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A recent and in-depth research regarding the influence of gut microbiota, diet and exercise on intestinal permeability II part

by luciano

Link I part A recent and in-depth research regarding the influence of gut microbiota, diet and exercise on intestinal permeability. I Part

6 Exercise as a regulator of intestinal barrier integrity

Regular moderate physical exercises are one of the most common recommendations for the prevention of various pathologies, including disruption of the integrity of the intestinal barrier. This may be due to the influence of the gut microbiota. In particular, exercises have been found to increase gut bacterial diversity (Hintikka et al., 2023). However, effects of physical exercises depend on their intensity. For example, endurance athletes have a high incidence of gastrointestinal disorders and the “leaky” gut is one of the most common disorders (Ribeiro et al., 2021). It is characterized by dysfunction of the intestinal epithelial barrier and its excessive permeability. This results in penetration of harmful microorganisms, toxins or undigested food particles into the bloodstream and has a negative effect on health of the whole organism (Aleman et al., 2023).
The effect of exercise on intestinal permeability depends on its duration and intensity. For example, people who exercise frequently and intensely have the same mortality rates as people who lead a sedentary lifestyle (Van Houten et al., 2015). A 60 min bout of intensive treadmill running increased the permeability of the small intestine in runners, whereas low-intensity running had no such effect (Pals et al., 1997). Using the overtraining model with male C57BL/6 mice, it was established that exhaustive exercise exacerbated intestinal inflammation, disrupted integrity and enhanced intestine wall permeability (Hou et al., 2020). Sustained strenuous exercise in racing sled dogs increased the intestinal permeability and the frequency of gastric erosions or ulcerations (Davis et al., 2005). High-intensity interval running increased intestine wall permeability and intestinal-fatty acid binding protein (I-FABP) release in male runners (Pugh et al., 2017). I-FABP is a cytoplasmic protein expressed exclusively in the enterocytes of the small intestine and its increased concentration in the blood is used as a marker of damage to intestinal epithelial cells (Sikora et al., 2019).
Physical exercise of low/moderate intensity can often have positive effects and can be considered as a method of non-pharmacological intervention in inflammatory bowel disease (Ordille and Phadtare, 2023). For example, mice that swam for 30 min before inducing intestinal barrier dysfunction had less intestinal dysfunction compared to mice that had not swum before. This might happen due to a strengthening of antimicrobial function of the intestine as a result of the increase in expression of antimicrobial peptides (Luo et al., 2014). Obese mice that were trained on a motorized treadmill for 45 min per day 5 days a week for 12 weeks had higher expression levels of colonic ZO-1 and occludin. Moderate exercise effectively prevented the development of dysbacteriosis caused by the HFD, as well as intestinal pathology (Wang et al., 2022). Dysbacteriosis and impaired intestinal barrier integrity induced by HFD in wild type mice was prevented by exercise. Exercise on a motor-driven rodent treadmill for 5 days a week for a total of 15 weeks significantly reversed the pathological changes. Ablation of Sestrin 2 protein attenuated the protective effects of exercise, suggesting its involvement in regulation of intestinal permeability (Yu et al., 2022). Thus, it can be concluded that high-intensity exercises often have a negative effect on the integrity of the intestine, whereas low- and moderate-intensity regular exercise can have a positive effects. It may be speculated that moderate damage to the intestinal wall is a hormetic factor that may be used to train organisms to cope with severe damaging challenges. This may be used to increase the adaptive potential of organisms to prevent damaging effects of any stresses of physical and chemical nature on the integrity of the intestinal wall.

6.1 Exercise-induced heat stress

It is known that physical exertion causes heat stress and associated dysfunction of gut integrity. A systematic review examining the relationship between an exercise-induced increase in core body temperature and intestinal permeability demonstrated that the magnitude of exercise-induced hyperthermia correlated with increased intestinal permeability (Pires et al., 2017). An increase in body temperature is a signal to activate the expression of heat shock proteins (HSP) which constitutively function as molecular chaperones maintaining the native structure of the proteins. Their expression is mainly triggered by heat shock signals. During exercise, the level of HSP70 and HSP90 increase (Krüger et al., 2019). Expression of HSP is regulated at the level of heat shock factors (HSF) such as HSF1 that is expressed in all mammalian tissues. Normally it resides in the cytoplasm as a monomer. In response to stressful conditions, it trimerizes, translocates into the nucleus, binds to the heat shock element of target genes and activates the transcription of HSPs, including HSP70/90 (Noble and Shen, 2012).
In this way, exercises cause a homeostatic imbalance, while regular training is adaptive and decreases the degree of this imbalance. Potentially, a higher adaptive steady-state level of HSPs due to regular training could explain their positive effect on gut integrity. At that time, during acute physical exertion, HSPs probably cannot cope with that level of homeostatic imbalance caused exercise-induced heat stress.

6.2 Exercise-induced hypoxia
It is well known, that exercise causes a redistribution of blood flow between tissues. This leads to the development of hypoxia (decreased oxygen levels) in intestinal epithelial cells and activation of hypoxia-inducible factor alpha (HIF-1α) (Wu et al., 2020). Figure 3 schematically shows the influence of exercise-induced hypoxia on intestinal permeability. In normoxia (normal oxygen levels), prolyl hydroxylase hydroxylates HIF-1α at two proline residues (Pro 402 and Pro 564). This results in ubiquitination followed by subsequent proteasomal degradation of HIF-1α (Lee et al., 2004).

intestinal barrier

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7 Conclusion and perspectives
The intestinal wall is a kind of checkpoint between the external and internal environments of organisms. The wall consists 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.
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. Conversely, a healthy composition of the gut microbiota can contribute to the integrity of the intestinal barrier due to increased expression and induction of the assembly of TJ proteins, activation of mucus synthesis, and antioxidant action.
Disruption of intestinal barrier function may trigger development of local and even systemic inflammation.
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In general, a vicious cycle of intestinal barrier disruption can be traced here, as excessive intestinal wall permeability provokes the development of chronic low-grade inflammation. The latter is characterized by increased production of pro-inflammatory cytokines and enhanced ROS generation, increasing intestinal barrier dysfunction.
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 and promoting the development of beneficial bacteria.
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. Potentially, this may be associated with an increase in the steady-state level of HSPs and chronic activation of HIF-1α which activates the transcription of genes responsible for strengthening the intestinal barrier function.
In general, it can be concluded that proper nutrition which promotes a healthy biodiversity of the gut microbiota, combined with moderate exercise, contribute to the integrity of the intestine. Disbalanced nutrition and excessive physical activity can provoke the development of dysbacteriosis and increase intestinal permeability which can potentially lead to a pro-inflammatory response. Figure 4 schematically shows potential consequences of acute intense exercises, unhealthy diet (e.g., high-fat diet), and dysbiosis on the intestinal barrier.
Taking into account all of the above, we can outline the following future prospects:
1. Development of healthy diets to support intestinal homeostasis;
2. Use of fermented dairy products as natural pre-, pro- and postbiotics to promote a healthy gut;
3. Selection of exercises to promote intestinal integrity by frequency, intensity and duration;
4. Study of the role of intestinal HIF-2α during exercise;
5. Systemic investigation of hypoxia-induced oxidative stress as a regulator of intestinal wall permeability.
Most of these perspective avenues are directed to enhance the capability of organisms to cope with disturbing factors. That increases an adaptive capability via preadaptation/hormetic mechanisms. However, some of them may be used “to patch holes” in “leaky” intestinal wall, which is characterized by increased specific permeability of the intestinal epithelium. Intestinal barrier permeability: the infuence of gut microbiota, nutrition, and exercise. Tetiana R. Dmytriv et al. DOI 10.3389/fphys.2024.1380713. PUBLISHED 08 July 2024

Note
[1] The term “intestinal barrier” emphasizes the barrier function of the intestinal wall which protects organism against invading by bacteria or other microorganisms and potentially toxic components of microorganisms. In fact, it is a complex selective physical barrier that separates the internal environment of the body from the contents of the intestinal lumen (Bischoff et al., 2014). Figure 1 shows a schematic structure of the intestinal barrier. It consists of several layers: i) a mucous layer including inner and outer mucous sublayers inhabited by commensal microorganisms in a different extent, ii) a single layer of epithelial cells, and iii) the lamina propria, which consists of immune cells that instantly react to the invasion of foreign substances (Schoultz and Keita, 2020).
The first layer, the mucous layer, that consists mainly of a mesh polymer called mucin, is located on the side of the intestinal lumen. It is associated with community of commensal microorganisms, including bacteria, fungi, viruses, and parasites, that form the individual microbial community (Chelakkot et al., 2018). A change in the microbial composition that causes a sharp imbalance between beneficial and potentially pathogenic bacteria, including changes in its functional composition, metabolic activity or changes in their local distribution, is called dysbiosis or dysbacteriosis. The latter usually results from loss of beneficial bacteria, overgrowth of potentially pathogenic bacteria, or loss of overall bacterial diversity. This disrupts the homeostatic balance of the intestinal microbiota and has a negative impact on the host’s health. In particular, dysbacteriosis is implicated in a wide range of diseases (DeGruttola et al., 2016).
The second layer, the intestinal epithelium, consists of a single layer of several specialized epithelial cells, such as enterocytes, Goblet cells, Paneth cells, enteroendocrine cells, and microfold cells (Figure 1). Enterocytes form the basis of the intestinal epithelium and play a main role in the absorption of all consumed nutrients. Goblet cells constitute about 10% of specialized epithelial cells. They secrete mucus to protect the intestinal wall from digestive enzymes (Kim and Ho, 2010). Paneth cells contain secretory granules filled with antimicrobial peptides, that are secreted in low amounts constitutively and provide the antimicrobial properties of the intestinal mucosa. Under certain conditions, their secretion can increase dramatically (Yokoi et al., 2019). Enteroendocrine cells produce hormones regulating secretion of digestive enzymes and insulin, peristalsis of the intestine, satiety, and immune response (Bonis et al., 2021). Microfold cells transport bacteria and antigens from the epithelium to enteric immune cells that either activate or suppress the immune response (Jung et al., 2010). All these cell types collectively contribute significantly to gut homeostasis.
The third layer, lamina propria, is located under the epithelium and forms the enteric immune system that consists of a large number of leukocytes with macrophages and dendritic cells being the dominant cell types (Shemtov et al., 2023). Resident intestinal macrophages are located in close proximity to the gut microbiota, with which they often interact. They play a key role in immune sampling of luminal bacteria, contributing to the maintenance of intestinal homeostasis and regulated immune response.

[2] TJ proteins are a complex of transmembrane and cytoplasmic proteins that form tight junctions, which seal cells together to create a selective barrier, maintain cell polarity, and regulate cell processes.

Key words
tight junction, tight junction proteins, inflammation,

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

The Gut Microbiota and Inflammation: An Overview

by luciano

Highlighted

“Role of the Gut Microbiota in Immunity and Inflammation
Microbes possess a variety of functions that influence their ability to grow and colonise, whilst bringing about downstream effects for the host that may be beneficial or otherwise [61]. Humans are not capable of digesting some components of dietary fibre due to the lack of the required enzymes to break down and harness the energy of these carbohydrates [62]. Certain species of microbes produce specific enzymes that enable fermentation of nutrients into absorbable forms, including that of indigestible carbohydrates into short-chain fatty acids (SCFAs) [62,63]. These SCFAs may have anti-inflammatory and immunomodulatory effects [63]. SCFAs are only a small part of the bigger picture as, in addition to enzymes and other metabolites produced, components of the bacteria themselves, including lipopolysaccharides, cell capsule carbohydrates and other endotoxins, may also be released and result in secondary effects to the host. These effects include maintenance of gut epithelium (and thereby integrity of the gut wall), production of vitamins, and interactions with several key immune system signalling molecules and cells, activating and inhibiting specific responses [1]. In addition to nutrient metabolism, gut microorganisms affect aspects of pharmacokinetics as they carry out drug metabolism [64]. They provide a natural defence against pathogenic species through competition and maintenance of the mucosa. It is through their contact with the immune system that the microorganisms occupying the gut can elicit or prevent inflammation. They may be associated with anti-inflammatory mechanisms, stimulating regulatory cells of the immune system to inhibit inflammation [65]. On the other hand, as bacteria regulate the permeability of the intestines, certain species can promote a “leaky gut”, where metabolites associated with the microbes leave the gut and enter the bloodstream. In response, the body produces cytokines and other mediators, effectively launching an inflammatory response [66]. Similarly, cells within the epithelial tissue of the gut deliver bacterial metabolites to immune cells, promoting inflammation on both a local and systemic scale. The persistence of this condition may lead to subacute or chronic inflammation, which may subsequently drive the development of diseases such as inflammatory bowel disease, diabetes or cardiovascular disease [65].”