerotic cardiovascular diseases risk assessment. Pharmacol. Res. 2023, 95, 106873. [Google Scholar] [CrossRef]
  29. Picos, A.; Seoane, N.; Campos-Toimil, M.; Viña, D. Vascular senescence and aging: Mechanisms, clinical implications, and therapeutic prospects. Biogerontology 2025, 26, 118. [Google Scholar] [CrossRef]
  30. Sun, Y.; Wang, X.; Liu, T.; Zhu, X.; Pan, X. The multifaceted role of the SASP in atherosclerosis: From mechanisms to therapeutic opportunities. Cell Biosci. 2022, 12, 74. [Google Scholar] [CrossRef] [PubMed]
  31. Cobo, I.; Tanaka, T.N.; Mangalhara, K.C.; Lana, A.; Yeang, C.; Han, C.; Schlachetzki, J.; Challcombe, J.; Fixsen, B.R.; Sakai, M.; et al. DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages. Immunity 2022, 55, 1386–1401. [Google Scholar] [CrossRef]
  32. Ghamar Talepoor, A.; Doroudchi, M. Immunosenescence in atherosclerosis: A role for chronic viral infections. Front. Immunol. 2022, 13, 945016. [Google Scholar] [CrossRef] [PubMed]
  33. Dicks, L.M.T. How important are fatty acids in human health and can they be used in treating diseases? Gut Microbes 2024, 16, 2420765. [Google Scholar] [CrossRef] [PubMed]
  34. Rinninella, E.; Raoul, P.; Cintoni, M.; Franceschi, F.; Miggiano, G.A.D.; Gasbarrini, A.; Mele, M.C. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms 2019, 7, 14. [Google Scholar] [CrossRef]
  35. de Crom, S.C.M.; Rossen, J.W.A.; van Furth, A.M.; Obihara, C.C. Enterovirus and parechovirus infection in children: A brief overview. Eur. J. Pediatr. 2016, 175, 1023–1029. [Google Scholar] [CrossRef]
  36. Kapoor, A.; Li, L.; Victoria, J. Multiple novel astrovirus species in human stool. J. Gen. Virol. 2009, 90, 2965–2972. [Google Scholar] [CrossRef]
  37. Ahmed, S.M.; Hall, A.J.; Robinson, A.E. Global prevalence of Norovirus in cases of gastroenteritis: A systematic review and meta-analysis. Lancet Infect. Dis. 2014, 14, 725–730. [Google Scholar] [CrossRef] [PubMed]
  38. Lecuit, M.; Eloit, M. The viruses of the gut microbiota. In The Microbiota in Gastrointestinal Pathophysiology; Academic Press: Cambridge, MA, USA, 2017; pp. 179–183. [Google Scholar]
  39. Rosenberg, E. Diversity of bacteria within the human gut and its contribution to the functional unity of holobionts. npj Biofilms Microbiomes 2024, 10, 134. [Google Scholar] [CrossRef] [PubMed]
  40. Coscia, A.; Bardanzellu, F.; Caboni, E.; Fanos, V.; Peroni, D.G. When a neonate is born, so is a microbiota. Life 2021, 11, 148. [Google Scholar] [CrossRef]
  41. Dicks, L.M.T.; Hurn, D.; Hermanus, D. Gut bacteria and neuropsychiatric disorders. Microorganisms 2021, 9, 2583. [Google Scholar] [CrossRef]
  42. Wang, J.; Lin, L. Early-life gut microbiota development from maternal vertical transmission. Gynecol. Obstet. Clin. Med. 2021, 1, 79–82. [Google Scholar] [CrossRef]
  43. Crovesy, L.; Masterson, D.; Rosado, E.L. Profile of the gut microbiota of adults with obesity: A systematic review. Eur. J. Clin. Nutr. 2020, 74, 1251–1262. [Google Scholar] [CrossRef]
  44. Roswall, J.; Olsson, L.M.; Kovatcheva-Datchary, P.; Nilsson, S.; Tremaroli, V.; Simon, M.-C.; Kiilerich, P.; Krämer, A.M.; Uhlén, M.; Gummesson, A.; et al. Developmental trajectory of the healthy human gut microbiota during the first 5 years of life. Cell Host Microbe 2021, 29, 765–776.e3. [Google Scholar] [CrossRef]
  45. Severino, A.; Tohumcu, E.; Tamai, L.; Dargenio, P.; Porcari, S.; Rondinella, D.; Venturini, I.; Maida, M.; Gasbarrini, A.; Cammarota, G.; et al. The microbiome-driven impact of western diet in the development of noncommunicable chronic disorders. Best Pract. Res. Clin. Gastroenterol. 2024, 72, 101923. [Google Scholar] [CrossRef]
  46. Magne, F.; Gotteland, M.; Gauthier, L.; Zazueta, A.; Pesoa, S.; Navarrete, P.; Balamurugan, R. The Firmicutes/Bacteroidetes ratio: A relevant marker of gut dysbiosis in obese patients? Nutrients 2020, 12, 1474. [Google Scholar] [CrossRef]
  47. Desai, M.S.; Seekatz, A.M.; Koropatkin, N.M.; Kamada, N.; Hickey, C.A.; Wolter, M.; Pudlo, N.A.; Kitamoto, S.; Terrapon, N.; Muller, A.; et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 2016, 167, 1339–1353. [Google Scholar] [CrossRef]
  48. Chen, D.; Wu, L.; Liu, X. Helicobacter pylori CagA mediated mitophagy to attenuate the NLRP3 inflammasome activation and enhance the survival of infected cells. Sci. Rep. 2024, 14, 21648. [Google Scholar] [CrossRef]
  49. Baragetti, A.; Severgnini, M.; Olmastroni, E.; Dioguardi, C.C.; Mattavelli, E.; Angius, A.; Rotta, L.; Cibella, J.; Caredda, G.; Consolandi, C.; et al. Gut microbiota functional dysbiosis relates to individual diet in subclinical carotid atherosclerosis. Nutrients 2021, 13, 304. [Google Scholar] [CrossRef] [PubMed]
  50. Ji, L.; Chen, S.; Gu, G.; Zhou, J.; Wang, W.; Ren, J.; Wu, J.; Yang, D.; Zheng, Y. Exploration of crucial mediators for carotid atherosclerosis pathogenesis through integration of microbiome, metabolome, and transcriptome. Front. Physiol. 2021, 12, 645212. [Google Scholar] [CrossRef] [PubMed]
  51. Meslier, V.; Laiola, M.; Roager, H.M.; De Filippis, F.; Roume, H.; Quinquis, B.; Giacco, R.; Mennella, I.; Ferracane, R.; Pons, N.; et al. Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake. Gut 2020, 69, 1258–1268. [Google Scholar] [CrossRef] [PubMed]
  52. Singh, V.; Lee, G.; Son, H.; Koh, H.; Kim, E.S.; Unno, T.; Shin, J.H. Butyrate producers, “The Sentinel of Gut”: Their intestinal 2ignificance with and beyond butyrate, and prospective use as microbial therapeutics. Front. Microbiol. 2023, 13, 1103836. [Google Scholar] [CrossRef]
  53. Odamaki, T.; Kato, K.; Sugahara, H.; Hashikura, N.; Takahashi, S.; Xiao, J.Z.; Abe, F.; Osawa, R. Age-related changes in gut microbiota composition from newborn to centenarian: A cross-sectional study. BMC Microbiol. 2016, 16, 90. [Google Scholar] [CrossRef]
  54. Furusawa, Y.; Obata, Y.; Fukuda, S.; Endo, T.A.; Nakato, G.; Takahashi, D.; Nakanishi, Y.; Uetake, C.; Kato, K.; Kato, T.; et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013, 504, 446–450, Erratum in Nature 2013, 504, 254. [Google Scholar] [CrossRef]
  55. Salazar, N.; Arboleya, S.; Fernandez-Navarro, T.; de Los, C.G.; Gonzalez, S.; Gueimonde, M. Age-associated changes in gut microbiota and dietary components related with the immune system in adulthood and old age: A cross-sectional study. Nutrients 2019, 11, 11. [Google Scholar] [CrossRef] [PubMed]
  56. Ragonnaud, E.; Biragyn, A. Gut microbiota as the key controllers of “healthy” aging of elderly people. Immun. Ageing 2021, 18, 2. [Google Scholar] [CrossRef] [PubMed]
  57. Lu, Z.; Imlay, J.A. When anaerobes encounter oxygen: Mechanisms of oxygen toxicity, tolerance and defence. Nat. Rev. Microbiol. 2021, 19, 774–785. [Google Scholar] [CrossRef]
  58. DeJong, E.N.; Surette, M.G.; Bowdish, D. The gut microbiota and unhealthy aging: Disentangling cause from consequence. Cell Host Microbe 2020, 28, 180–189. [Google Scholar] [CrossRef]
  59. Kanimozhi, N.V.; Sukumar, M. Aging through the lens of the gut microbiome: Challenges and therapeutic opportunities. Arch. Gerontol. Geriatr. Plus 2025, 2, 100142. [Google Scholar] [CrossRef]
  60. Zhao, M.; Chu, J.; Feng, S.; Guo, C.; Xue, B.; He, K.; Li, L. Immunological mechanisms of inflammatory diseases caused by gut microbiota dysbiosis: A review. Biomed. Pharmacother. 2023, 64, 114985. [Google Scholar] [CrossRef]
  61. Xiao, M.; Zhang, C.; Duan, H. Cross-feeding of bifidobacteria promotes intestinal homeostasis: A lifelong perspective on the host health. npj Biofilms Microbiomes 2024, 10, 47. [Google Scholar] [CrossRef]
  62. Martins, D.; Silva, C.; Ferreira, A.C.; Dourado, S.; Albuquerque, A.; Saraiva, F.; Batista, A.B.; Castro, P.; Leite-Moreira, A.; Barros, A.S.; et al. Unravelling the gut microbiome role in cardiovascular disease: A systematic review and a meta-analysis. Biomolecules 2024, 14, 731. [Google Scholar] [CrossRef]
  63. Zhang, S.M.; Huang, S.L. The commensal anaerobe Veillonella dispar reprograms its lactate metabolism and short-chain fatty acid production during the stationary phase. Microbiol. Spectr. 2023, 11, e0355822. [Google Scholar] [CrossRef]
  64. Yang, X.; Zhang, M.; Liu, Y.; Wei, F.; Li, X.; Feng, Y.; Jin, X.; Liu, D.; Guo, Y.; Hu, Y. Inulin-enriched Megamonas funiformis ameliorates metabolic dysfunction-associated fatty liver disease by producing propionic acid. npj Biofilms Microbiomes 2024, 9, 84, Correct in npj Biofilms Microbiomes 2024, 10, 9. [Google Scholar] [CrossRef]
  65. Sayols-Baixeras, S.; Dekkers, K.F.; Baldanzi, G.; Jönsson, D.; Hammar, U.; Lin, Y.T.; Ahmad, S.; Nguyen, D.; Varotsis, G.; Pita, S.; et al. Streptococcus species abundance in the gut is linked to subclinical coronary atherosclerosis in 8973 participants from the SCAPIS Cohort. Circulation 2023, 148, 459–472. [Google Scholar] [CrossRef]
  66. Wang, L.; Wang, S.; Zhang, Q.; He, C.; Fu, C.; Wei, Q. The role of the gut microbiota in health and cardiovascular diseases. Mol. Biomed. 2022, 3, 30. [Google Scholar] [CrossRef]
  67. Guamán, L.P.; Carrera-Pacheco, S.E.; Zúñiga-Miranda, J.; Teran, E.; Erazo, C.; Barba-Ostria, C. The impact of bioactive molecules from probiotics on child health: A comprehensive review. Nutrients 2024, 16, 3706. [Google Scholar] [CrossRef]
  68. Nie, K.; Ma, K.; Luo, W.; Shen, Z.; Yang, Z.; Xiao, M.; Tong, T.; Yang, Y.; Wang, X. Roseburia intestinalis: A beneficial gut organism from the discoveries in genus and species. Front. Cell. Infect. Microbiol. 2021, 11, 757718. [Google Scholar] [CrossRef] [PubMed]
  69. Rath, S.; Rox, K.; Kleine, B.S.; Schminke, U.; Dorr, M.; Mayerle, J.; Frost, F.; Lerch, M.M.; Karch, A.; Brönstrup, M.; et al. Higher trimethylamine-N-oxide plasma levels with increasing age are mediated by diet and trimethylamine-forming bacteria. mSystems 2021, 6, e94521. [Google Scholar] [CrossRef] [PubMed]
  70. Wong, J.; Piceno, Y.M.; DeSantis, T.Z.; Pahl, M.; Andersen, G.L.; Vaziri, N.D. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am. J. Nephrol. 2014, 39, 230–237. [Google Scholar] [CrossRef] [PubMed]
  71. Wang, X.; Yang, S.; Li, S.; Zhao, L.; Hao, Y.; Qin, J.; Zhang, L.; Zhang, C.; Bian, W.; Zuo, L.; et al. Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents. Gut 2020, 69, 2131–2142. [Google Scholar] [CrossRef]
  72. Zhu, W.; Gregory, J.C.; Org, E.; Buffa, J.A.; Gupta, N.; Wang, Z.; Li, L.; Fu, X.; Wu, Y.; Mehrabian, M.; et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 2016, 165, 111–124. [Google Scholar] [CrossRef]
  73. Ding, L.; Chang, M.; Guo, Y.; Zhang, L.; Xue, C.; Yanagita, T.; Zhang, T.; Wang, Y. Trimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism. Lipids Health Dis. 2018, 17, 286. [Google Scholar] [CrossRef]
  74. Chen, M.L.; Zhu, X.H.; Ran, L.; Lang, H.D.; Yi, L.; Mi, M.T. Trimethylamine-N-oxide induces vascular inflammation by activating the NLRP3 inflammasome through the sirt3-sod2-mtros signaling pathway. J. Am. Heart Assoc. 2017, 6, e003698. [Google Scholar] [CrossRef]
  75. Ma, G.; Pan, B.; Chen, Y.; Guo, C.; Zhao, M.; Zheng, L.; Chen, B. Trimethylamine N-oxide in atherogenesis: Impairing endothelial self-repair capacity and enhancing monocyte adhesion. Biosci. Rep. 2017, 37, BSR20160244. [Google Scholar] [CrossRef]
  76. Li, Y.; Zhang, L.; Ren, P.; Yang, Y.; Li, S.; Qin, X.; Zhang, M.; Zhou, M.; Liu, W. Qing-Xue-Xiao-Zhi formula attenuates atherosclerosis by inhibiting macrophage lipid accumulation and inflammatory response via TLR4/MyD88/NF-κB pathway regulation. Phytomedicine 2021, 93, 153812. [Google Scholar] [CrossRef]
  77. Yu, L.; Meng, G.; Huang, B.; Zhou, X.; Stavrakis, S.; Wang, M.; Li, X.; Zhou, L.; Wang, Y.; Wang, M.; et al. A potential relationship between gut microbes and atrial fibrillation: Trimethylamine N-oxide, a gut microbe-derived metabolite, facilitates the progression of atrial fibrillation. Int. J. Cardiol. 2018, 255, 92–98. [Google Scholar] [CrossRef]
  78. Baidoo, N.; Sanger, G.J. Age-related decline in goblet cell numbers and mucin content of the human colon: Implications for lower bowel functions in the elderly. Exp. Mol. Pathol. 2024, 139, 104923. [Google Scholar] [CrossRef] [PubMed]
  79. Buisine, M.P.; Devisme, L.; Savidge, T.C.; Gespach, C.; Gosselin, B.; Porchet, N.; Aubert, J.P. Mucin gene expression in human embryonic and fetal intestine. Gut 1998, 43, 519–524. [Google Scholar] [CrossRef] [PubMed]
  80. Yao, Y.; Kim, G.; Shafer, S.; Chen, Z.; Kubo, S.; Ji, Y.; Luo, J.; Yang, W.; Perner, S.P.; Kanellopoulou, C.; et al. Mucus sialylation determines intestinal host-commensal homeostasis. Cell 2022, 185, 1172–1188. [Google Scholar] [CrossRef]
  81. Choi, E.L.; Taheri, N.; Tan, E.; Matsumoto, K.; Hayashi, Y. The crucial role of the interstitial cells of Cajal in neurointestinal diseases. Biomolecules 2023, 13, 1358. [Google Scholar] [CrossRef]
  82. Broad, J.; Kung, V.W.S.; Palmer, A.; Elahi, S.; Karami, A.; Darreh-Shori, T.; Ahmed, S.; Thaha, M.A.; Carroll, R.; Chin-Aleong, J.; et al. Changes in neuromuscular structure and functions of human colon during ageing are region-dependent. Gut 2019, 68, 1210–1223. [Google Scholar] [CrossRef] [PubMed]
  83. Baidoo, N.; Sanger, G.J.; Belai, A. Effect of old age on the subpopulations of enteric glial cells in human descending colon. Glia 2023, 71, 305–316. [Google Scholar] [CrossRef]
  84. Palmer, A.; Epton, S.; Crawley, E.; Straface, M.; Gammon, L.; Edgar, M.M.; Xu, Y.; Elahi, S.; Chin-Aleong, J.; Martin, J.E.; et al. Expression of p16 within myenteric neurons of the aged Colon: A potential marker of declining function. Front. Neurosci. 2021, 15, 747067. [Google Scholar] [CrossRef] [PubMed]
  85. Baidoo, N.; Crawley, E.; Knowles, C.H.; Sanger, G.J.; Belai, A. Total collagen content and distribution is increased in human colon during advancing age. PLoS ONE 2022, 17, e0269689. [Google Scholar] [CrossRef]
  86. Shao, T.; Hsu, R.; Rafizadeh, D.L.; Wang, L.; Bowlus, C.L.; Kumar, N.; Mishra, J.; Timilsina, S.; Ridgway, W.M.; Gershwin, E. The gut ecosystem and immune tolerance. J. Autoimmun. 2023, 141, 103114. [Google Scholar] [CrossRef]
  87. Li, D.; Wu, M. Pattern recognition receptors in health and diseases. Signal Transduct. Target. Ther. 2021, 6, 291. [Google Scholar] [CrossRef]
  88. Holly, M.K.; Smith, J.G. Paneth cells during viral infection and pathogenesis. Viruses 2018, 10, 225. [Google Scholar] [CrossRef]
  89. Fernández-García, V.; González-Ramos, S.; Martín-Sanz, P.; García-del Portillo, F.; Laparra, J.M.; Boscá, L. NOD1 in the interplay between microbiota and gastrointestinal immune adaptations. Pharmacolog. Res. 2021, 171, 105775. [Google Scholar] [CrossRef]
  90. Ubeda, C.; Pamer, E.G. Antibiotics, microbiota, and immune defense. Trends Immunol. 2012, 33, 459–466. [Google Scholar] [CrossRef]
  91. Kulkarni, D.H.; Newberry, R.D. Intestinal macromolecular transport supporting adaptive immunity. Cell. Mol. Gastroenterol. Hepatol. 2019, 7, 729–737. [Google Scholar] [CrossRef]
  92. Zheng, D.; Liwinski, T.; Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020, 30, 492–506. [Google Scholar] [CrossRef] [PubMed]
  93. Ivanov, I.I. Review: Intestinal commensal microbes as immune modulators. Cell Host Microbe 2012, 12, 496–508. [Google Scholar] [CrossRef] [PubMed]
  94. Vanderpool, C.; Yan, F.; Polk, D.B. Mechanisms of probiotic action: Implications for therapeutic applications in inflammatory bowel diseases. Inflamm. Bowel Dis. 2008, 14, 1585–1596. [Google Scholar] [CrossRef]
  95. Fagundes, R.R.; Bravo-Ruiseco, G.; Hu, S.; Kierans, S.J.; Weersma, R.K.; Taylor, C.T.; Dijkstra, G.; Harmsen, H.J.M.; Faber, K.N. Faecalibacterium prausnitzii promotes intestinal epithelial IL-18 production through activation of the HIF1α pathway. Front. Microbiol. 2023, 14, 1298304. [Google Scholar] [CrossRef]
  96. Molla, M.D.; Akalu, Y.; Geto, Z.; Dagnew, B.; Ayelign, B.; Shibabaw, T. Role of caspase-1 in the pathogenesis of inflammatory-associated chronic noncommunicable diseases. J. Inflamm. Res. 2020, 13, 749–764. [Google Scholar] [CrossRef]
  97. Olivo-Martínez, Y.; Bosch, M.; Badia, J.; Baldomà, L. Modulation of the intestinal barrier integrity and repair by microbiota extracellular vesicles through the differential regulation of Trefoil Factor 3 in LS174T goblet cells. Nutrients 2023, 15, 2437. [Google Scholar] [CrossRef] [PubMed]
  98. Yang, Y.; Lin, Z.; Lin, Q.; Bei, W.; Guo, J. Pathological and therapeutic roles of bioactive peptide trefoil factor 3 in diverse diseases: Recent progress and perspective. Cell Death Dis. 2022, 13, 62. [Google Scholar] [CrossRef]
  99. Zia, S.; Tehreem, K.; Batool, S.; Ishfaq, M.; Mirza, S.B.; Khan, S.; Almashjary, M.N.; Hazzazi, M.S.; Qanash, H.; Shaikh, A.; et al. Epithelial cell adhesion molecule (EpCAM) expression can be modulated via NFκB. Biomedicines 2022, 10, 2985. [Google Scholar] [CrossRef] [PubMed]
  100. Mastrangelo, A.; Robles-Vera, I.; Mañanes, D.; Galán, M.; Femenía-Muiña, M.; Redondo-Urzainqui, A.; Barrero-Rodríguez, R.; Papaioannou, E.; Amores-Iniesta, J.; Devesa, A.; et al. Imidazole propionate is a driver and therapeutic target in atherosclerosis. Nature 2025. [Google Scholar] [CrossRef]
  101. Zhang, X.; Sergin, I.; Evans, T.D.; Jeong, S.J.; Rodriguez-Velez, A.; Kapoor, D.; Chen, S.; Song, E.; Holloway, K.B.; Crowley, J.R.; et al. High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy. Nat. Metab. 2020, 2, 110–125, Correct in Nat. Metab. 2020, 2, 991. [Google Scholar] [CrossRef]
  102. Zhang, X.; Kapoor, D.; Jeong, S.J.; Fappi, A.; Stitham, J.; Shabrish, V.; Sergin, I.; Yousif, E.; Rodriguez-Velez, A.; Yeh, Y.S.; et al. Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk. Nat. Metab. 2024, 6, 359–377. [Google Scholar] [CrossRef] [PubMed]
  103. Zhang, X.; Evans, T.D.; Chen, S.; Sergin, I.; Stitham, J.; Jeong, S.-J.; Rodriguez-Velez, A.; Yeh, Y.-S.; Park, A.; Jung, I.-H.; et al. Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1β Signaling. Circul. Res. 2023, 133, 200–219. [Google Scholar] [CrossRef]
  104. Aiello, R.J.; Bourassa, P.A.; Lindsey, S.; Weng, W.; Natoli, E.; Rollins, B.J.; Milos, P.M. Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 1518–1525. [Google Scholar] [CrossRef]
  105. Tuomisto, S.; Huhtala, H.; Martiskainen, M.; Goebeler, S.; Lehtimäki, T.; Karhunen, P.J. Age-dependent association of gut bacteria with coronary atherosclerosis: Tampere Sudden Death Study. PLoS ONE 2019, 14, e0221345. [Google Scholar] [CrossRef] [PubMed]
  106. Koren, O.; Spor, A.; Felin, J.; Fåk, F.; Stombaugh, J.; Tremaroli, V.; Behre, C.J.; Knight, R.; Fagerberg, B.; Ley, R.E.; et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc. Nat. Acad. Sci. USA 2011, 108 (Suppl. S1), 4592–4598. [Google Scholar] [CrossRef]
  107. Ott, S.J.; El Mokhtari, N.E.; Musfeldt, M.; Hellmig, S.; Freitag, S.; Rehman, A.; Kühbacher, T.; Nikolaus, S.; Namsolleck, P.; Blaut, M.; et al. Detection of diverse bacterial signatures in atherosclerotic lesions of patients with coronary heart disease. Circulation 2006, 113, 929–937. [Google Scholar] [CrossRef]
  108. Ho, Y.-H.; Del Toro, R.; Rivera-Torres, J.; Rak, J.; Korn, C.; Garcia-Garcia, A.; Macías, D.; González-Gómez, C.; del Monte, A.; Wittner, M.; et al. Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging. Cell Stem Cell 2019, 25, 407–418.e6. [Google Scholar] [CrossRef]
  109. Linton, P.J.; Dorshkind, K. Age-related changes in lymphocyte development and function. Nat. Immunol. 2004, 5, 133–139. [Google Scholar] [CrossRef]
  110. Muggen, A.F.; de Jong, M.; Wolvers-Tettero, I.L.M.; Kallemeijn, M.J.; Teodosio, C.; Darzentas, N.; Stadhouders, R.; Ijspeert, H.; van der Burg, M.; van Ijcken, W.F.J.; et al. The presence of CLL-associated stereotypic B cell receptors in the normal BCR repertoire from healthy individuals increases with age. Immun. Ageing 2019, 16, 22. [Google Scholar] [CrossRef]
  111. Tabibian-Keissar, H.; Hazanov, L.; Schiby, G.; Rosenthal, N.; Rakovsky, A.; Michaeli, M.; Shahaf, G.L.; Pickman, Y.; Rosenblatt, K.; Melamed, D.; et al. Aging affects B-cell antigen receptor repertoire diversity in primary and secondary lymphoid tissues. Eur. J. Immunol. 2016, 46, 480–492. [Google Scholar] [CrossRef] [PubMed]
  112. Gibson, K.L.; Wu, Y.C.; Barnett, Y.; Duggan, O.; Vaughan, R.; Kondeatis, E.; Nilsson, B.O.; Wikby, A.; Kipling, D.; Dunn-Walters, D.K. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 2009, 8, 18–25. [Google Scholar] [CrossRef] [PubMed]
  113. Stephan, R.P.; Reilly, C.R.; Witte, P.L. Impaired ability of bone marrow stromal cells to support B-lymphopoiesis with age. Blood 1998, 91, 75–88. [Google Scholar] [CrossRef]
  114. Snijckers, R.P.M.; Foks, A.C. Adaptive immunity and atherosclerosis: Aging at its crossroads. Front. Immunol. 2024, 15, 1350471. [Google Scholar] [CrossRef] [PubMed]
  115. Kumari, R.; Jat, P. Mechanisms of cellular senescence: Cell cycle arrest and senescence-associated secretory phenotype. Front. Cell Dev. Biol. 2021, 9, 645593. [Google Scholar] [CrossRef]
  116. Nordestgaard, B.G. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: New in-555 sights from epidemiology, genetics, and biology. Circ. Res. 2016, 118, 547–563. [Google Scholar] [CrossRef]
  117. Roy, P.; Orecchioni, M.; Ley, K. How the immune system shapes atherosclerosis: Roles of innate and adaptive immunity. Nat. Rev. Immunol. 2022, 22, 251–265. [Google Scholar] [CrossRef]
  118. Wolf, D.; Gerhardt, T.; Winkels, H.; Michel, N.A.; Pramod, A.B.; Ghosheh, Y.; Brunel, S.; Buscher, K.; Miller, J.; McArdle, S.; et al. Pathogenic autoimmunity in atherosclerosis evolves from initially protective apolipoprotein B100-reactive CD4+ T-regulatory cells. Circulation 2020, 142, 1279–1293. [Google Scholar] [CrossRef] [PubMed]
  119. Andreassi, M.G.; Botto, N.; Rizza, A.; Colombo, M.G.; Palmieri, C.; Berti, S.; Manfredi, S.; Masetti, S.; Clerico, A.; Biagini, A. Deoxyribonucleic acid damage in human lymphocytes after percutaneous transluminal coronary angioplasty. J. Am. Coll. Cardiol. 2002, 40, 862–868. [Google Scholar] [CrossRef]
  120. Liu, Z.; Liang, Q.; Ren, Y.; Guo, C.; Ge, X.; Wang, L.; Cheng, Q.; Luo, P.; Zhang, Y.; Han, X. Immunosenescence: Molecular mechanisms and diseases. Signal Transduct. Target. Ther. 2023, 8, 200. [Google Scholar] [CrossRef]
  121. Montenegro, J.; Armet, A.M.; Willing, B.P.; Deehan, E.C.; Fassini, P.G.; Mota, J.F.; Walter, J.; Prado, C.M. Exploring the influence of gut microbiome on energy metabolism in humans. Adv. Nutr. 2023, 14, 840–857. [Google Scholar] [CrossRef]
  122. Amiri, P.; Hosseini, S.A.; Ghaffari, S.; Tutunchi, H.; Ghaffari, S.; Mosharkesh, E.; Asghari, S.; Roshanravan, N. Role of butyrate, a gut microbiota derived metabolite, in cardiovascular diseases: A comprehensive narrative review. Front. Pharmacol. 2022, 12, 837509. [Google Scholar] [CrossRef]
  123. van den Munckhof, I.C.L.; Kurilshikov, A.; Ter Horst, R.; Riksen, N.P.; Joosten, L.A.B.; Rutten, J.H.W. Role of gut microbiota in chronic low-grade inflammation as potential driver for atherosclerotic cardiovascular disease: A systematic review of human studies. Obes. Rev. 2018, 19, 1719–1734. [Google Scholar] [CrossRef] [PubMed]
  124. Edfeldt, K.; Swedenborg, J.; Hansson, G.K.; Yan, Z.Q. Expression of toll-like receptors in human atherosclerotic lesions: A possible pathway for plaque activation. Circulation 2002, 105, 1158–1161. [Google Scholar] [CrossRef]
  125. Traore, K.; Zirkin, B.; Thimmulappa, R.K.; Biswal, S.; Trush, M.A. Upregulation of TLR1, TLR2, TLR4, and IRAK-2 expression during ML-1 cell differentiation to macrophages: Role in the potentiation of cellular responses to LPS and LTA. ISRN Oncol. 2012, 2012, 641246. [Google Scholar] [CrossRef]
  126. Dabravolski, S.A.; Sukhorukov, V.N.; Kalmykov, V.A.; Grechko, A.V.; Shakhpazyan, N.K.; Orekhov, A.N. The role of KLF2 in the regulation of atherosclerosis development and potential use of KLF2-558 targeted therapy. Biomedicines 2022, 10, 254. [Google Scholar] [CrossRef]
  127. Wang, L.; Huang, Z.; Huang, W.; Chen, X.; Shan, P.; Zhong, P.; Khan, Z.; Wang, J.; Fang, Q.; Liang, G.; et al. Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress. Sci. Rep. 2017, 8, 45917. [Google Scholar] [CrossRef]
  128. Zou, Z.G.; Rios, F.J.; Neves, K.B.; Alves-Lopes, R.; Ling, J.; Baillie, G.S.; Gao, X.; Fuller, W.; Camargo, L.L.; Gudermann, T.; et al. Epidermal growth factor signaling through transient receptor potential melastatin cation channel regulates vascular smooth muscle cell function. Clin. Sci. 2020, 134, 2019–2035. [Google Scholar] [CrossRef]
  129. Anshory, M.; Effendi, R.M.R.A.; Kalim, H.; Dwiyana, R.F.; Suwarsa, O.; Nijsten, T.E.C.; Nouwen, J.L.; Thio, H.B. Butyrate properties in immune-related diseases: Friend or foe? Fermentation 2023, 9, 205. [Google Scholar] [CrossRef]
  130. Karlsson, F.H.; Fåk, F.; Nookaew, I.; Tremaroli, V.; Fagerberg, B.; Petranovic, D.; Bäckhed, F.; Nielsen, J. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat. Commun. 2012, 3, 1245. [Google Scholar] [CrossRef] [PubMed]
  131. Liu, S.; Zhao, W.; Liu, X.; Cheng, L. Metagenomic analysis of the gut microbiome in atherosclerosis patients identify cross-cohort microbial signatures and potential therapeutic target. FASEB J. 2020, 34, 14166–14181. [Google Scholar] [CrossRef] [PubMed]
  132. Cui, L.; Zhao, T.; Hu, H.; Zhang, W.; Hua, X. Association study of gut flora in coronary heart disease through high-throughput sequencing. BioMed Res. Int. 2017, 2017, 3796359. [Google Scholar] [CrossRef] [PubMed]
  133. Jie, Z.; Xia, H.; Zhong, S.-L.; Feng, Q.; Li, S.; Liang, S.; Zhong, H.; Liu, Z.; Gao, Y.; Zhao, H.; et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat. Commun. 2017, 8, 845. [Google Scholar] [CrossRef]
  134. Zhu, Q.; Gao, R.; Zhang, Y.; Pan, D.; Zhu, Y.; Zhang, X.; Yang, R.; Jiang, R.; Xu, Y.; Qin, H. Dysbiosis signatures of gut microbiota in coronary artery disease. Physiol. Genom. 2018, 50, 893–903. [Google Scholar] [CrossRef]
  135. Feng, Q.; Liu, Z.; Zhong, S.; Li, R.; Xia, H.; Jie, Z.; Wen, B.; Chen, X.; Yan, W.; Fan, Y.; et al. Integrated metabolomics and metagenomics analysis of plasma and urine identified microbial metabolites associated with coronary heart disease. Sci. Rep. 2016, 6, 22525. [Google Scholar] [CrossRef]
  136. Yoshida, N.; Emoto, T.; Yamashita, T.; Watanabe, H.; Hayashi, T.; Tabata, T.; Hoshi, N.; Hatano, N.; Ozawa, G.; Sasaki, N.; et al. Bacteroides vulgatus and Bacteroides dorei reduce gut microbial lipopolysaccharide production and inhibit atherosclerosis. Circulation 2018, 138, 2486–2498. [Google Scholar] [CrossRef] [PubMed]
  137. Liu, H.; Chen, X.; Hu, X.; Niu, H.; Tian, R.; Wang, H.; Pang, H.; Jiang, L.; Qiu, B.; Chen, X.; et al. Alterations in the gut microbiome and metabolism with coronary artery disease severity. Microbiome 2019, 7, 68. [Google Scholar] [CrossRef]
  138. Panyod, S.; Wu, W.K.; Peng, S.Y.; Tseng, Y.J.; Hsieh, Y.C.; Chen, R.A.; Huang, H.S.; Chen, Y.H.; Chuang, H.L.; Hsu, C.C.; et al. Ginger essential oil and citral ameliorates atherosclerosis in ApoE−/− mice by modulating trimethylamine-N-oxide and gut microbiota. npj Sci. Food 2023, 7, 19. [Google Scholar] [CrossRef] [PubMed]
  139. Liu, F.-Y.; Wen, J.; Hou, J.; Zhang, S.-Q.; Sun, C.-B.; Zhou, L.-C.; Yin, W.; Pang, W.-L.; Wang, C.; Ying, Y.; et al. Gastrodia remodels intestinal microflora to suppress inflammation in mice with early atherosclerosis. Int. Immunopharmacol. 2021, 96, 107758. [Google Scholar] [CrossRef] [PubMed]
  140. Xie, B.; Zu, X.; Wang, Z.; Xu, X.; Liu, G.; Liu, R. Ginsenoside Rc ameliorated atherosclerosis via regulating gut microbiota and fecal metabolites. Front. Pharmacol. 2022, 13, 990476. [Google Scholar] [CrossRef]
  141. Yang, X.Y.; Yu, H.; Fu, J.; Guo, H.H.; Han, P.; Ma, S.R.; Pan, L.B.; Zhang, Z.W.; Xu, H.; Hu, J.C.; et al. Hydroxyurea ameliorates atherosclerosis in ApoE−/− mice by potentially modulating Niemann-Pick C1-like 1 protein through the gut microbiota. Theranostics 2022, 12, 7775–7787. [Google Scholar] [CrossRef]
  142. Liu, Q.; Li, Y.; Song, X.; Wang, J.; He, Z.; Zhu, J.; Chen, H.; Yuan, J.; Zhang, X.; Jiang, H.; et al. Both gut microbiota and cytokines act to atherosclerosis in ApoE−/− mice. Microb. Pathog. 2020, 138, 103827. [Google Scholar] [CrossRef]
  143. Zhu, B.; Zhai, Y.; Ji, M.; Wei, Y.; Wu, J.; Xue, W.; Tao, W.; Wu, H. Alisma orientalis beverage treats atherosclerosis by regulating gut microbiota in ApoE−/− mice. Front. Pharmacol. 2020, 11, 570555. [Google Scholar] [CrossRef]
Ijms 26 08276 g001
Figure 1. Persistent or chronic inflammation, typical in the elderly, leads to atherosclerosis (AS), characterized by the infiltration of immune cells into vascular smooth muscle cells (VSMCs, also referred to as smooth muscle cells, SMCs), and an increase in collagen, endothelin, and protein tissue factor (PTF), which leads to the thickening of the media. These changes in the arterial wall initiate the release of damage-associated molecular patterns (DAMPs), free radicals, and reactive oxygen species (ROS), which enhance inflammation. This increases the risk of blood clotting, thrombosis, a decrease in oxygen (O2) supply to the myocardium, and myocardial infarction (MI). The uptake of oxidised low-density lipoprotein (ox-LDL) by macrophages results in the formation of foam cells that adhere to the intima and contribute to plaque formation and restriction of blood flow. The surface of the intima of healthy coronary arteries is covered with receptors for LDL and thrombin, prostacyclin PGI2 (an antithrombotic agent), von Willebrand’s factor (a prothrombotic agent), interleukin-1 (IL-1), and plasminogen activator (a fibrinolytic agent). Damaged blood vessels are repaired by platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) released from platelets. NO = nitric oxide, IL = interleukin, INF-y = interferon y, MCP = monocyte chemoattractant protein, MMPs = matrix metalloproteinases, uPAR = urokinase plasminogen activator receptor. Red arrows showing upwards denotes an increase and downward arrows a decrease. The schematic representation was constructed using Biorender (Biorender.com), accessed on 14 July 2025.
Figure 1. Persistent or chronic inflammation, typical in the elderly, leads to atherosclerosis (AS), characterized by the infiltration of immune cells into vascular smooth muscle cells (VSMCs, also referred to as smooth muscle cells, SMCs), and an increase in collagen, endothelin, and protein tissue factor (PTF), which leads to the thickening of the media. These changes in the arterial wall initiate the release of damage-associated molecular patterns (DAMPs), free radicals, and reactive oxygen species (ROS), which enhance inflammation. This increases the risk of blood clotting, thrombosis, a decrease in oxygen (O2) supply to the myocardium, and myocardial infarction (MI). The uptake of oxidised low-density lipoprotein (ox-LDL) by macrophages results in the formation of foam cells that adhere to the intima and contribute to plaque formation and restriction of blood flow. The surface of the intima of healthy coronary arteries is covered with receptors for LDL and thrombin, prostacyclin PGI2 (an antithrombotic agent), von Willebrand’s factor (a prothrombotic agent), interleukin-1 (IL-1), and plasminogen activator (a fibrinolytic agent). Damaged blood vessels are repaired by platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) released from platelets. NO = nitric oxide, IL = interleukin, INF-y = interferon y, MCP = monocyte chemoattractant protein, MMPs = matrix metalloproteinases, uPAR = urokinase plasminogen activator receptor. Red arrows showing upwards denotes an increase and downward arrows a decrease. The schematic representation was constructed using Biorender (Biorender.com), accessed on 14 July 2025.
Ijms 26 08276 g001
Ijms 26 08276 g002
Figure 2. Butyrate and reactive oxygen species (ROS), produced by microbiota in the large intestinal tract, interact with Toll-like receptor 4 (TLR4), platelet glycoprotein 4 (CD36), and G-protein-coupled receptors (GPCRs). Trimethylamine-N-oxide (TMAO), produced by gut microbiota, activates Nod-like receptor protein 3 (NLRP3) and triggers platelet formation. This results in the stimulation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, which increases the expression of pro-inflammatory cytokines, chemokines, advanced glycation end products (AGEs), and reactive oxygen species (ROS). These increases lead to an increase in apoptosis, inflammation, oxidative stress, and oxidised low-density lipoprotein (ox-LDL). The latter is taken up by macrophages, which convert to foam cells that adhere to the tunica intima. The result is plaque buildup and restriction of blood flow. Plaques upregulate CD4+, which differentiates into helper T (Th) cells, Th1 and Th2. Th1 cells express interferon-γ (INF-γ) to promote atherosclerosis (AS), whilst Th2 cells produce IL-4, IL-5, and IL-13, which neutralize INF-γ. The schematic representation was constructed using Biorender (Biorender.com), accessed on 14 July 2025.
Figure 2. Butyrate and reactive oxygen species (ROS), produced by microbiota in the large intestinal tract, interact with Toll-like receptor 4 (TLR4), platelet glycoprotein 4 (CD36), and G-protein-coupled receptors (GPCRs). Trimethylamine-N-oxide (TMAO), produced by gut microbiota, activates Nod-like receptor protein 3 (NLRP3) and triggers platelet formation. This results in the stimulation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, which increases the expression of pro-inflammatory cytokines, chemokines, advanced glycation end products (AGEs), and reactive oxygen species (ROS). These increases lead to an increase in apoptosis, inflammation, oxidative stress, and oxidised low-density lipoprotein (ox-LDL). The latter is taken up by macrophages, which convert to foam cells that adhere to the tunica intima. The result is plaque buildup and restriction of blood flow. Plaques upregulate CD4+, which differentiates into helper T (Th) cells, Th1 and Th2. Th1 cells express interferon-γ (INF-γ) to promote atherosclerosis (AS), whilst Th2 cells produce IL-4, IL-5, and IL-13, which neutralize INF-γ. The schematic representation was constructed using Biorender (Biorender.com), accessed on 14 July 2025.
Ijms 26 08276 g002
Ijms 26 08276 g003
Figure 3. The tunica intima (intima) of aging endothelial membranes with AS is covered by proteoglycans. The negatively charged side chains, biglycan, versican, perlecan, and lumican, are linked to positively charged apolipoprotein B attached to oxidised low-density lipoprotein (ox-LDL). Senescence-associated secretory phenotype (SASP) factors, e.g., matrix metalloproteinase 9 (MMP-9) released from vascular smooth muscle cells (VSMCs), upregulate the inflammasome and stimulate the infiltration of foam cells into arteries. With the increase in MMP production, collagen is lysed and elastin degraded, destabilizing the fibrous cap of plaques. The rupture of plaques increases the risk of thrombosis. TET methylcytosine dioxygenase 2 (TET2)-deficient macrophages, prevalent in ageing blood cells, increase the release of Nod-like receptor protein 3 (NLRP3) inflammasome-mediated interleukin-1β (IL-1β), resulting in the formation of larger plaques. The red dashed arrow denotes an increase. The schematic representation was constructed using Biorender (Biorender.com), accessed on 14 July 2025.
Figure 3. The tunica intima (intima) of aging endothelial membranes with AS is covered by proteoglycans. The negatively charged side chains, biglycan, versican, perlecan, and lumican, are linked to positively charged apolipoprotein B attached to oxidised low-density lipoprotein (ox-LDL). Senescence-associated secretory phenotype (SASP) factors, e.g., matrix metalloproteinase 9 (MMP-9) released from vascular smooth muscle cells (VSMCs), upregulate the inflammasome and stimulate the infiltration of foam cells into arteries. With the increase in MMP production, collagen is lysed and elastin degraded, destabilizing the fibrous cap of plaques. The rupture of plaques increases the risk of thrombosis. TET methylcytosine dioxygenase 2 (TET2)-deficient macrophages, prevalent in ageing blood cells, increase the release of Nod-like receptor protein 3 (NLRP3) inflammasome-mediated interleukin-1β (IL-1β), resulting in the formation of larger plaques. The red dashed arrow denotes an increase. The schematic representation was constructed using Biorender (Biorender.com), accessed on 14 July 2025.
Ijms 26 08276 g003
Ijms 26 08276 g004
Figure 4. Butyrate prevents the infiltration of macrophages into VSMCs and suppresses the production of pro-inflammatory cytokines, thereby preventing plaque formation. Binding of butyrate to peroxisome proliferator-activated receptor γ (PPARγ) increases the activity of IkBα (nuclear factor kappa-B, NF-κB, inhibitor). This suppresses the production of pro-inflammatory cytokines that cause atherosclerosis (AS). Binding to PPARγ also stimulates adipogenesis, preventing plaque formation and AS. Binding butyrate to Toll-like receptor 4 (TLR4) increases the production of pro-inflammatory cytokines and induces plaque formation. Larger plaques are formed when TET methylcytosine dioxygenase 2 (TET-2)-deficient macrophages stimulate the release of Nod-like receptor protein 3 (NLRP3). Butyrate suppresses inflammation by inhibiting interferon γ (IFN-γ), TLR2, and platelet glycoprotein CD36 signalling. By suppressing CD36, the uptake of oxidised low-density lipoprotein (ox-LDL) by macrophages is prevented, and plaque formation is repressed. NADPH = nicotinamide adenine dinucleotide phosphate, MAPK = mitogen-activated protein kinase, eNOS = endothelial nitric oxide synthase, NO = nitric oxide, VSMCs = vascular smooth muscle cells. The schematic representation was constructed using Biorender (Biorender.com), accessed on 14 July 2025.
Figure 4. Butyrate prevents the infiltration of macrophages into VSMCs and suppresses the production of pro-inflammatory cytokines, thereby preventing plaque formation. Binding of butyrate to peroxisome proliferator-activated receptor γ (PPARγ) increases the activity of IkBα (nuclear factor kappa-B, NF-κB, inhibitor). This suppresses the production of pro-inflammatory cytokines that cause atherosclerosis (AS). Binding to PPARγ also stimulates adipogenesis, preventing plaque formation and AS. Binding butyrate to Toll-like receptor 4 (TLR4) increases the production of pro-inflammatory cytokines and induces plaque formation. Larger plaques are formed when TET methylcytosine dioxygenase 2 (TET-2)-deficient macrophages stimulate the release of Nod-like receptor protein 3 (NLRP3). Butyrate suppresses inflammation by inhibiting interferon γ (IFN-γ), TLR2, and platelet glycoprotein CD36 signalling. By suppressing CD36, the uptake of oxidised low-density lipoprotein (ox-LDL) by macrophages is prevented, and plaque formation is repressed. NADPH = nicotinamide adenine dinucleotide phosphate, MAPK = mitogen-activated protein kinase, eNOS = endothelial nitric oxide synthase, NO = nitric oxide, VSMCs = vascular smooth muscle cells. The schematic representation was constructed using Biorender (Biorender.com), accessed on 14 July 2025.
Ijms 26 08276 g004
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Dicks, L.M.T. Are an Aging Gut and a Decrease in Butyrate Production the Reasons for Atherosclerosis? Int. J. Mol. Sci. 2025, 26, 8276. https://doi.org/10.3390/ijms26178276

AMA Style

Dicks LMT. Are an Aging Gut and a Decrease in Butyrate Production the Reasons for Atherosclerosis? International Journal of Molecular Sciences. 2025; 26(17):8276. https://doi.org/10.3390/ijms26178276

Chicago/Turabian Style

Dicks, Leon M. T. 2025. "Are an Aging Gut and a Decrease in Butyrate Production the Reasons for Atherosclerosis?" International Journal of Molecular Sciences 26, no. 17: 8276. https://doi.org/10.3390/ijms26178276

APA Style

Dicks, L. M. T. (2025). Are an Aging Gut and a Decrease in Butyrate Production the Reasons for Atherosclerosis? International Journal of Molecular Sciences, 26(17), 8276. https://doi.org/10.3390/ijms26178276

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop