“What is inflammation?
We usually talk about “inflammation” in relation to infections and injuries. When the body is infected, the immune cells recognize the ‘non-self’ molecules and produce inflammatory factors, called “cytokines”, to coordinate the fight against the infection. Cytokines signal other immune cells and bring them to the site of infection. Inflammation is clinically assessed by measuring cytokine concentrations or other inflammatory markers in the blood and is used as a sign of infection.
What is low-grade inflammation?
It is a question that remains hard to answer. Low-grade inflammation is usually defined as “the chronic production, but a low-grade state, of inflammatory factors”. Conditions characterized by low-grade inflammation are for instance obesity (1), depression (2) or chronic pain (3). Low-grade inflammation does not come from an infection but several physiological mechanisms are involved. Concentrations of inflammatory factors in these conditions are overall slightly higher than in healthy populations, but still remain in the healthy ranges. It is therefore hard to determine whether a specific patient exhibits “low-grade inflammation” but it can be better defined at the level of a group of patients.
Inflammation and the brain
When we are sick, we often want to sleep, have reduced appetite, prefer to stay home alone, have difficulty concentrating and can be a bit moody. All these feelings and behaviors are induced by cytokines! Indeed, in addition to coordinating the fight against infection in the periphery of the body, cytokines also act in the brain and induce behavioral changes (4). All these behavioral changes are adaptive, with the purpose of limiting the spread of the infection and allowing the body to spare energy in order to fight the infection instead of, say, going out partying with friends.
However, the behavioral effects of cytokines are not always beneficial. When the cytokine signal is too strong or lasts a long time, such as in cancer patients during treatment with cytokines, these effects can become maladaptive and lead to more chronic and pathological behavioral alterations, such as depression (5). Inflammation is therefore one hypothesized contributor to depression (4). One critical difference between infection or cancer therapy and most cases of depression is, however, the level of production of inflammatory factors. Cytokine levels are high during immunotherapy, i.e., “inflammation”, while depression is characterized by a state of “low-grade inflammation”.
The proportion of subjects who suffer from depression is higher in conditions characterized by low-grade inflammation than in the general population. For instance, 20 to 30% of obese individuals suffer from depression while the prevalence in the general population is of 5-10% (6). While psychological factors are highly likely to be involved, we and others investigate the possibility that low-grade inflammation contributes to this psychiatric vulnerability (7). We have notably shown that low-grade inflammation is associated with behavioral changes in obese individuals, such as fatigue (8) or altered cognitive functions (9). One interpretation of this relationship is that the production of inflammatory factors at a low-grade state may be sufficient to induce behavioral alterations and therefore could be one factor participating to the vulnerability to depression.
Low-grade inflammation and chronic pain
The association between low-grade inflammation and behavioral alterations has caused the team of the Behavioral Medicine Pain Treatment Service at the Karolinska University Hospital in Stockholm (Sweden) to wonder whether low-grade inflammation could modulate the efficacy of behavioral treatments for chronic pain. Cognitive and behavioral strategies are indeed the targets of behavioral treatments for chronic pain and low-grade inflammation could prevent the effects of such treatments.
In collaboration with this group, we showed that treatment outcomes were improved in patients with chronic pain and low levels of inflammatory factors while patients with “low-grade inflammation”, i.e., with higher levels of inflammatory markers but still in the healthy range, exhibited less improvement (10).
Although this study was only exploratory, the findings suggest that low-grade inflammation may promote a state of resistance to behavioral treatment for chronic pain and give a potential explanation regarding non-responder patients.
About Julie Lasselin
Dr Julie Lasselin is a “psychoneuroimmunologist”, conducting research assessing the relationships between the brain and the immune system. She got her Ph.D. in 2012 in NutriNeuro in Bordeaux, France. She then has been working as a post-doc at the Department of Clinical Neuroscience (Psychology Division), Karolinska Institute and at the Stress Research Institute, Stockholm University in Stockholm, Sweden. Julie is currently a post-doc in the Institute of Medical Psychology and Behavioral Immunobiology in Essen, Germany and is affiliated to the Karolinska Institute and Stockholm University. Her research focuses on the contribution of inflammation on the development of neuropsychiatric symptoms in vulnerable populations, such as patients suffering from obesity and type 2 diabetes. She carries out both clinical observational studies and experimental studies using the model of administration of lipopolysaccharide (a component of bacterial shell) in humans. She also assesses more specifically the role of inflammation in fatigue and motivational changes, two symptoms that are highly sensitive to inflammation and may explain the psychiatric vulnerability of obese patients.”
References
1. Wellen, K.E. and G.S. Hotamisligil, Obesity-induced inflammatory changes in adipose tissue. J Clin Invest, 2003. 112:1785-8.
2. Dantzer, R., Depression and inflammation: an intricate relationship. Biol Psychiatry, 2012. 71: p. 4-5.
3. Parkitny, L., et al., Inflammation in complex regional pain syndrome: a systematic review and meta-analysis. Neurology, 2013. 80:106-17.
4. Dantzer, R., et al., From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci, 2008. 9:46-56.
5. Capuron, L. and A.H. Miller, Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther, 2011. 130:226-38.
6. Evans, D.L., et al., Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry, 2005. 58:175-89.
7. Capuron, L., J. Lasselin, and N. Castanon, Role of Adiposity-Driven Inflammation in Depressive Morbidity. Neuropsychopharmacology, 2016 (in press).
8. Lasselin, J., et al., Fatigue symptoms relate to systemic inflammation in patients with type 2 diabetes. Brain Behav Immun, 2012. 26:1211-9.
9. Lasselin, J., et al., Low-grade inflammation is a major contributor of impaired attentional set shifting in obese subjects. Brain Behav Immun, 2016. 58:63-68.
10. Lasselin, J., et al., Low-grade inflammation may moderate the effect of behavioral treatment for chronic pain in adults. J Behav Med, 2016. 39:916-24.
A recent and in-depth research regarding the influence of gut microbiota, diet and exercise on intestinal permeability.
A recent and in-depth research regarding the influence of gut microbiota, diet and exercise on intestinal permeability.
Tetiana R. Dmytriv et al. 2024.
For the full test: Tetiana R. Dmytriv et al. DOI 10.3389/fphys.2024.1380713. PUBLISHED 08 July 2024
Highlighted
1. The intestinal wall [21consists of three layers: mucous, epithelial, and lamina propria. The mucous layer is inhabited by microorganisms, many of which mutually beneficially coexistence within the human body. These microorganisms modulate many if not most living processes: from the development of the immune and nervous systems at early stages of life to the induction of chronic inflammation causing neurodegeneration at aging. Despite the fact that these microorganisms have coexisted with humans for many years, under certain conditions the enteral immune system of the lamina propria can perceive them as foreign and trigger a pro- inflammatory response.
2. Normally, the intestinal mucosa is semipermeable. It allows selective absorption of nutrients into the bloodstream but prevents the entrance of potentially harmful microorganisms and their waste products from contact with the enteral immune system. An imbalance of the intestinal microbiota, called dysbiosis, can cause a disturbance of intestinal integrity and increase intestinal permeability.
3. Excessive intestinal wall permeability provokes the development of chronic low-grade inflammation.
4. Nutrition looks to be the simplest non-pharmacological effector of integrity and permeability of the intestinal wall. It can have both a negative effect, such as HFD inducing metabolic endotoxemia, or a positive effect, such as a diet rich in plant polyphenols or fermented dairy products, increasing the expression of TJ proteins [2] and promoting the development of beneficial bacteria.
5. Exercise also can affect gut intestinal permeability. Its effects depend on duration and intensity of exercise. Acute extensive physical exertion often increases intestinal permeability which may be related to the induction of heat stress, that organisms cannot cope with at that time due to insufficient resources. On the other hand, regular low and moderate intensity exercises, that are adaptive in nature, mostly have a positive effect on the integrity of the intestine and decrease its permeability.
“The intestinal wall is a selectively permeable barrier between the content of the intestinal lumen and the internal environment of the body. Disturbances of intestinal wall permeability can potentially lead to unwanted activation of the enteric immune system due to excessive contact with gut microbiota and its components, and the development of endotoxemia, when the level of bacterial lipopolysaccharides increases in the blood, causing chronic low-intensity inflammation. In this review, the following aspects are covered: the structure of the intestinal wall barrier; the influence of the gut microbiota on the permeability of the intestinal wall via the regulation of functioning of tight junction proteins, synthesis/degradation of mucus and antioxidant effects; the molecular mechanisms of activation of the pro-inflammatory response caused by bacterial invasion through the TLR4-induced TIRAP/MyD88 and TRAM/TRIF signaling cascades; the influence of nutrition on intestinal permeability, and the influence of exercise with an emphasis on exercise-induced heat stress and hypoxia. Overall, this review provides some insight into how to prevent excessive intestinal barrier permeability and the associated inflammatory processes involved in many if not most pathologies. Some diets and physical exercise are supposed to be non-pharmacological approaches to maintain the integrity of intestinal barrier function and provide its efficient operation. However, at an early age, the increased intestinal permeability has a hormetic effect and contributes to the development of the immune system.
Introduction
The intestinal wall is a complex system consisting of four layers: mucosa, submucosa, muscularis, and serosa. The term “intestinal barrier” emphasizes the protective component of the intestinal wall, whereas intestinal permeability is a measurable characteristic of the functional status of the intestinal barrier (Bischoff et al., 2014). The wall provides selective absorption of nutrients and other components of the intestinal lumen. At the same time, the intestinal barrier protects the body from the entrance of unwanted foreign substances, food particles, microorganisms, and their components. In normally functioning organisms, the permeability of the intestinal wall is tightly controlled but its disturbance, if not adequately fixed, can lead to many, if not most, acquired pathologies (Gieryńska et al., 2022).
The gastrointestinal tract (GIT) is inhabited by diverse microbes called gut microbiota forming very dynamic community.
Figure 1 The schematic structure of the intestinal barrier. For details see the text.
The “Old Friends Hypothesis” suggests that people coevolved with many microbes that, in addition to many physiological functions, also stimulate the development of the immune system and regulate its operation (Rook, 2023). Microbial antigens are under constant surveillance by the enteric immune system. Regulatory immune T cells are responsible for maintaining immune tolerance of homeostatic gut microbiota (Wu and Wu, 2012). However, increased intestinal permeability can promote translocation of luminal bacteria and microbial-associated molecular patterns, in particular, lipopolysaccharides (LPS) from the gut into bloodstream, triggering the development of endotoxemia and chronic low- intensity inflammation (Vanuytsel et al., 2021). Diet-induced endotoxemia is defined as metabolic endotoxemia. For example, Cani et al. (2007) established that a high-fat diet chronically increased plasma LPS concentrations two-to threefold.
Endogenous lipopolysaccharides LPS are constantly released as a result of the death of Gram-negative bacteria in the gut. At increased intestinal barrier permeability, LPS are absorbed into the portal bloodstream, from where they are transported by lipoproteins directly into the liver, forming the gut-liver axis. Further, they are metabolized by liver enzymes and excreted with bile. However, if their degradation or biliary excretion are impaired, LPS can reach the systemic circulation, where they bind to Toll-like receptor 4 (TLR4) on leukocytes, endothelial cells, and platelets, causing arterial inflammation. Ultimately, this leads to activation of blood coagulation and thrombus formation, which demonstrates that LPS-induced inflammation associated with increased intestinal wall permeability may be involved in the development of atherosclerosis and thrombotic diseases (Violi et al., 2023). In general, disruption of intestinal barrier function is involved in many GIT-related and unrelated diseases, including inflammatory bowel disease, metabolic dysfunction-associated liver disease, bile acid malabsorption, celiac disease, type I diabetes, obesity, schizophrenia, and others (Vanuytsel et al., 2021). Potentially, this could be overcome by a non-pharmacological intervention based on diet and exercises (Pražnikar et al., 2020; Ordille and Phadtare, 2023) which promote a healthy gut ecosystem and alleviate the symptoms of many pathologies.
In this review, we describe the structure of the intestinal wall and molecular mechanisms of the pro-inflammatory response caused by bacterial invasion due to the disturbance of the intestinal wall permeability, as well as influences of the gut microbiota, diet, and exercises on the permeability of the intestinal wall. Specific diets and regular low- and moderate-intensity exercises are proposed as effective non-pharmacological approaches to maintain integrity of intestinal wall and its efficient operation. However, at an early age, controlled leakage of the intestine may be necessary to trigger the development of immune system via hormetic mechanisms.
2 The structure of the intestinal barrier
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3 Intestinal permeability
Semi-permeability or selective permeability is a crucial feature of the intestinal wall. It limits penetration of pathogens but allows the permeability of nutrients, water, and ions. Endogenous (e.g., inflammation) and exogenous (e.g., diet components, toxicants, or drugs) factors can increase intestinal permeability and cause the formation of a so-called “leaky gut.” The latter is characterized by the penetration of food antigens, commensals, or pathogenic bacteria into the blood, causing the development of inflammation (Vanuytsel et al., 2021). Some diseases can also act as a disruptor factor of the intestinal barrier. For example, several studies show that hyperglycemia, a key feature of diabetes, induces intestinal barrier dysfunction (Thaiss et al., 2018; Dubois et al., 2023). Prolonged exposure to glucose at high levels increases migration capacity of human colonic cell line Caco-2, resulting in layers appearing less organized than under physiological conditions. In particular, this is associated with decreased expression of tight junction (TJ) proteins, which contributes to the disruption of the structural network associated with them and an increase in the permeability of the intestinal barrier (Dubois et al., 2023). In turn, this contributes to the penetration of luminal bacteria, and the development of dysbacteriosis resulting in inflammation. For example, Harbison et al. (2019) showed that children with type I diabetes have gut microbiota dysbiosis associated with increased intestinal permeability. In particular, lower microbial diversity, lower numbers of anti-inflammatory bacterial species, and SCFA- producing bacteria were observed, and these changes were not explained by differences in diet. Thus, some diseases, including diabetes, can also play the role of disruptors of the intestinal barrier.
Mucus and epithelium are the most important components of the intestinal barrier that limit the development of inflammation. The mucous layer consists of two sublayers (Figure 1). The outerlayer is thick and loose. It is inhabited by a large number of commensal microorganisms that form colonies, and under healthy conditions pathogenic bacteria cannot outgrow them or penetrate further. In other words, homeostatic microorganisms efficiently compete with potentially pathogenic ones and prevent their excessive proliferation. The inner sublayer, on the contrary, is solid and contains only a few microbes (Usuda et al., 2021). The gut microbiota plays a major role in changing the composition of mucus, regulating its synthesis and degradation.
Epithelial cells are connected by TJ proteins (Lee et al., 2018) which regulate the absorption of water, ions, and dissolved substances. They include two functional categories of proteins: integral transmembrane proteins, located at the border of adjacent cell membranes, and adaptive peripheral membrane proteins that connect integral proteins with the actin cytoskeleton. The former includes occludin, claudins, junctional adhesion molecules, and tricellulin whereas the latter include zonula occludens-1 (ZO-1), ZO-2, and ZO-3 (Lee et al., 2018). The gut microbiota can influence the expression and localization of all of these TJ proteins.
3.1 Influence of the gut microbiota on tight junction proteins
TJ proteins regulate the rate of paracellular transport including the transport of consumed nutrients via the path between neighboring epithelial cells. In electron micrographs TJ proteins look like points of fusion of the membranes of neighboring cells where there is no intercellular space in these places (Gonzalez- Mariscal et al., 2003). They play the role of sensors of environmental conditions that dynamically regulate the paracellular transport of solutes (Ulluwishewa et al., 2011). Dysregulation of TJ proteins can lead to excessive permeability of the intestinal barrier.
Bacteria can change the expression and distribution of TJ proteins and thus affect intestinal permeability. For example, some pathogenic strains of Escherichia coli, including E. coli O157:H7 strain which causes bloody diarrhea, produce toxins such as Shiga toxins (STx). The latter suppress protein biosynthesis and contribute to the development of hemolytic uremic syndrome, which is a life-threatening complication. Pradhan et al. (2020) found that STx2a decreases the expression of TJ proteins such as ZO-2, occludin, and claudin-1 (Pradhan et al., 2020). However, this strain requires the presence of non-pathogenic E. coli, which enhances the expression of Stx2a. In this way, non- pathogenic E. coli decreases the expression of TJ proteins, increasing the production of the STx2a toxin by E. coli O157:H7 strain (Xiaoli et al., 2018). This indicates that, under certain conditions, even non- pathogenic microbiota can have a negative impact on intestinal wall permeability. Contrarily, the use of probiotics (living microorganisms that are beneficial to the host organism when administered in adequate amounts) may contribute to the integrity of the intestinal barrier (Ulluwishewa et al., 2011; Gou et al., 2022). In particular, Lactobacillus and Bifidobacterium species are the most commonly used probiotics. For example, Lactobacillus reuteri increases the expression of TJ proteins and thus supports the integrity of the intestinal wall (Gou et al., 2022). Oral administration of L. reuteri I5007 significantly increased the levels of claudin-1, occludin, and ZO-1 in newborn piglets. An in vitro study showed that pretreatment of intestinal porcine epithelial cell line J2 with this bacterial strain suppressed a LPS-induced decrease in TJ protein expression (Yang et al., 2015). Administration of L. plantarum into the duodenum of healthy people increased the level of ZO-1 and occludin. However, L. plantarum did not significantly affect expression of occludin in vitro human epithelial model but induced translocation of ZO-1 into the TJ region which forms a paracellular seal between epithelial cells (Karczewski et al., 2010; Caminero et al., 2023). Bifidobacterium infantis and L. acidophilus prevented dysregulation of occludin and claudin-1 levels in colon carcinoma cell line (Caco-2) stimulated by IL-1β treatment. These strains normalized their expression and contributed to the integrity of the intestinal barrier (Guo et al., 2017). For convenience, we have summarized some available information regarding the influence of different probiotic bacterial strains on TJ proteins in Table 1. In general, probiotic bacteria can both increase and decrease TJ proteins. However, in most cases, this does not cause excessive intestinal permeability, but on the contrary, normalizes it and contributes to its integrity.
Antibiotics used to treat bacterial infections may adversely affect the gut microbiota. They cause an imbalance between specific groups of bacteria and trigger the development of dysbacteriosis (Tulstrup et al., 2015). Dysbacteriosis, in turn, contributes to intestinal permeability. An increase in the population of pathogenic bacteria at dysbacteriosis which probably produce higher levels of LPS, can damage epithelial cells of the intestinal barrier and contribute to increased intestinal permeability. For example, it was shown that changes in the microbial composition correlated with an increase in intestinal permeability in alcohol- dependent subjects (Leclercq et al., 2014).
In addition, the gut microbiota is a significant source of digestive proteases used to break down host proteins for their own needs. However, excessive activity of microbial proteases can disrupt the epithelial components of the intestinal barrier due to cleavage of TJ proteins. In turn, changes in TJ proteins lead to an increase in the paracellular permeability of the epithelial barrier (Caminero et al., 2023).
3.2 The role of gut microbiota in biosynthesis and degradation of mucous layer components
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3.3 Antioxidant effects of intestinal microorganisms
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4 Molecular mechanisms of the activation of pro-inflammatory response caused by bacterial invasion
Dysbacteriosis of the gut microbiota can lead to disruption of intestinal barrier function and immune homeostasis. Increased intestinal permeability facilitates the translocation of microbes, their components, and microbial products into the blood stream and their recognition by the host immune cells (Longo et al., 2020). The gut microbiota is the main reservoir of pro-inflammatory endotoxins inside the body. In particular, LPS, the main component of the outer membrane of Gram-negative bacteria, can cause so-called endotoxemia. The latter develops when the level of LPS in the blood increases and this leads to the activation of a pro-inflammatory immune response triggering systemic low-grade inflammation (André et al., 2019). A diet-induced increase in LPS concentration in the blood is called metabolic endotoxemia. The level of LPS in the blood serum of mice that consumed high-fat diet (HFD) for 4 weeks is similar to its level in metabolic endotoxemia (Mohammad and Thiemermann, 2021). This clearly shows how nutrition can affect intestinal permeability and immune response.
The dynamic interaction between the gut microbiota and the intestinal immune system plays a key role in maintaining intestinal homeostasis. Host cells contain pattern recognition receptors (PRRs) which recognize bacterial pathogen-associated molecular patterns (PAMPs). The latter are highly conserved bacterial motifs, possessed in LPS, oligodeoxynucleotides, peptidoglycans, and others that can trigger host immune response (Asiamah et al., 2019).
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