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Does Intestine Morphology Still Have Secrets to Reveal? A Proposal about the “Ghost” Layer of the Bowel

Does Intestine Morphology Still Have Secrets to Reveal? A Proposal about the “Ghost”... Opinion Does Intestine Morphology Still Have Secrets to Reveal? A Proposal about the “Ghost” Layer of the Bowel 1 , 2 , 1 1 1 , 2 1 Francesco Cappello * , Dario Saguto , Stefano Burgio , Letizia Paladino and Fabio Bucchieri Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; dariosaguto@gmail.com (D.S.); stefano.burgio94@gmail.com (S.B.); letizia.paladino91@gmail.com (L.P.); fabio.bucchieri@unipa.it (F.B.) Euro-Mediterranean Institute of Science and Technology, 90139 Palermo, Italy * Correspondence: francesco.cappello@unipa.it Abstract: In this brief Opinion paper, the term “muco-microbiotic layer” is introduced to describe the innermost layer of the intestinal wall. This layer may contribute not only to the overall health of the bowel, but also to that of extraintestinal organs. Its constituents, in terms of soluble molecules and nanovesicles, need to be studied further. Moreover, one can hypothesize the existence of an analogous layer in other organs, such as the airways or some parts of the genital tracts. Further studies on it are needed. Keywords: microbiota; bowel; muco-microbiotic layer; cell differentiation; tissue homeostasis; organ remodeling; human anatomy; histology; pathophysiology; nanovesicles; exosomes 1. An Anatomical Introduction In Anatomy and Histology treatises, within the chapters on the structure of the intes- Citation: Cappello, F.; Saguto, D.; tine, little space is left to uncertainty and the readers’ imagination, whether they be young Burgio, S.; Paladino, L.; Bucchieri, F. students or expert scientists: the intestinal wall—just like the other organs of the alimentary Does Intestine Morphology Still canal—consists of four overlapping tunicae as if they were four soft cylinders inserted one Have Secrets to Reveal? A Proposal inside the other, which have been named—from the inner to the outer—“mucosa”, “submu- about the “Ghost” Layer of the Bowel. cosa”, “muscularis propria” and “adventitia” (the latter incorporated in the submesothelial Appl. Biosci. 2022, 1, 95–100. https:// connective tissue of the serosa, the peritoneum, when present) [1]. doi.org/10.3390/applbiosci1010006 Particular attention is given to the mucosa, usually defined as the innermost tunic, Academic Editor: Robert Henry which is, in turn, composed of three layers, all of the equal importance: the epithelium (the layer facing the lumen), whose cellular elements morpho-functionally better characterize Received: 13 May 2022 the two portions into which it is divided the intestine (i.e., small and large); the lamina Accepted: 6 June 2022 propria, containing not only the blood vessels for tissue trophism but also lymphatics, im- Published: 7 June 2022 mune cells, undifferentiated mesenchymal cells, nerve fibers, and other cells and structures Publisher’s Note: MDPI stays neutral that harbor—in some parts—glandular introflexions derived from the lining epithelium; with regard to jurisdictional claims in and, last but not least, the muscularis mucosae, a thin bundle of smooth muscle fiber cells, published maps and institutional affil- which has the dual purpose of protecting the submucosa (more richly vascularized and iations. innervated than the lamina propria) from chemical or traumatic insults that can affect the more abluminal layers on one hand, and to physically separate the two connective layers of the lamina propria and submucosa, thus actively participating in the creation of two different microenvironments, on the other [1]. Copyright: © 2022 by the authors. The concept of the microenvironment becomes more relevant as our knowledge of Licensee MDPI, Basel, Switzerland. the constituents of the human body increases, since it is now clear that cells can differ- This article is an open access article entiate, perform metabolic functions, communicate with each other, and cease (more or distributed under the terms and conditions of the Creative Commons less voluntarily) their existence based on the chemical–physical stimuli provided by the Attribution (CC BY) license (https:// environment [2]. creativecommons.org/licenses/by/ 4.0/). Appl. Biosci. 2022, 1, 95–100. https://doi.org/10.3390/applbiosci1010006 https://www.mdpi.com/journal/applbiosci Appl. Biosci. 2022, 1 96 Appl. Biosci. 2022, 1, FOR PEER REVIEW 2 2. The Microbiota and Its Microenvironment 2. The Microbiota and Its Microenvironment In the last few decades, a further constituent of the intestine structure has emerged In the last few decades, a further constituent of the intestine structure has emerged in the scientific literature: the microbiota, that is, the array of all living elements, bacterial in the scientific literature: the microbiota, that is, the array of all living elements, bacterial and not, that colonize our intestine, not having been generated together with it—therefore and not, that colonize our intestine, not having been generated together with it—therefore not sharing their genetic heritage with the cells of the individual who hosts them—but not sharing their genetic heritage with the cells of the individual who hosts them—but having reached a saprophytic balance with it [3]. The constituents of microbiotic flora are having reached a saprophytic balance with it [3]. The constituents of microbiotic flora are presented in Figure 1 and Tables 1–3. presented in Figure 1 and Tables 1–3. Figure 1. The microbiotic flora. The microbiota is mainly made up of prokaryotic elements (90%) Figure 1. The microbiotic flora. The microbiota is mainly made up of prokaryotic elements (90%) and, and, in a lesser extent, of eukaryotic (9%) and virii (1%) species. See Tables 1–3 for more information in a lesser extent, of eukaryotic (9%) and virii (1%) species. See Tables 1–3 for more information about about its composition. its composition. The microbiota is defined by some—improperly, from a strictly morphological point The microbiota is defined by some—improperly, from a strictly morphological point of of view—as “the organ within the organ”; instead, we would like to redefine and reframe view—as “the organ within the organ”; instead, we would like to redefine and reframe it in it in a morpho-functionally more appropriate way in the short text that follows. To do this, a morpho-functionally more appropriate way in the short text that follows. To do this, we we have to start by correlating the “morphology” with the “pathophysiology”. Thus, have to start by correlating the “morphology” with the “pathophysiology”. Thus, please please forgive us for the slightly pedantic nature of the following paragraphs. forgive us for the slightly pedantic nature of the following paragraphs. The human body can be subdivided into apparatuses (or systems), which can be split The human body can be subdivided into apparatuses (or systems), which can be split into organs, each formed of tissues, in turn composed of cells, each specialized for their into organs, each formed of tissues, in turn composed of cells, each specialized for their function (just remember how different they are, morpho-functionally, not just a neuron function (just remember how different they are, morpho-functionally, not just a neuron from a muscle cell, but also an absorbing epithelial cell from a secreting one) [4]. from a muscle cell, but also an absorbing epithelial cell from a secreting one) [4]. The alteration of cellular differentiation triggers the disorganization of the tissue, The alteration of cellular differentiation triggers the disorganization of the tissue, which, in turn, causes organ malfunction, causing the organism to display signs of illness. which, in turn, causes organ malfunction, causing the organism to display signs of illness. Physicians, through the knowledge of topographical anatomy, are called to identify the Physicians, through the knowledge of topographical anatomy, are called to identify the organ and/or the anatomical area affected by the disease, using semiotic tools (physical organ and/or the anatomical area affected by the disease, using semiotic tools (physical and and instrumental); the knowledge of the structures of the human body permits them to instrumental); the knowledge of the structures of the human body permits them to identify identify where those natural mechanisms regulating cell differentiation, tissue homeosta- where those natural mechanisms regulating cell differentiation, tissue homeostasis and sis and organ remodeling (all phenomena that continue throughout life, both pre- and organ remodeling (all phenomena that continue throughout life, both pre- and postnatally, postnatally, including not only infancy and adolescence but also tissue senescence and including not only infancy and adolescence but also tissue senescence and organ meiopragia organ meiopragia later in life) are malfunctioning [5]. later in life) are malfunctioning [5]. Appl. Biosci. 2022, 1 97 Table 1. The Prokaryotic kingdom and their phyla in the human microbiota. The percentages derive from literature data. Procaryota Kingdoms Phylum Genus (%) References Lactobacillus 5% [6–12] Faecalibacterium 5% [12] Halomonas 3% [12] Clostridium 3% [12] Firmicutes Ruminococcus 7% [12] Roseburia 4% [12] Streptococcus 2% [12] Others 21% [12] Bacteroides 19% [6–13] Bacteria Bacteroidetes Others 2% [12] Bifidobacterium 4% [9,12,14] Actinobacteria Others 1% [12] Escherichia 5% [10,13] Proteobacteria Shigella 2% [10] Others 9% [13] Brachyspira 3% [12] Spirochaetes Others 2% [12] Others Others 2% [11] Archea Euryarchaeota Halobacteria 2% [15] Table 2. The Eukaryotic kingdom and their phyla in the human microbiota. The percentages derive from literature data. Eukaryota Phylum Genus (%) References Debaryomycetaceae 13% [16–18] Ascomycota Dipodascaceae 14% [17] Saccharomycetaceae 13% [17] Tremellomycetes 20% [16] Basidiomycota Malasseziaceae 20% [19] Fusicatenibacter 5% [17] Mucorimycota Aspergiullus 5% [19] Table 3. The Virii kingdom in the human microbiota. The percentages derive from literature data. Virii Phylum Genus (%) References Siphoviridae 20% [11,20–23] Myoviridae 20% [17,22,23] Caudovirales Podoviridae 20% [17,22,23] Others 40% [11,22,23] Appl. Biosci. 2022, 1 98 The identification of “breakdown” at the cellular level can lead to targeted therapy (sometimes just lifestyle changes are enough; other times, drug therapy may be necessary; and, in extremis, surgical intervention could be inevitable for the demolition and eventual Appl. Biosci. 2022, 1, FOR PEER REVIEW 4 reconstruction of the irremediably sick part), and the efforts of the biomedical and bioengi- neering community are concentrated above all on developing such therapy protocols. It now seems certain that the microbiota is involved in many intestinal pathologies, It now seems certain that the microbiota is involved in many intestinal pathologies, therefore implying that it can transform itself from a combination of commensal germs therefore implying that it can transform itself from a combination of commensal germs to to a mix of pathogens under certain conditions and for causes that are not yet fully un- a mix of pathogens under certain conditions and for causes that are not yet fully under- derstood [24–27]. What mainly affects the health of the microbiota is certainly the mi- stood [24–27]. What mainly affects the health of the microbiota is certainly the microenvi- croenvironment in which we live and, in the first place, our diet: what passes through ronment in which we live and, in the first place, our diet: what passes through the intes- the intestinal lumen throughout our existence. However, to better understand how and tinal lumen throughout our existence. However, to better understand how and why the why the microbiota is altered and, above all, how and why this alteration affects not only microbiota is altered and, above all, how and why this alteration affects not only intestinal intestinal homeostasis but also that of other tissues physically distant from it, the context of homeostasis but also that of other tissues physically distant from it, the context of its mi- its microenvironment, i.e., the mucus that lines the epithelial surface of the intestine and in croenvironment, i.e., the mucus that lines the epithelial surface of the intestine and in which the microbiota is contained, must be contemplated [28]. which the microbiota is contained, must be contemplated [28]. 3. The Muco-Microbiotic Layer 3. The Muco-Microbiotic Layer Mucus and microbiota form a morpho-functional layer, the biological elements of the Mucus and microbiota form a morpho-functional layer, the biological elements of the microbiota being comparable to a “cellular component”, and the mucus to the “matrix” in microbiota being comparable to a “cellular component”, and the mucus to the “matrix” in which not only these cells reside, but also in which their products—both soluble molecules which not only these cells reside, but also in which their products—both soluble molecules (proteins, lipids, etc.) and nanovesicles (for example, the “outer membrane vesicles”, (proteins, lipids, etc.) and nanovesicles (for example, the “outer membrane vesicles”, OMV, of prokaryotic origin, equivalent to the exosomes produced by eukaryotic cells)—are OMV, of prokaryotic origin, equivalent to the exosomes produced by eukaryotic cells)— r aeleased re releas[e 28 d ,[29 28]. ,29]. F Figur igure e 2 2 shows, shows, schematically schematically,, the the composition composition of of the themuco-micr muco-micr obioti obiotic c (MuMi) (MuMi) layer layer with its main constituents. Why has the MuMi layer been ignored until now, and with its main constituents. Why has the MuMi layer been ignored until now, and why has why has it not yet been described in anatomy and histology books? This is probably due it not yet been described in anatomy and histology books? This is probably due to the to the fact that widely used histochemical stains contain alcohol, which solubilizes the fact that widely used histochemical stains contain alcohol, which solubilizes the mucus by mucus by sweeping it away along with the microbiota. Therefore, in histological sections, sweeping it away along with the microbiota. Therefore, in histological sections, neither neither of these two components are visible, if not in minute traces, and this has led scien- of these two components are visible, if not in minute traces, and this has led scientists to tists to dismiss it as a physiological constituent of our bodies. dismiss it as a physiological constituent of our bodies. Figure 2. The muco-microbiotic (MuMi) layer. This figure shows, schematically, the MuMi layer, its Figure 2. The muco-microbiotic (MuMi) layer. This figure shows, schematically, the MuMi layer, main constituents (in terms of microbiotic elements and nanovesicles) and its relationships with the its main constituents (in terms of microbiotic elements and nanovesicles) and its relationships with underlying mucosal components, i.e., epithelial cells and lamina propria. Whereas nanovesicles, ei- the underlying mucosal components, i.e., epithelial cells and lamina propria. Whereas nanovesicles, ther human- and microbiota-derived ones, can easily reach the lamina propria (in turn contributing either human- and microbiota-derived ones, can easily reach the lamina propria (in turn contributing to determine its microenvironment), the muscularis mucosae represents a wall between the connec- to determine its microenvironment), the muscularis mucosae represents a wall between the connective tive tissue of the lamina propria and that of the submucosa (not shown). tissue of the lamina propria and that of the submucosa (not shown). The MuMi layer is therefore located in the bowel internally to the mucosa, represent- The MuMi layer is therefore located in the bowel internally to the mucosa, representing ing the innermost “fifth layer” (or the first one) of the intestinal wall; the alterations of the the mucinnermost ous matrix “fifth can calayer” use a qu (or alitthe ative first and one) quan of titthe ativintestinal e modificat wall; ion ofthe thealterations populations of the mucous of germs matrix that hou can sedcause in it, a anqualitative d vice versaand [28,2 quantitative 9]. In additiomodification n, the intense of trathe ffic populations of soluble of products and nano-vesicles mutually influence human and microbiotic cells; the increase in pathogenic bacteria generates, for example, a disturbance in the microenvironment of Appl. Biosci. 2022, 1 99 germs that housed in it, and vice versa [28,29]. In addition, the intense traffic of soluble products and nano-vesicles mutually influence human and microbiotic cells; the increase in pathogenic bacteria generates, for example, a disturbance in the microenvironment of the lamina propria, triggering or perpetuating inflammatory processes; and since the nanovesicles (both human and bacterial) can easily reach both the bloodstream and the lymphatic one, the well-being of our intestinal MuMi layer can affect the homeostasis of extra-intestinal tissues, thus compromising the function of other organs, including the liver, lung, heart, and brain, just to mention the most important ones considering the anatomical progression of the blood mass originating from the abdominal splanchnic district [28]. 4. Conclusions Based on the consideration reported above, the existence of the MuMi layer, in our modest opinion, should not only no longer be ignored, but must also be investigated (also in other anatomical districts, e.g., the airways or some genital tract organs) in order to characterize, from a morpho-molecular point of view, its constituents and the mechanisms that fine-tune all the related physiological and pathophysiological events. Limiting our conclusion to the bowel, if the Hippocratic axiom “we are what we eat” is still true, and if it is correct to think that the health of our body depends, in the first instance, on the health of our intestine, omitting the observations of molecular phenomena that occur in this layer from scientific reasoning—as well as from scientific protocols—would undermine the achievement of better knowledge on human health. 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Does Intestine Morphology Still Have Secrets to Reveal? A Proposal about the “Ghost” Layer of the Bowel

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Opinion Does Intestine Morphology Still Have Secrets to Reveal? A Proposal about the “Ghost” Layer of the Bowel 1 , 2 , 1 1 1 , 2 1 Francesco Cappello * , Dario Saguto , Stefano Burgio , Letizia Paladino and Fabio Bucchieri Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; dariosaguto@gmail.com (D.S.); stefano.burgio94@gmail.com (S.B.); letizia.paladino91@gmail.com (L.P.); fabio.bucchieri@unipa.it (F.B.) Euro-Mediterranean Institute of Science and Technology, 90139 Palermo, Italy * Correspondence: francesco.cappello@unipa.it Abstract: In this brief Opinion paper, the term “muco-microbiotic layer” is introduced to describe the innermost layer of the intestinal wall. This layer may contribute not only to the overall health of the bowel, but also to that of extraintestinal organs. Its constituents, in terms of soluble molecules and nanovesicles, need to be studied further. Moreover, one can hypothesize the existence of an analogous layer in other organs, such as the airways or some parts of the genital tracts. Further studies on it are needed. Keywords: microbiota; bowel; muco-microbiotic layer; cell differentiation; tissue homeostasis; organ remodeling; human anatomy; histology; pathophysiology; nanovesicles; exosomes 1. An Anatomical Introduction In Anatomy and Histology treatises, within the chapters on the structure of the intes- Citation: Cappello, F.; Saguto, D.; tine, little space is left to uncertainty and the readers’ imagination, whether they be young Burgio, S.; Paladino, L.; Bucchieri, F. students or expert scientists: the intestinal wall—just like the other organs of the alimentary Does Intestine Morphology Still canal—consists of four overlapping tunicae as if they were four soft cylinders inserted one Have Secrets to Reveal? A Proposal inside the other, which have been named—from the inner to the outer—“mucosa”, “submu- about the “Ghost” Layer of the Bowel. cosa”, “muscularis propria” and “adventitia” (the latter incorporated in the submesothelial Appl. Biosci. 2022, 1, 95–100. https:// connective tissue of the serosa, the peritoneum, when present) [1]. doi.org/10.3390/applbiosci1010006 Particular attention is given to the mucosa, usually defined as the innermost tunic, Academic Editor: Robert Henry which is, in turn, composed of three layers, all of the equal importance: the epithelium (the layer facing the lumen), whose cellular elements morpho-functionally better characterize Received: 13 May 2022 the two portions into which it is divided the intestine (i.e., small and large); the lamina Accepted: 6 June 2022 propria, containing not only the blood vessels for tissue trophism but also lymphatics, im- Published: 7 June 2022 mune cells, undifferentiated mesenchymal cells, nerve fibers, and other cells and structures Publisher’s Note: MDPI stays neutral that harbor—in some parts—glandular introflexions derived from the lining epithelium; with regard to jurisdictional claims in and, last but not least, the muscularis mucosae, a thin bundle of smooth muscle fiber cells, published maps and institutional affil- which has the dual purpose of protecting the submucosa (more richly vascularized and iations. innervated than the lamina propria) from chemical or traumatic insults that can affect the more abluminal layers on one hand, and to physically separate the two connective layers of the lamina propria and submucosa, thus actively participating in the creation of two different microenvironments, on the other [1]. Copyright: © 2022 by the authors. The concept of the microenvironment becomes more relevant as our knowledge of Licensee MDPI, Basel, Switzerland. the constituents of the human body increases, since it is now clear that cells can differ- This article is an open access article entiate, perform metabolic functions, communicate with each other, and cease (more or distributed under the terms and conditions of the Creative Commons less voluntarily) their existence based on the chemical–physical stimuli provided by the Attribution (CC BY) license (https:// environment [2]. creativecommons.org/licenses/by/ 4.0/). Appl. Biosci. 2022, 1, 95–100. https://doi.org/10.3390/applbiosci1010006 https://www.mdpi.com/journal/applbiosci Appl. Biosci. 2022, 1 96 Appl. Biosci. 2022, 1, FOR PEER REVIEW 2 2. The Microbiota and Its Microenvironment 2. The Microbiota and Its Microenvironment In the last few decades, a further constituent of the intestine structure has emerged In the last few decades, a further constituent of the intestine structure has emerged in the scientific literature: the microbiota, that is, the array of all living elements, bacterial in the scientific literature: the microbiota, that is, the array of all living elements, bacterial and not, that colonize our intestine, not having been generated together with it—therefore and not, that colonize our intestine, not having been generated together with it—therefore not sharing their genetic heritage with the cells of the individual who hosts them—but not sharing their genetic heritage with the cells of the individual who hosts them—but having reached a saprophytic balance with it [3]. The constituents of microbiotic flora are having reached a saprophytic balance with it [3]. The constituents of microbiotic flora are presented in Figure 1 and Tables 1–3. presented in Figure 1 and Tables 1–3. Figure 1. The microbiotic flora. The microbiota is mainly made up of prokaryotic elements (90%) Figure 1. The microbiotic flora. The microbiota is mainly made up of prokaryotic elements (90%) and, and, in a lesser extent, of eukaryotic (9%) and virii (1%) species. See Tables 1–3 for more information in a lesser extent, of eukaryotic (9%) and virii (1%) species. See Tables 1–3 for more information about about its composition. its composition. The microbiota is defined by some—improperly, from a strictly morphological point The microbiota is defined by some—improperly, from a strictly morphological point of of view—as “the organ within the organ”; instead, we would like to redefine and reframe view—as “the organ within the organ”; instead, we would like to redefine and reframe it in it in a morpho-functionally more appropriate way in the short text that follows. To do this, a morpho-functionally more appropriate way in the short text that follows. To do this, we we have to start by correlating the “morphology” with the “pathophysiology”. Thus, have to start by correlating the “morphology” with the “pathophysiology”. Thus, please please forgive us for the slightly pedantic nature of the following paragraphs. forgive us for the slightly pedantic nature of the following paragraphs. The human body can be subdivided into apparatuses (or systems), which can be split The human body can be subdivided into apparatuses (or systems), which can be split into organs, each formed of tissues, in turn composed of cells, each specialized for their into organs, each formed of tissues, in turn composed of cells, each specialized for their function (just remember how different they are, morpho-functionally, not just a neuron function (just remember how different they are, morpho-functionally, not just a neuron from a muscle cell, but also an absorbing epithelial cell from a secreting one) [4]. from a muscle cell, but also an absorbing epithelial cell from a secreting one) [4]. The alteration of cellular differentiation triggers the disorganization of the tissue, The alteration of cellular differentiation triggers the disorganization of the tissue, which, in turn, causes organ malfunction, causing the organism to display signs of illness. which, in turn, causes organ malfunction, causing the organism to display signs of illness. Physicians, through the knowledge of topographical anatomy, are called to identify the Physicians, through the knowledge of topographical anatomy, are called to identify the organ and/or the anatomical area affected by the disease, using semiotic tools (physical organ and/or the anatomical area affected by the disease, using semiotic tools (physical and and instrumental); the knowledge of the structures of the human body permits them to instrumental); the knowledge of the structures of the human body permits them to identify identify where those natural mechanisms regulating cell differentiation, tissue homeosta- where those natural mechanisms regulating cell differentiation, tissue homeostasis and sis and organ remodeling (all phenomena that continue throughout life, both pre- and organ remodeling (all phenomena that continue throughout life, both pre- and postnatally, postnatally, including not only infancy and adolescence but also tissue senescence and including not only infancy and adolescence but also tissue senescence and organ meiopragia organ meiopragia later in life) are malfunctioning [5]. later in life) are malfunctioning [5]. Appl. Biosci. 2022, 1 97 Table 1. The Prokaryotic kingdom and their phyla in the human microbiota. The percentages derive from literature data. Procaryota Kingdoms Phylum Genus (%) References Lactobacillus 5% [6–12] Faecalibacterium 5% [12] Halomonas 3% [12] Clostridium 3% [12] Firmicutes Ruminococcus 7% [12] Roseburia 4% [12] Streptococcus 2% [12] Others 21% [12] Bacteroides 19% [6–13] Bacteria Bacteroidetes Others 2% [12] Bifidobacterium 4% [9,12,14] Actinobacteria Others 1% [12] Escherichia 5% [10,13] Proteobacteria Shigella 2% [10] Others 9% [13] Brachyspira 3% [12] Spirochaetes Others 2% [12] Others Others 2% [11] Archea Euryarchaeota Halobacteria 2% [15] Table 2. The Eukaryotic kingdom and their phyla in the human microbiota. The percentages derive from literature data. Eukaryota Phylum Genus (%) References Debaryomycetaceae 13% [16–18] Ascomycota Dipodascaceae 14% [17] Saccharomycetaceae 13% [17] Tremellomycetes 20% [16] Basidiomycota Malasseziaceae 20% [19] Fusicatenibacter 5% [17] Mucorimycota Aspergiullus 5% [19] Table 3. The Virii kingdom in the human microbiota. The percentages derive from literature data. Virii Phylum Genus (%) References Siphoviridae 20% [11,20–23] Myoviridae 20% [17,22,23] Caudovirales Podoviridae 20% [17,22,23] Others 40% [11,22,23] Appl. Biosci. 2022, 1 98 The identification of “breakdown” at the cellular level can lead to targeted therapy (sometimes just lifestyle changes are enough; other times, drug therapy may be necessary; and, in extremis, surgical intervention could be inevitable for the demolition and eventual Appl. Biosci. 2022, 1, FOR PEER REVIEW 4 reconstruction of the irremediably sick part), and the efforts of the biomedical and bioengi- neering community are concentrated above all on developing such therapy protocols. It now seems certain that the microbiota is involved in many intestinal pathologies, It now seems certain that the microbiota is involved in many intestinal pathologies, therefore implying that it can transform itself from a combination of commensal germs therefore implying that it can transform itself from a combination of commensal germs to to a mix of pathogens under certain conditions and for causes that are not yet fully un- a mix of pathogens under certain conditions and for causes that are not yet fully under- derstood [24–27]. What mainly affects the health of the microbiota is certainly the mi- stood [24–27]. What mainly affects the health of the microbiota is certainly the microenvi- croenvironment in which we live and, in the first place, our diet: what passes through ronment in which we live and, in the first place, our diet: what passes through the intes- the intestinal lumen throughout our existence. However, to better understand how and tinal lumen throughout our existence. However, to better understand how and why the why the microbiota is altered and, above all, how and why this alteration affects not only microbiota is altered and, above all, how and why this alteration affects not only intestinal intestinal homeostasis but also that of other tissues physically distant from it, the context of homeostasis but also that of other tissues physically distant from it, the context of its mi- its microenvironment, i.e., the mucus that lines the epithelial surface of the intestine and in croenvironment, i.e., the mucus that lines the epithelial surface of the intestine and in which the microbiota is contained, must be contemplated [28]. which the microbiota is contained, must be contemplated [28]. 3. The Muco-Microbiotic Layer 3. The Muco-Microbiotic Layer Mucus and microbiota form a morpho-functional layer, the biological elements of the Mucus and microbiota form a morpho-functional layer, the biological elements of the microbiota being comparable to a “cellular component”, and the mucus to the “matrix” in microbiota being comparable to a “cellular component”, and the mucus to the “matrix” in which not only these cells reside, but also in which their products—both soluble molecules which not only these cells reside, but also in which their products—both soluble molecules (proteins, lipids, etc.) and nanovesicles (for example, the “outer membrane vesicles”, (proteins, lipids, etc.) and nanovesicles (for example, the “outer membrane vesicles”, OMV, of prokaryotic origin, equivalent to the exosomes produced by eukaryotic cells)—are OMV, of prokaryotic origin, equivalent to the exosomes produced by eukaryotic cells)— r aeleased re releas[e 28 d ,[29 28]. ,29]. F Figur igure e 2 2 shows, shows, schematically schematically,, the the composition composition of of the themuco-micr muco-micr obioti obiotic c (MuMi) (MuMi) layer layer with its main constituents. Why has the MuMi layer been ignored until now, and with its main constituents. Why has the MuMi layer been ignored until now, and why has why has it not yet been described in anatomy and histology books? This is probably due it not yet been described in anatomy and histology books? This is probably due to the to the fact that widely used histochemical stains contain alcohol, which solubilizes the fact that widely used histochemical stains contain alcohol, which solubilizes the mucus by mucus by sweeping it away along with the microbiota. Therefore, in histological sections, sweeping it away along with the microbiota. Therefore, in histological sections, neither neither of these two components are visible, if not in minute traces, and this has led scien- of these two components are visible, if not in minute traces, and this has led scientists to tists to dismiss it as a physiological constituent of our bodies. dismiss it as a physiological constituent of our bodies. Figure 2. The muco-microbiotic (MuMi) layer. This figure shows, schematically, the MuMi layer, its Figure 2. The muco-microbiotic (MuMi) layer. This figure shows, schematically, the MuMi layer, main constituents (in terms of microbiotic elements and nanovesicles) and its relationships with the its main constituents (in terms of microbiotic elements and nanovesicles) and its relationships with underlying mucosal components, i.e., epithelial cells and lamina propria. Whereas nanovesicles, ei- the underlying mucosal components, i.e., epithelial cells and lamina propria. Whereas nanovesicles, ther human- and microbiota-derived ones, can easily reach the lamina propria (in turn contributing either human- and microbiota-derived ones, can easily reach the lamina propria (in turn contributing to determine its microenvironment), the muscularis mucosae represents a wall between the connec- to determine its microenvironment), the muscularis mucosae represents a wall between the connective tive tissue of the lamina propria and that of the submucosa (not shown). tissue of the lamina propria and that of the submucosa (not shown). The MuMi layer is therefore located in the bowel internally to the mucosa, represent- The MuMi layer is therefore located in the bowel internally to the mucosa, representing ing the innermost “fifth layer” (or the first one) of the intestinal wall; the alterations of the the mucinnermost ous matrix “fifth can calayer” use a qu (or alitthe ative first and one) quan of titthe ativintestinal e modificat wall; ion ofthe thealterations populations of the mucous of germs matrix that hou can sedcause in it, a anqualitative d vice versaand [28,2 quantitative 9]. In additiomodification n, the intense of trathe ffic populations of soluble of products and nano-vesicles mutually influence human and microbiotic cells; the increase in pathogenic bacteria generates, for example, a disturbance in the microenvironment of Appl. Biosci. 2022, 1 99 germs that housed in it, and vice versa [28,29]. In addition, the intense traffic of soluble products and nano-vesicles mutually influence human and microbiotic cells; the increase in pathogenic bacteria generates, for example, a disturbance in the microenvironment of the lamina propria, triggering or perpetuating inflammatory processes; and since the nanovesicles (both human and bacterial) can easily reach both the bloodstream and the lymphatic one, the well-being of our intestinal MuMi layer can affect the homeostasis of extra-intestinal tissues, thus compromising the function of other organs, including the liver, lung, heart, and brain, just to mention the most important ones considering the anatomical progression of the blood mass originating from the abdominal splanchnic district [28]. 4. Conclusions Based on the consideration reported above, the existence of the MuMi layer, in our modest opinion, should not only no longer be ignored, but must also be investigated (also in other anatomical districts, e.g., the airways or some genital tract organs) in order to characterize, from a morpho-molecular point of view, its constituents and the mechanisms that fine-tune all the related physiological and pathophysiological events. Limiting our conclusion to the bowel, if the Hippocratic axiom “we are what we eat” is still true, and if it is correct to think that the health of our body depends, in the first instance, on the health of our intestine, omitting the observations of molecular phenomena that occur in this layer from scientific reasoning—as well as from scientific protocols—would undermine the achievement of better knowledge on human health. 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Journal

Applied Biosciences – Multidisciplinary Digital Publishing Institute

Published: Jun 7, 2022

Keywords: microbiota; bowel; muco-microbiotic layer; cell differentiation; tissue homeostasis; organ remodeling; human anatomy; histology; pathophysiology; nanovesicles; exosomes

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