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Hydrocolloids and Food Emulsifiers II part

by luciano

C – Hydrocolloids also modulate gut microbiota, offering various health benefits. Certain hydrocolloids, such as inulin and pectin, act as prebiotics, promoting beneficial gut bacteria growth and influencing microbiota composition and diversity (Bouillon et al., 2022; Gularte & Rosell, 2011).

D – Hydrocolloids are long-chain hydrophilic polymers used in food systems for thickening, gelling, and stabilization. They significantly influence starch retrogradation, hydrolysis, and modulation of the gut microbiota, with both positive and negative effects. These effects depend on factors such as the type of hydrocolloid, its concentration, interactions with starch, and environmental conditions such as temperature and processing methods. Some hydrocolloids inhibit starch retrogradation by interrupting amylose recrystallization, while others promote it under certain conditions. They can also alter starch hydrolysis by modifying the accessibility of enzymes to starch granules, slowing or accelerating digestion. Furthermore, hydrocolloids act as fermentable fibers, promoting the growth of beneficial gut bacteria, which can influence metabolic processes. Despite significant advances, the complexity of these interactions remains incomplete, as the effects vary depending on the composition of the individual microbiota. This review explores the mechanisms by which hydrocolloids modulate starch behaviors and the gut microbiota, synthesizing the current literature and identifying future research directions to address existing knowledge gaps.
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In food systems, hydrocolloids influence starch retrogradation, starch hydrolysis, and gut microbiota modulation, essential factors for both food quality and human health.
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Several hydrocolloids, including xanthan gum, pectin, β-glucan, and konjac glucomannan, influence starch hydrolysis and reduce its digestibility. Their effects depend on their molecular structure, source, concentration, interactions with starch, and processing conditions (Ma et al., 2024). By increasing the viscosity of starch-based matrices, hydrocolloids create a resistant gel network, slowing the enzymatic degradation of starch in the gastrointestinal tract. This delayed hydrolysis results in a controlled glucose release and a lower postprandial glycemic response (Bae & Lee, 2018; Bellanco et al., 2024). Consequently, hydrocolloids have the potential to improve glycemic control and reduce the risk of metabolic disorders such as type 2 diabetes. Yassin et al. (2022) reported that incorporating xanthan gum, lambda-carrageenan, or psyllium husk (1–5% w/w of flour weight) into white bread significantly reduced glycemic potency, with psyllium husk at 5% w/w exerting the strongest effect. Similarly, Mæhre et al. (2021) found that white bread fortified with guar gum reduced postprandial glycemic responses.
Hydrocolloids also modulate the gut microbiota, offering several health benefits. Some hydrocolloids, such as inulin and pectin, act as prebiotics, promoting the growth of beneficial gut bacteria and influencing the composition and diversity of the microbiota (Bouillon et al., 2022; Gularte & Rosell, 2011). Their prebiotic effects depend on their physicochemical properties, with variations in polymeric structure and source influencing gut health outcomes (Ağagündüz et al., 2023). Reported benefits include improved digestion, enhanced immune function, and reduced inflammation, although the extent and mechanisms of these effects remain inconsistent in the literature (Zhang et al., 2023). Further research is needed to fully understand both the benefits and potential limitations of hydrocolloid applications for gut health. This review provides an in-depth analysis of the effects of hydrocolloids on starch retrogradation, digestibility, and the gut microbiota, addressing both positive and negative findings, and aims to inform the development of functional foods with improved health benefits. The multifunctional role of hydrocolloids in modulating retrogradation, starch hydrolysis, and the gut microbiota. Xikun Lu et al. Food Chemistry
Volume 489, 15 October 2025, 144974.

Hydrocolloids and Food Emulsifiers I part

by luciano

Introduction
Hydrocolloids and emulsifiers are both food additives, but they have different functions. Hydrocolloids are substances that thicken, gel, or stabilize foods, while emulsifiers help mix immiscible substances like oil and water.

Hydrocolloids
Are substances that, in aqueous solution, form a colloidal system, increasing viscosity or forming gels.Their main function is to modify the consistency of foods, making them thicker, creamier, or gelatinous. They can also stabilize emulsions or suspensions, preventing phase separation.
Some examples of hydrocolloids: agar-agar, modified starches, beta-glucans, carrageenans, pectin, carob seeds, bamboo fibers, potato fibers, pea fibers, gelatins, gum arabic, xanthan gum, guar gum, and inulin. In which products are they most likely to be found: baked goods and pastries, biscuits, ice cream, yogurt, sports drinks (especially maltodextrin

Emulsifiers:
They are molecules that have a hydrophobic (fat-loving) portion and a hydrophilic (water-loving) portion. This structure allows them to stabilize emulsions, which are mixtures of immiscible liquids such as oil and water. Emulsifiers sit between the two phases, reducing surface tension and preventing separation. Common examples include lecithin, mono- and diglycerides of fatty acids, and polysorbates.
In short, while hydrocolloids modify the overall texture of a food, emulsifiers work specifically to keep emulsions stable, preventing the separation of oil and water. Some hydrocolloids, such as lecithin, can also have emulsifying properties.

Hydrocolloids

A -Hydrocolloids enable products with long shelf lives, the inclusion of whole grain flours and fiber, the absence of trans fats, and, last but not least, the absence of gluten. Hydrocolloids are molecules capable of binding water in large quantities; among the most commonly used in baked goods are xanthan gum, pectin, modified cellulose, and fructo- and galacto-oligosaccharides. Some of these substances are considered dietary fibers, capable of stimulating a feeling of satiety and having positive effects on intestinal function. Hydrocolloids often achieve their technological-functional effect in the product even when added to dough in small quantities, for example, less than 1% of the total powdered ingredients. In bread dough and other baked goods, hydrocolloids help improve dough workability during production thanks to their rapid and uniform hydration. The volume, structure, and softness of the finished products are improved.
Fragility is reduced, for example, in the case of “foamy” baked goods with a high presence of air bubbles or suspended particles (chocolate, fruit, or nuts): these bubbles or particles are stabilized within the system thanks to hydrocolloids. During storage, the shelf life of the products is also increased by maintaining their softness for longer periods: the difference compared to products without hydrocolloids becomes more evident as time passes. Finally, it appears that the presence of hydrocolloids is also able to influence the size of ice crystals within bread dough or other semi-cooked products during freezing, resulting in a higher-quality thawed product (Reference H1).
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There are unit operations that are difficult to implement for foods that do not involve the use of gluten, such as the extrusion, drawing, or lamination phases that occur in pasta or some baked goods. The stresses that occur in these phases require elasticity in the dough, therefore, formulations capable of withstanding the continuous processing of a perhaps pre-existing plant are essential (Reference H2).
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Comparing gluten-free crackers, we find extremely simple formulations, with corn and rice flours, and more complex ones, with the addition of potato starch, dextrose, emulsifiers, and thickeners. From a nutritional standpoint, it’s clear that the food may be richer in sugars and some fats than the same conventional product. Sandwich bread, more difficult to make because it’s leavened, features rather complex formulations based on corn, rice, or buckwheat, starches, vegetable fibers, proteins, sugars, thickeners (including hydrocolloids), emulsifiers, and acidifiers. This recipe implies, nutritionally, either an increase in carbohydrates of approximately 10-15% compared to the conventional product in the same category, or an increase in fats, especially saturated fats, of approximately 30-50% (Reference H3).
In the confectionery sector, the considerations are more or less the same, since from a nutritional point of view, compared to conventional products, they remain higher values of carbohydrates, especially sugars, and fats, mainly saturated, to compensate for the lack of viscoelasticity of the protein part. Prodotti e tecnologie per alimenti senza glutine. Macchine alimentari – Anno XVII -1 – Genn. Feb 2015

B – The food industry has been committed to providing consumers with high-quality rheological properties along with healthy and nutritious food products (Goff & Guo, 2019; Manzoor, Singh, Bandral, Gani, & Shams, 2020). Consequently, recent years have seen the widespread use of food hydrocolloids in the formulation/reformulation of various food categories, the production of functional foods, and innovation initiatives (Manzoor et al., 2020). Food hydrocolloids are considered crucial food components due to their improvements in viscosity, gelation, and thickening, enhancing the rheology and sensory properties of foods (Saha & Bhattacharya, 2010; Goff & Guo, 2019). The terms gum and mucilage may also be used interchangeably with hydrocolloids. Regardless of what they are called, these ingredients are generally found in industrial applications as viscosity improvers, emulsifiers, coating agents, gelling agents, stabilizing agents, and thermodynamic stability providers (Goff & Guo, 2019; Maity, Saxena e Raju, 2018; Manzoor et al., 2020) (Fig. 1).
They find functional applications mainly in food products, including confectionery (glazing agents, texturizers), specific beverages (emulsifiers), dairy products (thickeners and stabilizers), pastries (bulking agents, sensory quality and shelf-life improvers), and frozen fruits and vegetables (cryoprotectant) (Maity et al., 2018; Salehi, 2020; Viebke, Al-Assaf, and Phillips, 2014). Recently, food-grade hydrocolloids have reached the forefront due to their health benefits and significant pharmaceutical, as well as food, applications. Furthermore, their potential health effects and the mechanisms of their dietary intake have been studied.
Recent literature has indicated that dietary hydrocolloids play crucial roles on the gut microbiota due to their diverse physicochemical or structural properties (Tan & Nie, 2021). Some of these important roles are their prebiotic impacts, stimulating the production of short-chain fatty acids (SCFA), reducing gastrointestinal discomfort as well as preserving normal intestinal function (Marciani et al., 2019; Viebke et al., 2014; Williams & Phillips, 2021, pp. 3–26), an increase in viscosity within the intestinal lumen, a reduction or increase in the absorption of some nutrients (Nybroe et al., 2016), lower cholesterol (Manzoor et al., 2020; McClements, 2021), a decrease in hyperglycemia (Lu, Li, & Fang, 2021) as well as normal body weight regulation (Johansson, Andersson, Alminger, Landberg, & Langton, 2018; Viebke et al., 2014). Furthermore, research on hydrocolloids and intestinal modulation appears to be expanding day by day thanks to cutting-edge multi-omics technologies and detailed analysis of the human microbiome. This article provides a comprehensive overview of specific dietary hydrocolloids, particularly those with a polysaccharide structure in intestinal modulation, and their potential interactions with nutrition and health.
A comprehensive review on food hydrocolloids as gut modulators in the food matrix and nutrition: The hydrocolloid-gut-health axis. al. 2023. https://doi.org/10.1016/j.foodhyd.2023.10906

Emulsifiers and Hydrocolloids

by luciano

Premise

Hydrocolloids and emulsifiers are both food additives, but they have different functions. Hydrocolloids are substances that thicken, gel or stabilize food, while emulsifiers help mix immiscible substances such as oil and water.

Hydrocolloids

They are substances that, in aqueous solution, form a colloidal system, increasing viscosity or forming gels.

Their main function is to modify the consistency of foods, making them denser, creamier or gelatinous.

They can also stabilize emulsions or suspensions, preventing phase separation.

Some examples of hydrocolloids: agar-agar, modified starches, beta-glucans, carrageenin, pectin, carob seeds, bamboo fibers, potato fibers, pea fibers, gelatins, gum arabic, xanthan gum, guar, inulin. In which products is it easier to find them: bakery and pastry products, biscuits, ice cream, yogurt, sports drinks (especially maltodextrins).

Emulsifiers:

They are molecules that have a hydrophobic part (fat lover) and a hydrophilic part (water lover).

This structure allows them to stabilize emulsions, i.e. mixtures of immiscible liquids such as oil and water.

The emulsifiers are arranged between the two phases, reducing the surface tension and preventing separation.

Common examples include lecithin, mono- and diglycerides of fatty acids and polysorbates.

In summary, while hydrocolloids modify the general consistency of a food, emulsifiers work specifically to keep the emulsions stable, avoiding the separation of oil and water. Some hydrocolloids, such as lecithin, may also have emulsifying properties.

Emulsifiers

Highlighted:
A recent study, published in The Lancet Diabetes & Endocrinology, evaluated for the first time the association between emulsifiers and the risk of developing type 2 diabetes

I – Emulsifiers and diabetes risk: Lancet’s study

Although the Health Authorities consider their use in defined quantities safe, based on criteria of cytotoxicity and genotoxicity, recently, evidence is emerging of their negative effects on the intestinal microbiota, which in turn trigger inflammation and metabolic alterations.

After being accused of contributing to the risk of obesity, cancer and cardiovascular diseases, a recent analysis (Seven emulsifiers incriminated for potential increased risk of type 2 diabetes SID, Italian Society of Diabetology 07-05-2024) conducted on the prospective study of NutriNet Santé cohort identifies them as factors that increase the risk of type 2 diabetes.
The study, published in The Lancet Diabetes & Endocrinology [1] evaluated for the first time the association between emulsifiers and risk of developing type 2 diabetes. The Authors analyzed the data of over 104 thousand adults enrolled from 2009 to 2023 who were asked to fill out 24-hour dietary records every 6 months. The objective was to evaluate the exposure to emulsifiers.
1% of the sample developed type 2 diabetes during the 6-8 year follow-up.

Of the 61 identified additives, seven are ‘attention’ emulsifiers associated with a potential increase in the risk of diabetes (eyes, therefore, on the labels!):

E407 (total carrageenan);
E340 (polyglycerol esters);
E472e (fatty acid esters);
E331 (sodium citrate);
E412 (guar gum);
E414 (gum arabic);
E415 (xanthan gum);

In addition to a group called ‘carrageenine’.

Emulsifier additives were taken in 5% from ultra-processed fruits and vegetables (such as canned vegetables and fruit in syrup), in 14.7% from cakes and biscuits, in 10% from dairy products.

Three consequences highlighted by prof. Angelo Avogaro, President of SID

1. The need to contain the consumption of ultra-processed foods;

2. The call for greater attention to labels;

3. The need to call for stricter regulation in order to protect consumers.

“Although further long-term studies are needed, changes in the intestinal microbiota suggest that RDAs (Recommended Daily Allowance) may need to be reviewed. Previous evidence linking carrageenan intake to intestinal inflammation has led JECFA to limit its use in formulas and infant foods. We are witnessing a worrying increase in type 2 diabetes even among children and adolescents” underlines Prof. Raffaella Buzzetti, President-elect of the ISD.

Notes

[1] Food additive emulsifiers and the risk of type 2 diabetes: analysis of data from the NutriNet-Santé prospective cohort study. The Lancet Diabete and Endocrinology, volume 12, issue 5, p339-349, May 2024.

2 – Direct impact of commonly used dietary emulsifiers on human gut microbiota
Abstract.
Background: Epidemiologic evidence and animal studies implicate dietary emulsifiers in contributing to the increased prevalence of diseases associated with intestinal inflammation, including inflammatory bowel diseases and metabolic syndrome. Two synthetic emulsifiers in particular, carboxymethylcellulose and polysorbate 80, profoundly impact intestinal microbiota in a manner that promotes gut inflammation and associated disease states. In contrast, the extent to which other food additives with emulsifying properties might impact intestinal microbiota composition and function is not yet known.
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Conclusions: These results indicate that numerous, but not all, commonly used emulsifiers can directly alter gut microbiota in a manner expected to promote intestinal inflammation. Moreover, these data suggest that clinical trials are needed to reduce the usage of the most detrimental compounds in favor of the use of emulsifying agents with no or low impact on the microbiota. Direct impact of commonly used dietary emulsifiers on human gut microbiota. Sabrine Naimi. et al. Microbiome (2021) 9:66 https://doi.org/10.1186/s40168-020-00996-6

3 – Dietary Emulsifiers Alter Composition and Activity of the Human Gut Microbiota in vitro, Irrespective of Chemical or Natural Emulsifier Origin.
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Discussion
We found dietary emulsifiers to significantly alter human gut microbiota toward a composition and functionality with potentially higher pro-inflammatory properties. While donor-dependent differences in microbiota response were observed, our in vitro experimental setup showed these effects to be primarily emulsifierdependent. Rhamnolipids and sophorolipids had the strongest impact with a sharp decrease in intact cell counts, an increased abundance in potentially pathogenic genera-like Escherichia/Shigella and Fusobacterium, a decreased abundance of beneficial Bacteroidetes and Barnesiella, and a predicted increase in flagellar assembly and general motility. The latter was not substantiated through direct measurements, though. The effects were less pronounced for soy lecithin, while chemical emulsifiers P80 and CMC showed the smallest effects. Short chain fatty acid production, with butyrate production, in particular, was also affected by the respective emulsifiers, again in an emulsifier‐ and donordependent manner.

….omissis. One of the most profound impacts of emulsifier treatment toward gut microbiota was the decline in intact microbial cell counts. The degree of microbiome elimination in this study seems comparable to what has been observed for antibiotic treatments (Francino, 2016; Guirro et al., 2019). Since antibiotics are considered detrimental for gut ecology, this may serve as a warning sign with respect to emulsifier usage. Emulsifiers also act as surfactants, which are known for their membrane solubilizing properties (Jones, 1999). The fact that the observed decline in microbial viability was dependent on emulsifier dose and on the emulsifying potential of the supplemented compound, as measured by the aqueous surface tension reduction (Table 1), leads us to conclude that the dietary emulsifiers attack the bacterial cells principally at the level of the cell membrane.

………….omissis. A last important element in the putative health impact from dietary emulsifiers concern’s interindividual variability. An individual’s unique microbiota and metabolism are important determinants of the potential health effects dietary emulsifiers could cause. While the overall effects from the different emulsifiers toward microbiota composition and functionality were quite consistent in our study, important interindividual differences in susceptibility of the microbiota were noted. Understanding what underlying factors and determinants drive this interindividual variability will be crucial to future health risk assessment of novel and existing dietary emulsifiers. Dietary Emulsifiers Alter Composition and Activity of the Human Gut Microbiota in vitro, Irrespective of Chemical or Natural Emulsifier Origin. Lisa Miclotte et al. Front. Microbiol., 05 November 2020. Sec. Microbial Symbioses
Volume 11 – 2020 | https://doi.org/10.3389/fmicb.2020.577474

Low-grade inflammation and the brain

by luciano

“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.

by luciano

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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