Gut Disease and Microbiota: Comparison
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How can the knowledge of probiotics and their mechanisms of action be translated into clinical practice when treating patients with diverticular disease and acute diverticulitis? Changes in microbiota composition have been observed in patients who were developing acute diverticulitis, with a reduction of taxa with anti-inflammatory activity, such as Clostridium cluster IV, Lactobacilli and Bacteroides

  • gut microbiota
  • probiotics and gut disease

1. Introduction—Microbiota in Health and Disease

Over the last three decades, the importance of gut microbiota in determining health and disease has become increasingly clear.

Over the last three decades, the importance of gut microbiota in determining health and disease has become increasingly clear.Already in the late 1800s, researchers were warning the public that the bacteria living in our intestine could be “pathological” [1] even though the concept of dysbiosis had yet to be formulated.Microbiota has proven to be an important player in the pathogenesis of many different diseases, ranging from more “obvious” disorders, for instance small intestine bacterial overgrowth (SIBO) [2], to more complicated diseases, such as immune deficits, thyroid disorders, neurodegenerative diseases [3][4][5], and have also been linked to mood disorders [6].In this review, our aim was to discuss the potential role of probiotics for the treatment of diverticular disease and acute diverticulitis, with particular attention to their possible mechanisms of action.The most important mechanisms through which microbiota can influence systemic health is through immune/inflammatory mechanisms [7][8]. The presence of certain bacterial strains can exert regulatory functions, improving immune-tolerance and stimulating regulatory T-cell (T-reg) expression [9]. This activity was observed, for instance, in Bacteroides fragilis [10] and in some Clostridium species [11].Immune modulation also takes place through the production of short-chain fatty acids (SCFAs). Indeed, when digesting fibre, bacteria produce a vast array of SCFAs. Butyrate is particularly important among them, as it directly modulates the expression of histone deacetylase (HDAC), consequently increasing the expression of T-regs. Moreover, its role in obesity and metabolic control is not yet clear [12].Additionally, a “healthy” microbiota works as a physical barrier against pathogens, stopping them from overcoming the gut mucosa and spreading systemically [13]. Indeed, beneficial species compete for nutrients and can produce antimicrobial substances which do not allow the growth of other microorganisms. Yet, it is worth noting that a certain microbial population can shift from protective to harmful even in the same individual based on circumstance.In Table 1 there is a short summary of the relevant literature we discussed.

Already in the late 1800s, researchers were warning the public that the bacteria living in our intestine could be “pathological” [1] even though the concept of dysbiosis had yet to be formulated.

Table 1. Summary of the most relevant research.

Microbiota has proven to be an important player in the pathogenesis of many different diseases, ranging from more “obvious” disorders, for instance small intestine bacterial overgrowth (SIBO) [2], to more complicated diseases, such as immune deficits, thyroid disorders, neurodegenerative diseases [3,4,5], and have also been linked to mood disorders [6].
TitleTopicReference Number
Belkaid Y, Hand TW. “Role of the microbiota in immunity and inflammation”. Cell. 2014Microbiota-driven immune responses[8]
Iebba V, Totino V, Gagliardi A, Santangelo F, Cacciotti F, Trancassini M, et al. “Eubiosis and dysbiosis: the two sides of the microbiota”. New Microbiol. 2016Dysbiosis and eubiosis in defining a “healthy” gut microbiota[14]
Cianci R, Franza L. “The Interplay between Immunity and Microbiota at Intestinal Immunological Niche: The Case of Cancer”. 2019The intestinal niche in health and disease[15]
Lange K, Buerger M, Stallmach A, Bruns T. “Effects of Antibiotics on Gut Microbiota”. Dig Dis. 2016The role of antibiotics in shaping the microbiota[16]
Suez J, Zmora N, Segal E. “The pros, cons, and many unknowns of probiotics”. 2019The role of probiotics in shaping the microbiota[17]
Kim SK, Guevarra RB, Kim YT, Kwon J, Kim H, Cho JH, et al. “Role of Probiotics in Human Gut Microbiome-Associated Diseases”. J Microbiol Biotechnol. 2019Probiotics in gut-microbiota associated diseases[18]
Ticinesi A, Nouvenne A, Corrente V, Tana C, Di Mario F, Meschi T. “Diverticular Disease: a Gut Microbiota Perspective. Journal of gastrointestinal and liver diseases”. JGLD. 2019The role of microbiota in diverticular disease[19]
Ojetti V, Petruzziello C, Cardone S, Saviano L, Migneco A, Santarelli L, et al. “The Use of Probiotics in Different Phases of Diverticular Disease. Reviews on recent clinical trials”. 2018Action of probiotics in diverticular disease[20]
Petruzziello C, Migneco A, Cardone S, Covino M, Saviano A, Franceschi F, et al. Supplementation with Lactobacillus reuteri ATCC PTA 4659 in patients affected by acute uncomplicated diverticulitis: a randomised double-blind placebo controlled trial. 2019Action of probiotics in diverticular disease[21]
Petruzziello C, Marannino M, Migneco A, Brigida M, Saviano A, Piccioni A, et al. The efficacy of a mix of three probiotic strains in reducing abdominal pain and inflammatory biomarkers in acute uncomplicated diverticulitis. European review for medical and pharmacological sciences. 2019Action of probiotics in diverticular disease[22]
In this review, our aim was to discuss the potential role of probiotics for the treatment of diverticular disease and acute diverticulitis, with particular attention to their possible mechanisms of action.

3. What Is a Healthy Microbiota?

The most important mechanisms through which microbiota can influence systemic health is through immune/inflammatory mechanisms [7,8]. The presence of certain bacterial strains can exert regulatory functions, improving immune-tolerance and stimulating regulatory T-cell (T-reg) expression [9]. This activity was observed, for instance, in Bacteroides fragilis [10] and in some Clostridium species [11].

As discussed above, the role of microbiota in determining health and disease, via immune modulation, is becoming increasingly clear. Some microbes have been identified as definitely pathogenic, for instance Clostridium difficile, yet there still are some grey areas, in particular when it comes to determine what defines a healthy microbiota [14].An example of this comes from studies on microbiota and cancer: Helicobacter pylori is a known risk factor for the development of gastric cancer, but it has a protective effect against oesophageal cancer [23]. Similarly, Escherichia coli protects against pancreatic cancer, but favours colorectal and liver tumours [15]. In these cases, the ambivalent role of these bacteria was determined by the site of colonisation.It is, indeed, important to underline that, even though it is common to refer to “gut microbiota”, this does change widely throughout the gastrointestinal tract. In the oral cavity, for instance, it is common to find Neisseria spp., which is instead difficult to find in other sites [24]. The stomach has a completely different microbiota than all the other parts of the gastrointestinal tract in healthy patients, but resembles oesophageal or intestinal microbiota in those with gastric cancer [25]. The small intestine even has a different composition based on which tract is being studied, and its composition is different from that of the colon.Even considering specific parts of the gastrointestinal tract, microbiota changes with age [26], and even depending on geographic localisation, diet and ethnicity [27].Yet, even though it is not possible to precisely define what species compose a healthy microbiota, it is worth noting that some general characteristics have been observed: a healthy microbiota is made up of a dynamic and diverse community of microbes, which is able to self-regulate [28].While these do seem to be vague concepts, it is interesting to notice that the modern, western diet directly affects microbiota diversity, reducing its capacity to bounce back when frankly pathogenic species start colonising the gut [29].

Immune modulation also takes place through the production of short-chain fatty acids (SCFAs). Indeed, when digesting fibre, bacteria produce a vast array of SCFAs. Butyrate is particularly important among them, as it directly modulates the expression of histone deacetylase (HDAC), consequently increasing the expression of T-regs. Moreover, its role in obesity and metabolic control is not yet clear [12].

4. Gut Disease and Microbiota

Additionally, a “healthy” microbiota works as a physical barrier against pathogens, stopping them from overcoming the gut mucosa and spreading systemically [13]. Indeed, beneficial species compete for nutrients and can produce antimicrobial substances which do not allow the growth of other microorganisms. Yet, it is worth noting that a certain microbial population can shift from protective to harmful even in the same individual based on circumstance.

While gut microbiota influences all aspects of human health, its action on the gastrointestinal system is particularly important.Indeed, gut microbiota directly modulates gastrointestinal homeostasis, through a variety of mechanisms. The presence of pathogens at the intestinal barrier, for instance, can directly damage the gastrointestinal mucosa and determine inflammation. This is the mechanism through which C. difficile, Salmonella spp and others can create direct intestinal damage [30].Direct damage also activates immunologic pathways, particularly through the activation of the inflammasome. IL-1β and IL-18 are a direct consequence of its activation, causing pyroptosis, a particular form of immune-mediated cellular death [31]. Meanwhile, the activation of the inflammasome is important to maintain gut homeostasis, as it helps restore microbiota eubiosis, and it can also lead to chronic gut inflammation, which in turn promotes an inflammatory gut microbiota, in a difficult-to-break vicious circle.It was observed that Bifidobacterium adolescentis, Lactobacillus, Phascolarctobacterium, Akkermansia muciniphila are all reduced in patients with intestinal inflammation. Interestingly, when present, they are capable of reducing inflammation, particularly acting on C-reactive protein (CRP), IL-6, and tumour necrosis factor (TNF)-α [32]. The action on these inflammatory mediators partly explains how gut microbiota can influence systemic health.In the gut, the action of these mediators has direct consequences in terms of permeability and inflammation, both extremely important in the pathogenesis of different gastrointestinal disorders [33]. The presence of dysbiosis can trigger the development of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). The role of microbiota has been particularly underlined in the pathogenesis of IBDs, in which dysbiosis is marked by the presence of Mycobacterium avium subsp. paratuberculosis, Fusobacterium nucleatum, adherent–invasive E. coli [34].Inflammation caused by microbiota dysbiosis is also responsible of liver disorders, particularly non-alcoholic liver steatosis. In this case, there is a direct colonisation of the bile ducts, which adds up to the action of bacterial metabolic products. Interestingly, the capacity of bacteria to metabolise biliary salts is also linked to dysbiosis [35].Inflammation is also a well-known risk factor for the development of cancer, and it is no different in the intestine; the impact of microbiota composition in modulating the intestinal immunologic niche has proven essential in different forms of cancer [15].

In Table 1 there is a short summary of the relevant literature we discussed.

5. Microbiota Modulation: The Case for Probiotics

Table 1. Summary of the most relevant research.
TitleTopicReference Number
Belkaid Y, Hand TW. “Role of the microbiota in immunity and inflammation”. Cell. 2014Microbiota-driven immune responses[8]
Iebba V, Totino V, Gagliardi A, Santangelo F, Cacciotti F, Trancassini M, et al. “Eubiosis and dysbiosis: the two sides of the microbiota”. New Microbiol. 2016Dysbiosis and eubiosis in defining a “healthy” gut microbiota[14]
Cianci R, Franza L. “The Interplay between Immunity and Microbiota at Intestinal Immunological Niche: The Case of Cancer”. 2019The intestinal niche in health and disease[16]
Lange K, Buerger M, Stallmach A, Bruns T. “Effects of Antibiotics on Gut Microbiota”. Dig Dis. 2016The role of antibiotics in shaping the microbiota[33]
Suez J, Zmora N, Segal E. “The pros, cons, and many unknowns of probiotics”. 2019The role of probiotics in shaping the microbiota[35]
Kim SK, Guevarra RB, Kim YT, Kwon J, Kim H, Cho JH, et al. “Role of Probiotics in Human Gut Microbiome-Associated Diseases”. J Microbiol Biotechnol. 2019Probiotics in gut-microbiota associated diseases[38]
Ticinesi A, Nouvenne A, Corrente V, Tana C, Di Mario F, Meschi T. “Diverticular Disease: a Gut Microbiota Perspective. Journal of gastrointestinal and liver diseases”. JGLD. 2019The role of microbiota in diverticular disease[41]
Ojetti V, Petruzziello C, Cardone S, Saviano L, Migneco A, Santarelli L, et al. “The Use of Probiotics in Different Phases of Diverticular Disease. Reviews on recent clinical trials”. 2018Action of probiotics in diverticular disease[49]
Petruzziello C, Migneco A, Cardone S, Covino M, Saviano A, Franceschi F, et al. Supplementation with Lactobacillus reuteri ATCC PTA 4659 in patients affected by acute uncomplicated diverticulitis: a randomised double-blind placebo controlled trial. 2019Action of probiotics in diverticular disease[50]
Petruzziello C, Marannino M, Migneco A, Brigida M, Saviano A, Piccioni A, et al. The efficacy of a mix of three probiotic strains in reducing abdominal pain and inflammatory biomarkers in acute uncomplicated diverticulitis. European review for medical and pharmacological sciences. 2019Action of probiotics in diverticular disease[51]

3. What Is a Healthy Microbiota?

As discussed above, the role of microbiota in determining health and disease, via immune modulation, is becoming increasingly clear. Some microbes have been identified as definitely pathogenic, for instance Clostridium difficile, yet there still are some grey areas, in particular when it comes to determine what defines a healthy microbiota [14].
An example of this comes from studies on microbiota and cancer: Helicobacter pylori is a known risk factor for the development of gastric cancer, but it has a protective effect against oesophageal cancer [15]. Similarly, Escherichia coli protects against pancreatic cancer, but favours colorectal and liver tumours [16]. In these cases, the ambivalent role of these bacteria was determined by the site of colonisation.
It is, indeed, important to underline that, even though it is common to refer to “gut microbiota”, this does change widely throughout the gastrointestinal tract. In the oral cavity, for instance, it is common to find Neisseria spp., which is instead difficult to find in other sites [17]. The stomach has a completely different microbiota than all the other parts of the gastrointestinal tract in healthy patients, but resembles oesophageal or intestinal microbiota in those with gastric cancer [18]. The small intestine even has a different composition based on which tract is being studied, and its composition is different from that of the colon.
Even considering specific parts of the gastrointestinal tract, microbiota changes with age [19], and even depending on geographic localisation, diet and ethnicity [20].
Yet, even though it is not possible to precisely define what species compose a healthy microbiota, it is worth noting that some general characteristics have been observed: a healthy microbiota is made up of a dynamic and diverse community of microbes, which is able to self-regulate [21].
While these do seem to be vague concepts, it is interesting to notice that the modern, western diet directly affects microbiota diversity, reducing its capacity to bounce back when frankly pathogenic species start colonising the gut [22].

4. Gut Disease and Microbiota

While gut microbiota influences all aspects of human health, its action on the gastrointestinal system is particularly important.
Indeed, gut microbiota directly modulates gastrointestinal homeostasis, through a variety of mechanisms. The presence of pathogens at the intestinal barrier, for instance, can directly damage the gastrointestinal mucosa and determine inflammation. This is the mechanism through which C. difficile, Salmonella spp and others can create direct intestinal damage [23].
Direct damage also activates immunologic pathways, particularly through the activation of the inflammasome. IL-1β and IL-18 are a direct consequence of its activation, causing pyroptosis, a particular form of immune-mediated cellular death [24]. Meanwhile, the activation of the inflammasome is important to maintain gut homeostasis, as it helps restore microbiota eubiosis, and it can also lead to chronic gut inflammation, which in turn promotes an inflammatory gut microbiota, in a difficult-to-break vicious circle.
It was observed that Bifidobacterium adolescentis, Lactobacillus, Phascolarctobacterium, Akkermansia muciniphila are all reduced in patients with intestinal inflammation. Interestingly, when present, they are capable of reducing inflammation, particularly acting on C-reactive protein (CRP), IL-6, and tumour necrosis factor (TNF)-α [25]. The action on these inflammatory mediators partly explains how gut microbiota can influence systemic health.
In the gut, the action of these mediators has direct consequences in terms of permeability and inflammation, both extremely important in the pathogenesis of different gastrointestinal disorders [26]. The presence of dysbiosis can trigger the development of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). The role of microbiota has been particularly underlined in the pathogenesis of IBDs, in which dysbiosis is marked by the presence of Mycobacterium avium subsp. paratuberculosis, Fusobacterium nucleatum, adherent–invasive E. coli [27].
Inflammation caused by microbiota dysbiosis is also responsible of liver disorders, particularly non-alcoholic liver steatosis. In this case, there is a direct colonisation of the bile ducts, which adds up to the action of bacterial metabolic products. Interestingly, the capacity of bacteria to metabolise biliary salts is also linked to dysbiosis [28].
Inflammation is also a well-known risk factor for the development of cancer, and it is no different in the intestine; the impact of microbiota composition in modulating the intestinal immunologic niche has proven essential in different forms of cancer [16].

5. Microbiota Modulation: The Case for Probiotics

Given the importance of microbiota in human health, the possibility of modulating it to obtain benefits is an interesting potential therapeutic target.
Microbiota modulation can take place in two different ways, either through the use of antibiotics or through the use of probiotics.
Antibiotic use can target specific pathological bacteria in the gut, eliminating it, as in the case of vancomycin in C. difficile infection [29]. Some antibiotics, such as rifaximin, can instead be used to target a larger number of pathogens, improving conditions such as IBS, SIBO and preventing encephalopathy in patients suffering from liver disease [30]. Ozone, for instance, also seems to have a similar capacity to reduce inflammation in the gut, also through microbiota modulation [31,32].
Yet the use of antibiotics can be tricky. The use of antibiotics can reduce taxonomic diversity of gut microbiota and induce resistance mechanisms in pathogenic species, while also favouring the development of C. difficile infection and other dangerous pathogens [33].
Using probiotics can provide similar positive effects to antibiotics, in reducing pathogens, but at the same time avoiding many of the side effects [34]. Probiotics have been used with different degrees of success in patients suffering from IBS, gastroenteritis and even in C. difficile-associated diarrhoea [35]. Probiotics have also been used in neonatal sepsis and necrotising enterocolitis [36].
Probiotic use has also been discussed in extra-gut conditions, such as autism and acute respiratory infections [37,38].
Some authors even suggest that microbiota modulation through probiotics could be beneficial in preventing cancer [39] and improving response to chemotherapy, reducing gastrointestinal side effects [40].

Given the importance of microbiota in human health, the possibility of modulating it to obtain benefits is an interesting potential therapeutic target.Microbiota modulation can take place in two different ways, either through the use of antibiotics or through the use of probiotics.Antibiotic use can target specific pathological bacteria in the gut, eliminating it, as in the case of vancomycin in C. difficile infection [36]. Some antibiotics, such as rifaximin, can instead be used to target a larger number of pathogens, improving conditions such as IBS, SIBO and preventing encephalopathy in patients suffering from liver disease [37]. Ozone, for instance, also seems to have a similar capacity to reduce inflammation in the gut, also through microbiota modulation [38][39].Yet the use of antibiotics can be tricky. The use of antibiotics can reduce taxonomic diversity of gut microbiota and induce resistance mechanisms in pathogenic species, while also favouring the development of C. difficile infection and other dangerous pathogens [16].Using probiotics can provide similar positive effects to antibiotics, in reducing pathogens, but at the same time avoiding many of the side effects [40]. Probiotics have been used with different degrees of success in patients suffering from IBS, gastroenteritis and even in C. difficile-associated diarrhoea [17]. Probiotics have also been used in neonatal sepsis and necrotising enterocolitis [41].Probiotic use has also been discussed in extra-gut conditions, such as autism and acute respiratory infections [42][18].Some authors even suggest that microbiota modulation through probiotics could be beneficial in preventing cancer [43] and improving response to chemotherapy, reducing gastrointestinal side effects [44].

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