Dr. Rhonda Patrick was the keynote speaker for the Metabolic Health Summit, held May 5 – 8, 2022, in Santa Barbara, California. Her presentation described the role that intestinal permeability and bacterial products play in aging, inflammation, and chronic disease.

In this presentation, she describes how...

• 00:03:12
  Intestinal permeability promotes the release of bacterial products from the gut into the bloodstream and how this stimulates the immune response, sometimes chronically.
• 00:05:20
  Bacterial products, called lipopolysaccharide, bind to lipoproteins like LDL, promoting atherosclerosis.
• 00:10:57
  How lipopolysaccharide that originates from the gut ultimately compromises the blood-brain barrier, leading to neurodegeneration and behavioral effects.=
• 00:21:09
  Lifestyle factors regulate intestinal permeability.

The intestinal barrier serves as a gatekeeper to the human body. The loss of the health and integrity of this barrier influences multiple aspects of human health – including cardiometabolic function, neurological health, behavior, and more – in surprising and unexpected ways. One of these ways involves lipopolysaccharide, or LPS, a bacterial product that arises in the intestine, and its interaction with far distal tissues and organs via the induction of immune mediators.

LPS exploits intestinal permeability.

Intrinsic to this interaction is the barrier's structure: a single-celled, semipermeable layer of epithelial cells held together by tight junctions and protected by a double layer of mucus – a haven for the commensal bacteria that reside in the gut. If the tight junctions between the cells degrade, gaps form, increasing the barrier's permeability. LPS exploits this permeability to gain access to the bloodstream. There, pattern-recognition molecules called toll-like receptors detect its presence and activate an immune response that drives the expression of an array of proinflammatory proteins and mediators. This cascade of events, starting with the loss of barrier function and culminating with immune activation, likely plays roles in the pathogenesis of many chronic disorders, including cardiovascular disease, neurodegenerative disease, behavioral disorders, and metabolic dysfunction.

• Learn more about intestinal permeability in our overview article.

LPS binds to lipoproteins, leading to atherosclerosis.

Circulating LPS can also bind to lipoproteins, facilitating their absorption in the liver during LDL recycling, effectively removing LPS from circulation and lowering systemic inflammation – a phenomenon demonstrated mechanistically with statins that increase lipoprotein recycling by increasing LDL receptors.

But some types of LDL particles, especially the small, dense variety, are not easily recycled. These minute LPS-bound particles remain in circulation and eventually insert themselves into arterial walls, triggering an immune response. Immune factors engulf the particles, creating foam cells and initiating the process of atherosclerosis. Interestingly, findings from animal studies suggest that this cycle can be reversed by increasing butyrate-producing bacteria in the gut – another indication of the ties between the gut and overall health.

LPS compromises the blood-brain barrier, leading to neurodegeneration.

The blood-brain barrier shares many similarities with the intestinal barrier, consisting of cells held together by tight junctions and supported by other cell types, including astrocytes, pericytes, and microglia cells – the brain's resident immune cells. Microglia protect the brain following acute brain injury and help maintain brain homeostasis. LPS can bind to toll-like receptors on microglial cells, switching them from "protect" to "attack" mode and initiating a vicious cycle of blood-brain barrier breakdown and neuroinflammation. The loss of blood-brain barrier function is particularly evident during aging, with markers of barrier breakdown preceding the formation of tau tangles and amyloid-beta plaques in early cognitive dysfunction.

• Learn more about the blood-brain barrier in our overview article.

LPS promotes inflammation, affecting behavior.

Mounting evidence suggests that inflammation plays a role in depression. Inflammation is a conserved biological response that developed during humans' ancient past, when regular exposure to pathogens dictated highly coordinated behavioral and immunological responses to ensure survival. The fallout of these responses is an "inflammatory bias" – a propensity for the body to launch an indiscriminate response to a stressor, regardless of its source. Elevated biomarkers of inflammation, which are commonly observed in people who have depression, chronically activate the body's inflammatory response system, promoting the development of depressive symptoms and inducing changes in brain and neuroendocrine function.

Compelling evidence suggests that the relationship between inflammation and depression is indeed causal – and LPS may play a role. In studies in which participants receive LPS injections, their circulating levels of proinflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor-alpha (which are downstream of toll-like receptor activation), increase markedly. Interestingly, depressive symptoms, anxiety, feelings of social disconnection, and anhedonia (a lack of reactivity to pleasurable stimuli) increase, as well, coinciding with the peak of the proinflammatory response.

LPS promotes "inflammaging," driving metabolic dysfunction.

During aging, a unique form of inflammation occurs. Dubbed "inflammaging," this low-grade inflammation occurs even in the absence of pathogenic attack. A fundamental component of the inflammaging process is immune system recognition of metabolic, hormonal, and immune stimuli (such as chronic infections or age-related changes in the gut microbiota), thereby promoting an inflammatory environment. In addition, the cellular senescence that accompanies aging activates pro-inflammatory signaling pathways and drives the release of cytokines, chemokines, and growth factors. Other contributors to inflammaging are cellular debris from normal cell death and the accumulation of metabolic byproducts, such as amyloid-beta proteins, which are involved in the pathogenesis of Alzheimer's disease.

Even a low-dose exposure to LPS can drive inflammaging, increasing inflammatory markers as much as a hundredfold. This systemic inflammation can promote insulin resistance in muscles and fat accumulation in the liver. The downstream effect is accelerated epigenetic aging, a phenomenon that occurs when an individual's epigenetic age exceeds their chronological age.

Factors that increase intestinal permeability

Robust evidence suggests that dietary behaviors and components can increase intestinal permeability and promote LPS release. For example, some evidence suggests that having obesity increases intestinal permeability and circulating LPS concentrations – by as much as 71 percent. These effects may simply be the result of the inflammatory effects of eating an obesogenic diet. Interestingly, eating any meal – regardless of content – can provoke an increase in LPS, a phenomenon known as postprandial endotoxemia. And alcohol consumption, especially in excess, has similar effects on the gut, with both moderate intake and binge drinking eliciting increases in permeability.

The role of diet in intestinal permeability is particularly evident in people with celiac disease, for whom gluten is a major concern. Gluten is a complex mixture of hundreds of related but distinct proteins, mainly gliadin and glutenin, found in wheat. Gliadin binds to a receptor on gut cells, stimulating the release of zonulin, a protein that regulates the tight junctions between cells in the gut. Zonulin binds to other receptors, resulting in the disassembly of tight junctions and increasing intestinal permeability. In healthy people, this change in the tight junctions is transient, but in people with celiac disease, the junctions may remain open for extended periods, driving LPS release into the bloodstream and causing multiple complications.

Factors that reduce intestinal permeability

Dietary factors can also decrease intestinal permeability. For example, dietary fiber undergoes microbial fermentation in the gut to produce butyrate – a short-chain fatty acid that provides energy to cells that line the colon. Whole grains are the primary sources of fermentable fiber, but non-gluten-containing dietary sources include pectins, beta-glucans, inulin, and resistant starch. Evidence from animal models suggests that having a microbiota that is enriched in butyrate-producing bacteria prevents intestinal permeability and atherosclerosis. But to reap the benefits of butyrate production, it's important to promote a population of butyrate-producing bacteria in the gut. Factors that may contribute to increased numbers of butyrate-producing bacteria include time-restricted eating, aerobic exercise, and the consumption of omega-3 fatty acids.

The overall quality of the fats in a person's diet can influence intestinal permeability, as well. Whereas saturated fats tend to promote postprandial LPS leakage, omega-3 fatty acids tend to prevent leakage. This may be because omega-3s increase intestinal alkaline phosphatase, an enzyme that degrades LPS. They also alter the microbiota, favoring butyrate-producing species. It's noteworthy that some of the studies on which these conclusions are based used processed oils and provided refined carbohydrates with the test meals, muddying the findings.

Surprisingly, no evidence suggests that higher levels of LPS leak into circulation during a ketogenic diet – likely due to the profound metabolic changes induced during ketosis. In addition, beta-hydroxybutyrate, a ketone produced during a ketogenic diet, may travel to the colon and nourish colonocytes.

Mounting evidence points to the intersecting roles that intestinal permeability and LPS play in human health. In this episode, Dr. Rhonda Patrick describes how intestinal permeability and LPS influence inflammation, aging, and chronic disease.

Related Topics and Episodes

Topics

• Intestinal permeability - In-depth overview on intestinal permeability

• Toll-like receptors - TLRs are specialized receptors that detect the presence of bacterial components in the bloodstream and trigger the body to secrete inflammatory cytokines. Prolonged immune stimulation mediated by toll-like receptors contributes to aspects of aging known as inflammaging.

• Blood-brain barrier - Another membranous barrier in the body that loses its integrity with age. Increased microbial toxins in the blood because of increased intestinal permeability is a source of stress for the blood-brain barrier, injuring neurons and promoting disease.

• Polyphenols - Plant nutrients that improve the gut barrier and enhance health in a number of other ways; learn more from our overview article on the topic.

Episodes

• Dr. Eran Elinav on Microbiome Insights into Personalized Response to Diet, Obesity, and Leaky Gut

Clips

• In this clip, Dr. Eran Elinav elaborates on the connection between leaky gut and chronic diseases such as cancer.
• In this clip, Dr. Satchin Panda discusses how time-restricted eating affects leaky gut and systemic inflammation in this clip from the FoundMyFitness podcast.