From Gut Bacteria to Blood Vessels: New Insights into Inflammation and Heart Disease

A new publication was released by the ENDOTARGET consortium, which investigates how bacterial components originating from the gut can trigger inflammatory responses in the cells lining coronary arteries and potentially contribute to cardiovascular disease. This scientific work was published in April 2026 in the journal Cellular and Molecular Life Sciences. Authors of this study are: Katariina Nurmi, Martina B. Lorey, Jukka Parantainen, Wojciech Cypryk, Eirini Kalogerakou, Vesa-Petteri Kouri, Juha Kaivola, Marcelina Bilicka, Arzu Beklen, Yan Chen, Maria Stensland, Sampsa Matikainen, Tuula A. Nyman and Kari K. Eklund.

The publication, entitled “Lipopolysaccharides Drive Proinflammatory Extracellular Vesicle Secretion in Coronary Artery Endothelial Cells via Noncanonical Inflammasome Activation”, explores an important question in modern cardiovascular research: how can changes in the gut microbiome influence inflammation in blood vessels of the heart? The researchers discovered a previously underappreciated mechanism by which bacterial components can activate endothelial cells, leading to inflammatory signalling and communication with immune cells. These findings provide valuable insights into the biological connections between gut health, chronic inflammation and cardiovascular disease.

Why is this research topic important?

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, and it is the most important comorbidity in rheumatoid arthritis. A major underlying process is atherosclerosis, a condition in which fatty deposits, immune cells and inflammatory molecules accumulate within artery walls. While factors such as cholesterol levels, smoking, high blood pressure, age, and sex are well-established contributors, scientists increasingly recognise inflammation as a key driver of disease progression. Over the past decade, growing evidence has pointed to the gut microbiome as an unexpected player in cardiovascular health. The trillions of microorganisms living in our digestive system influence digestion, metabolism and immune function. When this microbial balance is disrupted, a condition known as dysbiosis can develop. Dysbiosis is often associated with intestinal inflammation and increased permeability of the gut barrier, allowing bacterial components to enter the bloodstream. Lipopolysaccharide (LPS), a molecule found in the outer membrane of many bacteria, is one of the most important of these components. Elevated levels of LPS in the blood circulation, sometimes referred to as metabolic endotoxemia, create a persistent low-grade inflammatory state. Metabolic endotoxemia has been associated with a range of chronic inflammatory and metabolic conditions. Understanding exactly how circulating LPS affects different tissues is therefore an important area of research. Previous studies have shown associations between increased LPS levels and CVD, but the biological mechanisms linking the two have not been fully understood.

The ENDOTARGET study set out to explore whether LPS could directly affect vascular endothelial cells, the cells that form the inner lining of blood vessels, and whether this interaction could promote vascular inflammation in the heart. Understanding these processes may help explain how gut dysfunction contributes to cardiovascular disease and why patients with rheumatoid arthritis have increased risk of CVD .

How was the study conducted?

The researchers used primary human coronary artery endothelial cells as their experimental model. These cells originate from the blood vessels that supply the heart and allowed the researchers to study inflammatory responses in a biologically relevant vascular cell type. A central focus of the study was the noncanonical inflammasome pathway. Inflammasomes are intracellular systems that allow cells to recognise potentially harmful signals and initiate inflammatory responses. The noncanonical inflammasome is particularly interesting because it can directly detect LPS that has entered the cell. To investigate this pathway, the researchers introduced LPS into endothelial cells and examined the resulting cellular responses, including activation of inflammatory pathways, changes in adhesion molecule expression and the release of proteins in extracellular vesicles, which protect the cargo proteins from degradation and transport them to other cells. They also examined whether the vesicles produced by LPS-stimulated endothelial cells could influence macrophages, an important type of immune cell. By combining molecular analyses, microscopy, protein profiling and cell-based experiments, the team was able to follow the inflammatory response from the initial detection of LPS to communication between endothelial and immune cells.

What does the analysis show us?

Intracellular LPS activates an inflammatory pathway in endothelial cells

A central finding of the study was that intracellular LPS activates the noncanonical inflammasome in coronary artery endothelial cells. This is significant because inflammasome activation has traditionally been studied mostly in immune cells. The results demonstrate that endothelial cells are not merely structural components of blood vessel walls but can directly respond to intracellular bacterial products and actively participate in inflammatory processes. Notably, the study found no evidence for involvement of the NLRP3 inflammasome pathway, which is a well known inflammatory pathway in macrophages for initiating inflammatory responses. Primary human coronary endothelial cells did not express key NLRP3 inflammasome components, and inhibition of the NLRP3 inflammasome activity did not alter the observed responses. Instead, the response relied predominantly on the noncanonical inflammasome system.

Activated endothelial cells release extracellular vesicles

One of the most interesting observations was a substantial increase in the release of extracellular vesicles (EVs) by noncanonical inflammasome activation. EVs are tiny membrane-bound particles naturally released by cells. They contain biologically active material such as proteins, lipids and nucleic acids and can transport this material from one cell to another. EVs are therefore increasingly recognised as an important form of cell-to-cell communication. The researchers observed a massive increase in EV secretion, as well as their cargo proteins, after exposure to intracellular LPS. More than 1,800 proteins showed increased secretion, and over 200 proteins were newly incorporated into EVs. Protein analysis showed that EVs produced after intracellular LPS stimulation contained proteins associated with inflammatory signalling, responses to bacterial infection and other cellular processes. This indicates that the vesicles reflect the inflammatory state of the endothelial cells from which they originate.

Extracellular vesicles activate macrophages

To investigate whether these vesicles are able to influence immune cells, the researchers isolated EVs from activated endothelial cells and exposed them to human macrophages. Macrophages are immune cells involved in detecting harmful substances, removing damaged cells and coordinating inflammatory responses. The macrophages responded to the endothelial-derived vesicles by increasing the expression of inflammatory cytokines and interferon-related genes. Thus, the EVs were capable of transmitting proinflammatory signals to immune cells. This observation is particularly interesting because it suggests that the inflammatory consequences of LPS exposure are not restricted to the cell that initially encounters the bacterial molecule. Instead, extracellular vesicles could contribute to the communication and amplification of inflammation between different cell types. Since endothelial cells form the interface between circulation and the vessel wall, they may serve as first line cells that sense circulating signals such as LPS.

LPS promotes interactions between endothelial and immune cells

Another interesting observation was an increased expression of the adhesion molecule VCAM-1 on the surface of endothelial cells. Such molecules help circulating immune cells attach to the blood vessel wall. In the experiments, this indeed resulted in an increased adhesion of monocytes, immune cells that can migrate into tissues and develop into macrophages. Recruitment of monocytes to the vascular wall is an important feature of vascular inflammation and is also involved in the development of atherosclerosis. The results therefore point towards several interconnected consequences of intracellular LPS exposure: endothelial cells become activated, attract immune cells and release inflammatory extracellular vesicles capable of influencing those immune cells.

What can we learn from the study?

The study reveals a previously underappreciated mechanism through which bacterial products may contribute to vascular inflammation. LPS can activate cell-surface pattern recognition receptors, but it can also be delivered in bacterial vesicles that enter cells and activate the noncanonical inflammasome. In response, endothelial cells release proinflammatory extracellular vesicles and increase their interactions with circulating immune cells. This creates a possible chain of events:

LPS enters endothelial cells → noncanonical inflammasome activation → release of proinflammatory extracellular vesicles → activation of immune cells → amplification of vascular inflammation.

With prolonged stimulation, the process may ultimately progress towards inflammatory cell death. These findings broaden our understanding of the endothelium. Instead of viewing endothelial cells simply as a barrier between the blood and surrounding tissues, the study demonstrates that they actively sense bacterial signals and communicate inflammatory information to immune cells. The findings are also relevant to understanding atherosclerosis, a chronic inflammatory condition in which plaques develop within artery walls. Endothelial activation and  monocyte recruitment are important events that contribute to both the initiation and perpetuation of the process. The mechanism identified in this study provides one potential biological link between circulating bacterial products and inflammatory changes in the vascular wall. Importantly, the study was performed using cellular models. Further research is therefore needed to determine how strongly this mechanism contributes to vascular inflammation in patients and whether it could eventually provide a target for prevention or treatment.

Read the full article here: Lipopolysaccharides Drive Proinflammatory Extracellular Vesicle Secretion in Coronary Artery Endothelial Cells via Noncanonical Inflammasome Activation

Glossary

Atherosclerosis: A chronic disease in which plaques containing fats, immune cells and other substances accumulate in artery walls. Over time, arteries become narrower and less flexible, increasing the risk of heart attack and stroke.

Cardiovascular diseases (CVDs): A group of conditions affecting the heart and blood vessels, including coronary artery disease, heart attack, stroke and heart failure.

Cytokines: Small signalling proteins released by cells, particularly immune cells, to help coordinate the body’s response to infection, injury or inflammation. They act as messengers, allowing cells to communicate with one another.

 Dysbiosis: An imbalance in the normal community of microorganisms living in the gut. Dysbiosis can affect digestion, immune responses and overall health.

Endothelial cells: The cells that form the inner lining of blood and lymphatic vessels. They help regulate blood/ lymph fluid flow, immune cell movement and communication between tissues and the bloodstream/ lymph fluid. Thus, human coronary artery endothelia cells are the endothelial cells that specifically line the coronary arteries, which supply blood to the heart muscle.

Extracellular vesicles (EVs): Small membrane-bound particles released by cells. They carry biological information, including proteins, lipids, and genetic material, and help cells communicate with one another.

 Gene expression: The process by which a cell uses the information stored in a gene to produce proteins or other molecules needed for its functions. Changes in gene expression allow cells to respond to signals such as infection, inflammation or environmental changes.

Inflammasome: A large protein complex inside cells that detects danger signals and triggers inflammatory responses designed to protect the body from infection or damage.

Inflammation: The body’s natural response to infection, injury or harmful stimuli, helping to protect tissues and support healing. When it becomes excessive or long-lasting, it can contribute to the development of diseases. Low-grade inflammation is a persistent, mild form of inflammation that develops over time and often occurs without obvious symptoms. It has been linked to chronic conditions such as CVD, diabetes and obesity.

Interferons: Interferons are signalling proteins produced by cells in response to infections and other immune stimuli. They help regulate the immune response by activating defence mechanisms and influencing inflammation.

 Lipopolysaccharide (LPS): A component of the outer membrane of Gram-negative bacteria. When LPS enters the circulation and is detected by cellular receptors, it can activate strong inflammatory responses.

Macrophages: Immune cells that remove microorganisms, damaged cells and other material from tissues. They also produce signalling molecules that regulate inflammation.

Metabolic endotoxemia: A condition characterised by persistently increased levels of bacterial products such as LPS in the bloodstream, usually at much lower concentrations than during severe bacterial infection. It is associated with chronic low-grade inflammation.

Microbiome: Refers to the community of microorganisms, including bacteria, fungi and viruses, that live in and on the human body. These microorganisms play important roles in health, including digestion, metabolism and immune function. Thus, the gut microbiome is the collection of microorganisms that live in the digestive tract. It helps break down food, supports the immune system and influences many aspects of human health.

Monocytes: A type of white blood cell that circulates in the bloodstream and helps defend the body against infections and tissue damage. When they enter tissues, they can develop into macrophages and contribute to inflammation and immune responses.

Noncanonical inflammasome: A specialised inflammatory pathway that detects LPS inside human cells through caspase-4 and caspase-5 proteins.

NLRP3 inflammasome: A protein complex inside cells that detects signs of infection, stress or tissue damage and triggers inflammation. When activated, it promotes the release of inflammatory cytokines such as IL-1β and IL-18, helping the body respond to potential threats.

VCAM-1: An adhesion molecule expressed by endothelial cells that helps immune cells attach to blood vessel walls and migrate into tissues.