Differences in the composition of the microbiota throughout the gastrointestinal tract (adapted from [9]).
\\n\\n
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6979",leadTitle:null,fullTitle:"Parasites and Parasitic Diseases",title:"Parasites and Parasitic Diseases",subtitle:null,reviewType:"peer-reviewed",abstract:"Parasitic diseases are considered nowadays as an important public health problem due to the high morbidity and mortality rates registered in the world. These diseases result in more severe consequences for the social order of tropical and subtropical countries because many of them have low economic income that makes it even more difficult to design and implement health control programs. This situation opens the door to the emergence and reemergence of these diseases; therefore, it is convenient, necessary, and essential to study and update the epidemiological behavior of tropical diseases with the objective of offering official health professionals and institutions current information for decision-making in this area to ensure social welfare.",isbn:"978-1-83880-128-1",printIsbn:"978-1-83880-127-4",pdfIsbn:"978-1-83962-140-6",doi:"10.5772/intechopen.73726",price:100,priceEur:109,priceUsd:129,slug:"parasites-and-parasitic-diseases",numberOfPages:98,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"f55304c8bd1d92268e33689c368f9e33",bookSignature:"Gilberto Bastidas",publishedDate:"April 24th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/6979.jpg",numberOfDownloads:6651,numberOfWosCitations:2,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:14,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:22,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 27th 2018",dateEndSecondStepPublish:"April 17th 2018",dateEndThirdStepPublish:"June 16th 2018",dateEndFourthStepPublish:"September 4th 2018",dateEndFifthStepPublish:"November 3rd 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"238219",title:"Dr.",name:"Gilberto Antonio",middleName:null,surname:"Bastidas Pacheco",slug:"gilberto-antonio-bastidas-pacheco",fullName:"Gilberto Antonio Bastidas Pacheco",profilePictureURL:"https://mts.intechopen.com/storage/users/238219/images/system/238219.jpeg",biography:"Prof. Gilberto Antonio Bastidas Pacheco is a physician with degrees in Pre-hospital Emergency Care, Executive Direction for Senior Management in Health, and Occupational Health and Safety. Along with a Health Management Course equivalent to the Public Health Middle Course, Magister Scientiae in Education Management and also in Protozoology, Prof. Bastidas holds a Ph.D. in Parasitology. He is a full professor at the Faculty of Health Sciences, Department of Public Health, University of Carabobo, Valencia, Venezuela. He has authored several articles published in national and international journal, and is also an arbitrator of scientific articles, member of the editorial committees of several journals, and a textbook writer and lecturer.",institutionString:"University of Carabobo",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Carabobo",institutionURL:null,country:{name:"Venezuela"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"909",title:"Parasitology",slug:"parasitology"}],chapters:[{id:"66212",title:"Introductory Chapter: Parasitology and Parasitism Areas of Knowledge That Must Be Constantly Studied",doi:"10.5772/intechopen.85181",slug:"introductory-chapter-parasitology-and-parasitism-areas-of-knowledge-that-must-be-constantly-studied",totalDownloads:2323,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Bastidas Gilberto",downloadPdfUrl:"/chapter/pdf-download/66212",previewPdfUrl:"/chapter/pdf-preview/66212",authors:[{id:"238219",title:"Dr.",name:"Gilberto Antonio",surname:"Bastidas Pacheco",slug:"gilberto-antonio-bastidas-pacheco",fullName:"Gilberto Antonio Bastidas Pacheco"}],corrections:null},{id:"63084",title:"Organ Pathology and Associated IFN-γ and IL-10 Variations in Mice Infected with Toxoplasma gondii Isolate from Kenya",doi:"10.5772/intechopen.79700",slug:"organ-pathology-and-associated-ifn-and-il-10-variations-in-mice-infected-with-toxoplasma-gondii-isol",totalDownloads:859,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Toxoplasma gondii is an important foodborne opportunistic pathogen that causes a severe disease in immunocompromised patients. The pathology and immune responses associated with the ensuing disease have not been well described in strains from different parts of the world. The aim of the present study is to determine the IFN-γ and IL-10 variations and organ pathology in immunocompetent and immunocompromised mice infected with T. gondii isolated from a Kenyan chicken. Two groups of BALB/c mice were infected with T. gondii cysts and administered with dexamethasone (DXM) in drinking water. Other two groups: infected untreated and uninfected mice were kept as controls. The mice were euthanized at various time points: blood collected for serum and assayed for IFN-γ and IL-10 variations. After infection, significant (p<0.05) elevated levels of IFN-γ and IL-10 were observed. A significant decline in IFN-γ and IL-10 levels (p<0.05) was observed after dexamethasone treatment. Histological sections in the liver, heart, and spleen of the mice administered with DXM revealed various degrees of inflammation characterized by infiltration of inflammatory cells. The dexamethasone-treated mice presented with progressively increased (p<0.001) inflammatory responses is compared with the infected untreated mice.",signatures:"John Mokua Mose, David Muchina Kamau,\nJohn Maina Kagira, Naomi Maina, Maina Ngotho,\nLucy Mutharia and Simon Muturi Karanja",downloadPdfUrl:"/chapter/pdf-download/63084",previewPdfUrl:"/chapter/pdf-preview/63084",authors:[{id:"255664",title:"Dr.",name:"John",surname:"Kagira",slug:"john-kagira",fullName:"John Kagira"},{id:"255668",title:"Dr.",name:"John",surname:"Mokua",slug:"john-mokua",fullName:"John Mokua"},{id:"255669",title:"Dr.",name:"David",surname:"Kamau",slug:"david-kamau",fullName:"David Kamau"},{id:"255670",title:"Prof.",name:"Naomi",surname:"Maina",slug:"naomi-maina",fullName:"Naomi Maina"},{id:"255671",title:"Dr.",name:"Maina",surname:"Ngotho",slug:"maina-ngotho",fullName:"Maina Ngotho"},{id:"255672",title:"Ms.",name:"Adele",surname:"Njuguna",slug:"adele-njuguna",fullName:"Adele Njuguna"},{id:"255673",title:"Prof.",name:"Simon",surname:"Karanja",slug:"simon-karanja",fullName:"Simon Karanja"},{id:"265279",title:"Dr.",name:"Lucy",surname:"Mutharia",slug:"lucy-mutharia",fullName:"Lucy Mutharia"}],corrections:null},{id:"62896",title:"Malaria Pathophysiology as a Syndrome: Focus on Glucose Homeostasis in Severe Malaria and Phytotherapeutics Management of the Disease",doi:"10.5772/intechopen.79698",slug:"malaria-pathophysiology-as-a-syndrome-focus-on-glucose-homeostasis-in-severe-malaria-and-phytotherap",totalDownloads:1253,totalCrossrefCites:3,totalDimensionsCites:5,hasAltmetrics:1,abstract:"Severe malaria presents with varied pathophysiological manifestations to include derangement in glucose homeostasis. The changes in glucose management by the infected human host emanate from both Plasmodium parasitic and host factors and/or influences which are aimed at creating a proliferative advantage to the parasite. This also includes morphological changes that that take place to both infected and uninfected cells as structural alterations occur on the cell membranes to allow for increased nutrients (glucose) transportation into the cells. Without the availability, effective and efficient intervention there is a high cost incurred by the human host. Hyperglycaemia, hypoglycaemia and hyperinsulinemia are critical aspects displayed in severe malaria. Conventional treatment to malaria renders itself hostile to the host with negative glucose metabolism changes experiences in the young, pregnant women and malaria naïve individuals. In malaria, therefore, host effects, parasite imperatives and treatment regimens play a pivotal role in the return to wellness of the patient. Phytotherapeutics are emerging as treatment alternatives that ameliorate glucose homeostasis alternations as well as combat malaria parasitaemia. The phytochemicals e.g. triterpenes, have been shown to alleviate the “disease” and “parasitic” aspects of malaria pointing at key aspects in ameliorating malaria glucose homeostasis fallings-out that are experienced in malaria.",signatures:"Greanious Alfred Mavondo, Joy Mavondo, Wisdom Peresuh, Mary\nDlodlo and Obadiah Moyo",downloadPdfUrl:"/chapter/pdf-download/62896",previewPdfUrl:"/chapter/pdf-preview/62896",authors:[{id:"202805",title:"Prof.",name:"Alfred Mavondo-Nyajena Mukuwa",surname:"Greanious",slug:"alfred-mavondo-nyajena-mukuwa-greanious",fullName:"Alfred Mavondo-Nyajena Mukuwa Greanious"},{id:"263433",title:"Dr.",name:"Obadiah",surname:"Moyo",slug:"obadiah-moyo",fullName:"Obadiah Moyo"},{id:"263434",title:"Mrs.",name:"Joy",surname:"Mavondo",slug:"joy-mavondo",fullName:"Joy Mavondo"},{id:"263435",title:"Ms.",name:"Mary",surname:"Dlodlo",slug:"mary-dlodlo",fullName:"Mary Dlodlo"},{id:"263436",title:"Mr.",name:"Wisdom",surname:"Peresu",slug:"wisdom-peresu",fullName:"Wisdom Peresu"}],corrections:null},{id:"62893",title:"Prevalence and Intensity of Intestinal Parasites and Malaria in Pregnant Women at Abobo District in Abidjan, Côte d’Ivoire",doi:"10.5772/intechopen.79699",slug:"prevalence-and-intensity-of-intestinal-parasites-and-malaria-in-pregnant-women-at-abobo-district-in-",totalDownloads:866,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"A prospective study was carried out from 2010 to 2012 at the Hôpital Général d’Abobo (HGA) in Abidjan, in order to determine the impact of infectious and parasitic diseases on child cognitive development. Blood samples were examined by means of drop thick and blood smear, as for stool by direct examination and concentration by formalin-ether method. We evaluated the prevalence and the parasite load of malaria and gastrointestinal parasites and then investigated the risk factors for these disorders. Overall, 331 pregnant women in the last trimester of their pregnancy were enrolled. The plasmodic index was 3.9% with an infestation specific rate for P. falciparum of 100%. Concerning digestive protozoa, it has been observed 71.3% of nonpathogenic, against 9.7% of pathogens, either an overall prevalence of 51.4% of digestive parasites. The calculated average parasitic loads revealed 3089.2 tpz/μl of blood (95% CI, 591.1–5587.3) for malaria, 6.5 eggs per gram of stool (95% CI, 0.4–13.4) for intestinal helminths, and one (1) parasite by microscopic field for protozoa (common infestation). It has been shown that the occurrence of malaria has been linked to the nonuse of impregnated mosquito nets (χ2 = 0.012, p = 0.018) to age. No link could be established between the presence of digestive parasites and the age of pregnant women or socioeconomic conditions (level of education, profession, type of toilet). Malaria is less common in pregnant women, while the rate of digestive parasites remains high.",signatures:"Gaoussou Coulibaly, Kouassi Patrick Yao, Mathurin Koffi, Bernardin\nAhouty Ahouty, Laurent Kouassi Louhourignon, Monsan N’Cho and\nEliézer Kouakou N’Goran",downloadPdfUrl:"/chapter/pdf-download/62893",previewPdfUrl:"/chapter/pdf-preview/62893",authors:[{id:"254981",title:"Ph.D. Student",name:"Gaoussou",surname:"Coulibaly",slug:"gaoussou-coulibaly",fullName:"Gaoussou Coulibaly"}],corrections:null},{id:"63554",title:"Current Aspects in Trichinellosis",doi:"10.5772/intechopen.80372",slug:"current-aspects-in-trichinellosis",totalDownloads:1350,totalCrossrefCites:2,totalDimensionsCites:8,hasAltmetrics:0,abstract:"Currently, it is estimated that more than 11 million humans in the world are infected by helminth parasites of Trichinella species, mainly by Trichinella spiralis (T. spiralis), responsible for causing Trichinellosis disease in both animals and humans. Trichinellosis is a cosmopolitan parasitic zoonotic disease, which has direct relevance to human and animal health, because it presents a constant and important challenge to the host’s immune system, especially through the intestinal tract. Currently, there is an intense investigation of new strategies in pharmacotherapy and immunotherapy against infection by Trichinella spiralis. In this chapter, we will present the most current aspects of biology, epidemiology, immunology, clinicopathology, pharmacotherapy and immunotherapy in Trichinellosis.",signatures:"José Luis Muñoz-Carrillo, Claudia Maldonado-Tapia, Argelia López-\nLuna, José Jesús Muñoz-Escobedo, Juan Armando Flores-De La\nTorre and Alejandra Moreno-García",downloadPdfUrl:"/chapter/pdf-download/63554",previewPdfUrl:"/chapter/pdf-preview/63554",authors:[{id:"214236",title:"Dr.",name:"Jose Luis",surname:"Muñoz-Carrillo",slug:"jose-luis-munoz-carrillo",fullName:"Jose Luis Muñoz-Carrillo"},{id:"216080",title:"Dr.",name:"Alejandra",surname:"Moreno-García",slug:"alejandra-moreno-garcia",fullName:"Alejandra Moreno-García"},{id:"254888",title:"Dr.",name:"Juan Armando",surname:"Flores-De La Torre",slug:"juan-armando-flores-de-la-torre",fullName:"Juan Armando Flores-De La Torre"},{id:"254889",title:"Dr.",name:"José Jesús",surname:"Muñoz-Escobedo",slug:"jose-jesus-munoz-escobedo",fullName:"José Jesús Muñoz-Escobedo"},{id:"254890",title:"Dr.",name:"Argelia",surname:"López-Luna",slug:"argelia-lopez-luna",fullName:"Argelia López-Luna"},{id:"254891",title:"Dr.",name:"Claudia",surname:"Maldonado-Tapia",slug:"claudia-maldonado-tapia",fullName:"Claudia Maldonado-Tapia"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"9025",title:"Parasitology and Microbiology Research",subtitle:null,isOpenForSubmission:!1,hash:"d9a211396d44f07d2748e147786a2c8b",slug:"parasitology-and-microbiology-research",bookSignature:"Gilberto Antonio Bastidas Pacheco and Asghar Ali Kamboh",coverURL:"https://cdn.intechopen.com/books/images_new/9025.jpg",editedByType:"Edited by",editors:[{id:"238219",title:"Dr.",name:"Gilberto Antonio",surname:"Bastidas Pacheco",slug:"gilberto-antonio-bastidas-pacheco",fullName:"Gilberto Antonio Bastidas Pacheco"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1692",title:"Parasitology",subtitle:null,isOpenForSubmission:!1,hash:"b2110e81c765897e4ffdfbd340495e25",slug:"parasitology",bookSignature:"Mohammad Manjur Shah",coverURL:"https://cdn.intechopen.com/books/images_new/1692.jpg",editedByType:"Edited by",editors:[{id:"94128",title:"Dr.",name:"Mohammad Manjur",surname:"Shah",slug:"mohammad-manjur-shah",fullName:"Mohammad Manjur Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5527",title:"Natural Remedies in the Fight Against Parasites",subtitle:null,isOpenForSubmission:!1,hash:"d705be119e74a50305952521b2b5ece0",slug:"natural-remedies-in-the-fight-against-parasites",bookSignature:"Hanem Khater, M. 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The treatment of Crohn’s disease and ulcerative colitis has central purposes such as to induce and maintain the patients’ remission, while restraining the disease’s secondary effects and improving the quality of life of the affected subjects. Pharmacological therapy against these pathologies converges on controlling the exacerbation of immune response, either with systemic agents, such as corticosteroids, azathioprine (AZA), aminosalicylates, and methotrexate, or topical anti-inflammatory drugs. Traditionally, the treatment for CD and UC follows a “step-up” approach. However, in the last years, a “top-down” strategy was implemented in IBD therapy, beginning to treat patients with biological agents, especially for more aggressive diseases [1]. After the main control of the inflammation, biologicals can be withdrawn, and weaker immunosuppressor medicines can be used, such as AZA, aminosalicylates, or other drug alternatives for maintenance of disease remission [2], with different mechanisms of action, as discussed in the following section.
Corticosteroids, a type of steroid hormones, are lipophilic molecules derived from cholesterol. Glucocorticoids, whose major representative is cortisol, play a role in the metabolism of lipids and carbohydrates and in the immune response, through immunosuppressive mechanisms. These hormones are synthesized by the adrenal glands in response to psychological or physiological stressful stimuli, such as excessive inflammation. The synthesis of glucocorticoids occurs after hypothalamic production of corticotropin-releasing hormone (CRH), which activates the pituitary secretion of corticotropin (ACTH) that, in turn, leads to adrenal release of cortisol, in a fine-tuned circadian rhythm [3].
Many of the immunosuppressive and anti-inflammatory functions of glucocorticoids occur after the binding of this hormone to the glucocorticoid receptor (GR). This molecule was described in the 1970s [4] and presents two isoforms of GR, GRα and GRβ, which differ in the C-terminal domain, being that the α forms the most prevalent in many human cells [5].
Glucocorticoids may exert their effects by non-genomic and mainly by the genomic signaling pathways [6]. One of the first evidences on the formation of a glucocorticoid-GR complex dated from 1972 in a study, which showed that free glucocorticoids penetrate hepatoma cells and bind to a cytoplasmic receptor, forming a complex which migrates to the nucleus shortly thereafter [7]. In the nucleus, the glucocorticoid/receptor complex binds to specific DNA sequences, named
Cortisol was first synthesized around 1937/1938 by Tadeusz Reichstein, who won the Nobel Prize about 10 years later for his work [14]. The first use of corticosteroids as an immunosuppressive and anti-inflammatory treatment occurred in the 1940s for rheumatoid arthritis in a study by Hench et al., who showed a decrease in symptoms when patients were treated with these hormones, besides disease relapse when treatment was stopped [15]. Since then, corticosteroids have been effective in treating other diseases, including intestinal inflammation [16].
Today, corticosteroid therapy is one of the most widely used and most effective drugs in the treatment of IBD, especially in acute inflammation, to induce disease remission [17]. However, there are important limitations regarding their long-term use, because of the drug’s side effects. In line with that, despite the anti-inflammatory role in experimental colitis, budesonide worsens the general status of the mice, leading to endotoxemia and impaired epithelial repair in the gut, which are findings that could partially explain the fails in long-term glucocorticoid therapy for intestinal inflammation [18]. In contrast, mice exposed to dextran sodium sulfate for colitis development and treated for short term with the glucocorticoid dexamethasone had decreased intestinal inflammation, with reduced expression of pro-inflammatory cytokines such as IFN-γ and IL-1, diminishment of IFN- γ-producing CD4+ T cells and augmented frequency of anti-inflammatory cytokine-producing cells such as IL-10. Moreover, the increase in the frequency of regulatory markers such as GITR, CTLA-4, PD-1, CD73, and FoxP3 in treated mice pointed to a relevant role for this short-term therapy in the induction of immune regulation [19], despite the long-term adverse effects of these drugs. These findings corroborate the relevance of this hormone in the regulation of mucosal immunity. In fact, regulatory T cells deficient for glucocorticoid receptor fail to control intestinal inflammatory diseases, in vivo. In addition, these knockout regulatory T cells acquire Th1 phenotype and secrete IFN-γ, with a consequent failure to inhibit the proliferation of CD4+ T cells. Then, not only the synthetic glucocorticoid is important to inflammation control, but the glucocorticoid receptor is critical for regulatory T cell functions neither [20].
Regarding the pivotal role of microbiota in the development of gut inflammation [21], it is known that the commensal intestinal bacteria may be involved in the mechanisms of action of glucocorticoid and mediate the anti-inflammatory effects of dexamethasone in the colon [22]. Indeed, the evaluation of mucosa transcriptomics of ulcerative colitis patients pointed to a corticosteroid-response gene signature that could predict response to this therapy, together with notable changes in gut microbiota [23]. In Crohn’s disease or ulcerative colitis, the bacteria translocation in the gut is originally restrained by local phagocytic cells such as neutrophils, which in turn may contribute to tissue damage due to their excessive inflammation triggered in an attempt to control microbial invasion. Then, the mechanisms and efficacy of corticosteroids in IBD also involve the reduction in the chemokines responsible for the recruitment of neutrophils, besides natural killer cells and activated T lymphocytes to the gut, during ulcerative colitis [24]. There is also a decrease in adhesion and chemotaxis of these cells to the intestinal mucosa [25].
Although the efficacy of corticosteroid for the treatment of autoimmune and inflammatory diseases has been demonstrated, prolonged utilization of these drugs is associated with an increased risk of developing eye diseases such as glaucoma or cataract, hyperglycemia or insulin resistance, dermatological affections, and purpura [26]. Moreover, there is an increased risk of gastrointestinal problems such as peptic ulcer with perforations, bleeding, and acute pancreatitis [27]. The use of corticosteroids can also cause psychiatric and cognitive disorders [28], psychosis, and also sleep-related disorders [29]. Moreover, because of its immunosuppressive and anti-inflammatory effects, many patients who use corticosteroids may suffer from reduced effectiveness of the immune system and are at risk for opportunistic infections [30].
The aminosalicylates (5-aminosalicylic acid, 5-ASA, or mesalazine) are one of the most used therapeutic choices to control mild to moderate inflammatory bowel diseases (IBD). Sulfasalazine (SASP), balsalazide, and olsalazine are prodrugs in which an azo bond is added to the structure to connect the 5-ASA moiety to carrier molecules. Sulfasalazine was the first aminosalicylate used for IBD and provided the basis for this class of medications. It was developed in the late 1930s, by the Swedish physician Nanna Svartz for the treatment of patients with rheumatic polyarthritis. Interestingly, some of the patients who were treated with SASP had ulcerative colitis too, and, surprisingly, their condition became more stable [31]. Therefore, SASP was soon being chosen as a treatment option for patients with IBD. Later, metabolic studies revealed that when this drug reaches the colon, the azo bond is cleaved by bacterial azoreductase, liberating 5-ASA and sulfapyridine, which is responsible for most of the usual adverse effects related to sulfasalazine [32]. In fact, in earlier elegant studies from the 70–80 decades, 5-ASA was shown to be the therapeutically active compound in sulfasalazine, while sulfapyridine plays a role as a carrier molecule, not required for clinical efficacy of the drug. These works were very important to drive the development of pure 5-ASA preparations useful for the treatment of IBD. Therefore, since aminosalicylates are among the most common therapeutic agents for these diseases, many studies have been performed in an attempt to discover the mechanisms of action of these drugs in the gut inflammation.
When the initial triggers break the mucosal tolerance in IBD, there is a vast infiltration of leukocytes in the intestine, with consequent production of soluble mediators of inflammation such as cytokines, chemokines, and eicosanoids. Some of these mediators are significantly elevated in the inflamed mucosa of IBD individuals, corroborating the pathogenesis of the disease, due to their pro-inflammatory impacts upon the bowel. In fact, the increased levels of seven eicosanoids, including prostaglandin (PG)E2, PGD2, thromboxane (TBX)B2, 5-HETE, 11-HETE, 12-HETE, and 15-HETE are found on mucosal biopsies from patients with ulcerative colitis, being correlated with the severity of inflammation [33]. Similarly, prostacyclin I2, PGE2, and TBXA2 are increased in cultured gut biopsies of active colitis patients, and, notably, the levels of these inflammatory mediators are reduced in the presence of 5-ASA. In fact, the activated leucocytes in patients’ mucosa release toxic reactive oxygen metabolites and harmful eicosanoids such as LTB4, which seems to be an essential chemotactic agent in these diseases [34]. Therefore, considering the therapy mechanisms, sulfasalazine can effectively repress LTB4 and 5-HETE production by human polymorphonuclear leukocytes [35], while sulfasalazine, 5-ASA, and olsalazine (a 5-ASA dimer) potently inhibit colonic macrophage chemotaxis toward LTB4 [36]. These data suggested that one of the mechanisms of action of these drugs could be the inhibition of eicosanoids and then it is plausible to infer that the therapeutic inhibition of LOX or COX pathways could be useful in both ulcerative colitis and Crohn’s disease.
Platelet-activating factor (PAF) is another phospholipid mediator released early in inflammation by a diversity of cell types, playing important roles in inflammatory conditions, including IBD. In active Crohn’s disease, PAF levels are significantly higher and more elevated in inflamed than in noninflamed areas [37]. In parallel, PAF is increased in the colon and ileum from Crohn’s disease patients [38], while biopsies of inflamed areas taken from ulcerative colitis subjects produce PAF spontaneously [39]. In this context, sulfasalazine and 5-ASA greatly reduce the synthesis of this mediator when incubated with mucosal biopsy specimens, indicating that these drugs exert beneficial effects in the inhibition of inflammation induced by PAF [40].
Chronic gut inflammation is also related to enhanced production of reactive metabolites of oxygen and nitrogen, since both reactive oxygen species (ROS) and nitric oxide (NO) deeply modulate the inflammatory responses. The generation of these reactive species can be attenuated by sulfasalazine, as it inhibits the binding of N-formyl-methionyl-leucyl-phenyl-alanine (fMLP) to its receptor on neutrophils [41] and also the superoxide production [42]. Interestingly, olsalazine and sulfasalazine are both potent inhibitors of superoxide production and degranulation of human neutrophils stimulated with fMLP, in contrast to 5-ASA and sulfapyridine, which do not have this ability [43]. On the other hand, 5-ASA can be converted to the oxidation products salicylate and gentisate, when the drug is incubated with activated human mononuclear cells and neutrophils, indicating that 5-ASA may scavenge toxic oxygen and nitrogen metabolites [44]. Similarly, evidences from an in vivo study pointed once more to a scavenge role of sulfasalazine as a mechanism of action, thus reducing experimental intestinal inflammation induced by acetic acid [45]. In humans, 5-ASA oxidation products can be found in the stools of IBD patients using sulfasalazine, suggesting that this drug indeed plays a role as scavenger for ROS and NO in these diseases [46].
A series of studies have demonstrated that sulfasalazine and its metabolites, at clinically relevant concentrations, also inhibit the release of cytokines produced by multiple cell types, including T cell mediators such as interleukin (IL)-2 [47] and those produced by monocytes or macrophages, like IL-12 [48], IL-1β, and tumor necrosis factor (TNF) [49]. Precisely, how sulfasalazine represses the release of cytokines has not been fully elucidated yet, but some studies have shown, for example, that sulfasalazine inhibits TNF expression in macrophages by inducing apoptosis [49] or inhibiting nuclear factor kappa B (NF-KB), a transcription factor crucial to the production of inflammatory mediators [50]. In the last years, the effects of sulfasalazine have been extensively studied in experimental models of intestinal inflammation. The chemically treated animals develop inflammation signs similar to those of human IBD, such as severe bloody diarrhea, body weight loss, colon length shortening, and gut pathological changes. In general, sulfasalazine treatment is able to reduce these signs and the colitis severity. Moreover, the drug significantly decreases the levels of inflammatory markers such as ROS [51], NF-KB, COX-2 [52], IL-6, TNF, IL-1 [53], NO [53], inducible nitric oxide synthase (iNOS) [52], myeloperoxidase (MPO) [54], monocyte chemoattractant protein-1 (MCP-1) [51], intercellular adhesion molecule-1 (ICAM-1) [51], and LTB4 [55], which are frequently overexpressed in IBD and widely known to be involved in chronic inflammatory disorders. Taken together, these experimental findings pointed to different mechanisms of action of sulfasalazine in the control of innate inflammatory reactions in gut mucosa, with outstanding relevance to the disease outcome.
Regarding adaptive and regulatory responses, it is known that a close relationship exists between colonic inflammation and T helper 1 (Th1) or Th17 immune reactions, which are related to the severity of inflammation in both human and experimental IBD [56]. In accordance, in a colitis model, mesalazine is able to inhibit Th1 and Th17 responses in contrast to an induction of regulatory immune profile, as observed by the disease amelioration, reduced expression neutrophil activity, IL-1β, TNF, IL-12, IFNγ, IL-17, IL-6, and RORγt, along with an augment in the suppressive cytokines IL-10 and TGF-β and in the transcription factor Foxp3 [57]. These data indicate that another mechanism of action of aminosalicylate drugs could be by decreasing pathogenic while increasing regulatory responses in intestinal inflammation.
The peroxisome proliferator-activated receptor ligand-γ (PPARγ) plays a significant role in the immune control through its capacity to repress the expression of inflammatory cytokines and induce the differentiation of leukocytes toward anti-inflammatory phenotypes. Importantly, by using experimental approaches with epithelial colon cell lines and human biopsies, Rousseaux et al. showed that 5-ASA activates PPARγ, pointing to the receptor as an important drug’s target for the control of intestinal inflammation [58]. In line with that, regulatory T cells (Tregs) play an indispensable role in suppressing exacerbated inflammatory immune responses that can be harmful to the host, such as in IBD [59]. Recently, Oh-Oka et al. proposed a new anti-inflammatory mechanism for mesalamine (5-ASA) in colitis, involving colonic Tregs. The oral treatment with this drug leads to the accumulation of Tregs in the colon lamina propria associated with increased levels of the active form of the anti-inflammatory cytokine TGF-β. These alterations attributed to mesalamine are dependent on the activation of aryl hydrocarbon receptor (AhR), a transcription factor that regulates several immune processes, including Treg activation and differentiation [60].
Altogether, these studies show that aminosalicylates play an important role in the regulation of IBD responses.
One of the most prescribed strategies for IBD therapy is the use of thiopurines, mainly azathioprine (AZA) and 6-mercaptopurine (6-MP). AZA is a prodrug that is metabolized by nonenzymatic mechanisms to be converted to 6-MP and other metabolites. Therefore, patients could be treated with AZA or directly with 6-MP, but the final metabolites produced from the thiopurines are the same. Also, both drugs generate endogenously active products able to interfere on DNA and RNA synthesis [61].
The discovery of AZA and 6-MP yielded a Nobel Prize in Medicine in 1988 for Gertrude B. Elion and George Hitchings. At first, the thiopurines were used in cancer therapy, in order to stop cell proliferation. Nonetheless, the immunosuppressive effect of thiopurines was evident as well as their efficiency in prolonging renal allograft transplant survival [62]. Thereafter, AZA and 6-MP began to be used in the clinics for inflammatory and rheumatic diseases. Since then, many mechanisms of action of thiopurines were proposed, mainly involving immunological axis in an attempt to unravel their immunosuppressive effects.
Some thiopurine metabolites, such as deoxyguanosine triphosphate (dGTP) and 6-thioguanine (6-TG), can be incorporated to DNA, replacing the natural purines adenine (A) and guanine (G). Then, during the DNA replication, a high level of substitution 6-TG could be particularly cytotoxic [63]. These DNA modifications are not restricted to cancer cells, and lymphocytes can be affected by the purine analogue 6-TG as well [64]. Besides that, some evidences point to the inhibition of de novo synthesis, which produce purines, by the thiopurine therapy. Then, the lack of abundant nitrogenous bases impairs the lymphocyte replication either, which contributes to the immunosuppression [65].
The thiopurines have the capacity to downregulate the expression of inflammatory genes in activated T lymphocytes [66]. One of these genes is the TNF-related apoptosis-inducing ligand (TRAIL), which is important to induce apoptosis and is upregulated in activated T lymphocytes. Despite being apparently contradictory, TRAIL could increase T cell proliferation and IFN-γ production [67], a phenomenon that is pathogenic for Crohn’s disease patients. It is important to state that IFN-γ is a cytokine that accompanies the Th1 response, which increases gut inflammation. Also, CD27, which is a member of TNF superfamily, is downregulated by AZA [66]. This receptor is required to T cell maintenance and for B cell activation. Consequently, a low expression of CD27 could facilitate the lymphocyte death [68]. Besides, CD27 is involved in the NF-κB activation and IFN-γ production [69]. In fact, the 6-TG incorporation into T cell DNA is correlated to the decreased IFN-γ production in CD patients [70]. Lastly, the thiopurines could reduce the expression of the α4-integrin as well [66]. This integrin is mandatory to the lymphocyte accumulation in the gut and the chronic inflammation [71].
It is clear that the accumulation of T lymphocytes in the gut mucosa is one of the main hallmarks for the exacerbated inflammation and disease worsening. Accordingly, thiopurines also reduce T cell proliferation and the consequent excessive inflammatory mediators produced by this population. Indeed, 6-MP that impairs the A and T purine integration into the replicant DNA and replaces them for mimetic purines compromises the cell cycle and T cell proliferation. 6-MP interferes in the G1 to S phase transition and progression through S phase in cell cycle, with consequent increase in lymphocyte death [72]. Thereby, it is unquestionable that the thiopurine metabolites incorporate into the genetic material and negatively influence the DNA integrity or stability, which causes cellular death. In the last decade, the first conclusive and detailed studies about the thiopurines’ molecular mechanism of action in T lymphocytes explained better the delayed effects of these drugs, besides the incorporation of mimetic purines, as described above.
The Ras-related C3 botulinum toxin substrate 1 (Rac1) is a GTPase protein that activates MEKK/IκB/NF-κB (mitogen-activated protein kinase kinase/IKK/nuclear factor kappa-light-chain-enhancer of activated B cells) and signal transducer and activator of transcripition-3 (STAT-3) pathways, both of which lead to the accumulation of B-cell lymphoma-extra large (Bcl-xL) in the mitochondria. The enhancement of this protein results in an anti-apoptotic effect to cell survival. However, AZA and the 6-MP metabolite 6-thioguanine triphosphate (6-Thio-GTP) bind to Rac1, which impairs MEKK and STAT-3 phosphorylation, and consequently the anti-apoptotic effect by Bcl-xL is lost. Instead of that, there is an enhancement of Caspase-9, an apoptotic pathway of human cells involving mitochondria [73]. Interestingly, these mechanisms require the co-stimulation by CD28 in T cells.
The bind of CD28 by costimulatory molecules leads to lymphocyte’s lamellipodia formations, which are projections of the cytoskeletal protein actin, necessary for T cell movement and membrane readjustment to make contact with antigen-presenting cells (APC). GTPase Rac1 also mediates this process [74]. Later, it was observed that thiopurines also bind to and block Rac2 activation, while the treatment with these drugs impairs the lamellipodia formation. Additionally, upon binding to Rac proteins, AZA and its metabolites reduce ezrin-radixin-moesin protein (ERM) desphosphorylation and subsequently the formation of APC-T cell conjugates, necessary for an effective immune adaptive response. Likewise, that was dependent on CD28 activation too [74]. Taken together, these results suggested that AZA and its metabolites binding Rac1 promote T cell apoptosis, by decreasing Bcl-xL and increasing caspase-9, but also interfere in T cell function or activation. Recently, a Bcl-2 inhibitor was suggested as a novel therapy to patients refractory to AZA treatment, despite Bcl-2, as a biomarker, cannot predict AZA treatment response in IBD patients [75].
In 2009 a study confirmed that 6-MP and 6-TG decrease the lymphoproliferative capacity of T cells, but in a physiological concentration (5 μM) [76]. The thiopurine therapy causes, in vivo, specifically depletion of T CD4 memory cells, thus reducing the capacity of response to a recurrent antigen. Considering that in IBD there is continuous microbial translocation and antigen presentation [77], this should explain, at least in part, the delayed onset of the drug’s effect on the disease.
Thiopurine metabolites are also capable to inhibit the inflammatory response of macrophages and epithelial cells. These drugs significantly reduce the activity of c-Jun N-terminal kinase (JNK) and STAT3, as well IL-6, IL-8, CCL2, and CCL5 and inducible nitric oxide synthase (iNOS) expression. However, only iNOS in macrophages and IL-8 in epithelial cells are decreased dependent on Rac1 [78]. In fact, AZA restores the paracellular permeability after TNF-induced apoptosis. The treatment improves the expression of tight junctions and adherens junctions, such as occludin and E-cadherin [79]. Thus, the reduction of Rac1 is proposed as a biomarker for effectiveness of thiopurine treatment in patients with IBD [80].
It seems that the use of thiopurines can modulate the frequency of diverse immune cell populations, even by an indirect pathway. For example, patients treated with AZA have increased CCR5 expression in circulating monocytes. These CCR5+ cells are considered to have an anti-inflammatory profile, with increased CD163 and diminished TLR4-induced TNF and IL-6 secretion, probably in an attempt to achieve immunoregulation under AZA treatment [81]. Moreover, thiopurine therapy decreases CD160 expression [82], as well as natural killer (NK) cells and the population of B lymphocytes in the peripheral blood of IBD patients [83]. Indeed, the reduction in B cells is one of the reasons for using combo therapy with AZA plus infliximab (IFX), instead of IFX alone. AZA diminishes the antibody formation against IFX and then improves the patients’ responsiveness to the biological treatment [84].
The presence of variant Tγδ cells, specifically the TCR Vδ2, in the gut mucosa of Crohn’s disease patients is associated with worse clinical prognosis and inflammation [85]. However, AZA is able to ablate this population in the blood and mucosa of patients treated with this drug, suggesting other potential mechanisms of action of AZA in the control of intestinal inflammation [86].
Besides the cellular changes, thiopurines are also capable of modulating soluble mediators, by decreasing IL-1β, TNF, and IFN-γ or increasing IL-10
Finally, a last mechanism of immune regulation was recently described involving AZA’s use. This drug can induce autophagy, which is a natural mechanism to recycle cellular components and to promote cell survival, depending on PERK sensor and mTORC1 in lymphocytes. Hence, modulation of autophagy could represent an additional mechanism of inflammation control through AZA treatment in IBD [90].
Methotrexate (MTX), originally known as amethopterin, is a folate antagonist. Its history and clinical use refers to Faber and Diamond [91], who reported the utilization of aminopterin, the first folic acid antagonist, as a treatment for acute leukemia in children. MTX, which is a derivative of aminopterin and is distinguished by having an additional methyl in its structure, subsequently replaced aminopterin after a study reported its lower toxicity in an experimental model of acute leukemia in rats [92]. The idea behind the use of antifolates for the treatment of neoplasias was based on the knowledge that folates function as cofactors for DNA biosynthesis. Subsequently, the ability of MTX to interfere in DNA synthesis was proven experimentally [93], and years later lower doses of MTX also began to be studied for other conditions such as psoriasis [94] and rheumatoid arthritis [95].
For IBD, Kozarek et al. [96] were the first to report the ability of this drug to induce clinical and histological remission in patients with Crohn’s disease, but it was only after two randomized controlled trials (RCTs) of the North American Crohn’s Study Group (NACSG) that MTX was formally established as a possible therapy for this disease [97]. On the other hand, there is no strong scientific basis for recommending the use of MTX as a monotherapy for UC. Nevertheless, the utilization of high or low doses of MTX in combination with anti-TNF has been shown to be effective in disease control at the same extent in both Crohn’s disease and ulcerative colitis patients [98]. In summary, because of these and other results, MTX is usually recommended in specific conditions, especially depending on disease outcome and response to other therapies [99].
MTX acts as an antineoplastic drug when used at high doses and as immunosuppressive at low doses [100]. This led to the investigation of other possible mechanisms capable of inducing immunosuppression, in addition to interfering in cell proliferation. In line with that, there is a lack of specific investigation unraveling the exact mechanisms of action of MTX in IBD, but this drug is capable of inducing apoptosis in activated T cells [101], inhibiting IL-8 production by peripheral blood mononuclear cells [102], and increasing extracellular adenosine levels. This metabolite has potent anti-inflammatory properties [103] in patients with rheumatoid arthritis [104] and potentially in IBD [105]. Clearly, more experimental studies are needed to better understand the action of MTX in IBD, but those mentioned above represent possible mechanisms that could explain the relative success of MTX as an immunomodulatory therapy, especially for Crohn’s disease.
The cyclosporine A (CsA) is an immunosuppressor drug initially used for organ transplantation on the late 70 and 80 decades [106]. Some years later, it was utilized as an alternative treatment for ulcerative colitis (UC) patients refractory to glucocorticoids, because of its strong immune regulatory effects [107].
CsA is a lipophilic cyclic peptide that is metabolized by hepatic enzymes of cytochrome P450 pathway [108]. Its immunosuppressor activity depends on the intracellular binding to cyclophilins with further inhibition of the calcium-calcineurin pathway and the resulting blockage of the nuclear activated T cell factor (NFAT) translocation to the nucleus [109], thus avoiding cellular activation. Consequently, there is reduction in the transcription of genes related to cytokine production such as IL-2, IL-4, and IFN-γ [110], inhibition of CD4 expression, cell proliferation [111], and activation of CD8 lymphocytes [112]. Therefore, the blockage of NFAT is considered one of the main effects of this immunosuppressor drug [113].
Upon in vitro treatment of peripheral blood mononuclear cells (PBMCs), from ulcerative colitis or Crohn’s disease patients with CsA, there is reduction of TNF, IL-17, and IL-10 in samples from all donors, besides an exclusive significant IL-13 decrease in subjects with UC. Also, CsA stimulates the cellular apoptosis of PBMC from patients with UC, though not by the mitochondrial route [114]. In an experimental colitis model, the treatment with CsA reduces the clinical activity of the disease and mRNA expression of several inflammatory cytokines such as IL-1β, IL-6, and TNF [115].
Hence, though the therapy with CsA has shown to be beneficial, the systemic treatment can be limited due to its side effects such as nephrotoxicity, hypertension, seizures, production of ROS or hydrogen peroxide, and opportunistic infections [116].
Tacrolimus (Tac) was isolated in 1984 from the fungus strain
The Tac, compared to CsA, has a more potent inhibitory action against T cell activation, leading to immunosuppression. It binds to FKBP-12, with further inhibition of the calmodulin-dependent phosphatase activity of calcineurin [119]. Thus, it inhibits the action of activated nuclear T cell factor (NFAT), reducing the production of IL-2. In line with that, Tac can also decrease the activity of NF-κB [120]. Therefore, besides IL-2, Tac is a calcineurin inhibitor that leads to reduced production of IL-3, TNF, IFN-γ, and IL-17, as well as the release of histamine from mast cells and proliferation of CD4+ or CD8+ T cells in a variety of inflammatory processes [121]. Tac treatment in bone marrow-derived macrophages also leads to reduced IL-12p40, IL-12p70, and IL-23 during LPS stimuli [122].
As described, in vitro treatment with Tac inhibits the activity of leukocytes such as T lymphocytes, NKT, and antigen-presenting cells, usually present on colon tissue. Moreover, the administration of Tac in trinitrobenzene sulfonic acid (TNBS) colitis results in the reduction of neutrophil infiltrate in the intestinal mucosa associated with inhibition of T cell activation, as well as decreased expression of CXCL1 and CXCL2 chemokines [123]. Most interestingly, Tac is able to inhibit the expression of IL-17 and TNF [124], suggesting that this drug could assume therapeutic effect on diseases mediated by Th17 responses, such as IBD. Furthermore, the rectal treatment in mice leads to better results than oral administration of the drug [125].
In experimental granulomatous colitis, treatment with Tac results in the reduction of intestinal permeability, neutrophil activity, as well as extra-intestinal manifestations of the disease, such as hepatic and splenic granulomas, caused by the colitis-inducing agent [126]. On the other scenario, myofibroblasts isolated from normal gut tissues and stimulated in vitro with TNF show increased phosphorylation of the p38 subunit of MAP kinase, leading to augmented CCL2 and CXCL10 expression. However, in vitro treatment with Tac suppresses the expression of CCL2 and CXCL10 mRNA by inhibiting phosphorylation of MAP kinase, indicating that these effects could be one of the mechanisms of therapeutic action of Tac on intestinal inflammation [127].
Hence, although this therapy may result in satisfactory IBD outcome, research has pointed that after mucosal healing, it is desirable to change this therapeutic intervention to other immunosuppressor drugs, in order to reduce the long-term adverse effects caused by Tac, such as nephrotoxicity [128].
The introduction of pharmacological therapies for IBD is of high importance to achieve remission and maintenance of quiescent disease in affected patients. Nonetheless, although these drugs act by diverse mechanisms, all of them are relevant in constraining the activation and perpetuation of the exacerbated immune-inflammatory responses that underline the gut inflammation in Crohn’s disease and ulcerative colitis. Then, the balance between adequate control of inflammatory responses and drugs’ adverse effects dictates the efficiency of corticosteroid and suppressor treatments in IBD.
The authors would like to thank Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), for the financial support 2017/08651.1 and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), 310174/2016-3.
Homeostasis is key for the normal performance of a human body. Many parameters are constantly maintained in fairly narrow vital ranges, such as temperature, acidity in the intracellular and intercellular spaces, the electrolyte concentrations, hormones, vitamins, etc. The traditional view is that the body itself is able to maintain the constancy of its internal environment due to a complex system of feedback (Figure 1). Each organ helps to maintain homeostasis, ensuring its specific function. It acts as a backward force that returns the system to equilibrium in the event of deviations from the normal state. Along with other organs, the microbiota plays an important role in maintaining homeostasis, despite being an “invisible organ.”
Diagram of the interaction of organs that support the state of homeostasis.
By the way, in terms of weight, the microbiota should be attributed to the largest organ that can be compared only with the brain or liver: this can be easily ascertained using simple calculations based on known facts about the weight of human organs relative to the body weight of an adult (Figure 2). The human microbiota, which is a community of gut microorganisms, can be considered as an independent organ with many functions.
Microbiota as a big but “invisible organ,” % of body mass compared to other vital organs in an adult weighing 70 kg.
In the twenty-first century, a new insight on the processes occurring in the human body in health and disease on the basis of the new knowledge of the microbiota is formed. Detection and identification of the trillions of bacteria that form the microbiota of healthy and sick people are made possible by the use of modern technologies, for example, sequencing of the 16S rRNA gene.
The host organism is a habitat for the microbiota, so maintaining homeostasis is vital for the survival of hundreds of bacterial species. The microbiota seeks to restore homeostasis in the case of minor metabolic disorders that are not systemic in nature, and it has a huge amount of possibilities for this. If changes in the vital functions of the body are serious, a new quality (pathology) is formed, the microbiota is also radically rebuilt: this is manifested not only in changes in the species composition of bacteria (taxonomy) but also in metabolic processes. Other non-normal products of microbial metabolism from the intestines enter the systemic circulation, and they can interfere with the endogenous metabolic pathways. When the microbiota works against the host, it is manifested by diseases, even death (sepsis).
The medical community has not yet formed an understanding of the role of the microbiota as a separate organ. A search query (“microbiota as an organ”) or (“microbiome as an organ”) in specialized databases, such as the Web of Science, Scopus, and Pubmed, gives a negative result. At the same time, a number of review articles are actually present which describe in detail the physiology and biochemistry of the close interaction of the intestinal microbiota with the host organism, in which there are many qualities and attributes of the organ.
This chapter formulates ideas about the microbiota as an organ, which has become possible due to the results of studies with metabolomic equipment of recent years. The material presented in this chapter relies primarily on articles published after 2010. Specialists working in both fundamental and clinical medicine are undoubtedly interested in the growing information about the role of microbiota in maintaining homeostasis, as well as the participation of microorganisms of the human body in the metabolic pathways, which are directly related to the development of various pathologies.
Food intake, its conversion, and excretion of waste products are material sources for the normal functioning of a human body. The aim of nutrition from a biochemical viewpoint is to maintain the body’s critical parameters in narrowly defined value rates. The concept of a “living healthy organism” consists precisely in the ability to resist change and maintain the constancy of the composition and properties of its internal environment. The basis of digestion is a fairly universal mechanism, which includes splitting of the main components, such as carbohydrates (including polysaccharides), fats, biopolymers (proteins, macromolecules based on nucleotide sequences), etc., to individual low-molecular substances and then to the synthesis of low- and high-molecular weight compounds, which are the material basis for cells and organs as well as the energy source for biochemical reactions. Interest to low-molecular weight compounds has grown particularly in recent years. The Human Metabolome Database (HMDB) was created and is constantly updated by the international researcher group. Now it contains information on more than 100,000 individual low-molecular compounds (metabolites), constituting about 25,000 pathways of metabolism [2].
Food digestion is one of the main complex processes that form homeostasis. Transformation of the matter occurs throughout the gastrointestinal tract. Food undergoes ever-deeper processing as you move through it. Enzymes directly involved in this can potentially have endogenous and exogenous origin. The endogenous pathway is carried out with the participation of its own secrets produced by the body with the participation of organs that promote digestion and the excretion of waste products. The complex of biochemical reactions that coincide with the active participation of the microbiota, consisting of hundreds, sometimes reaching up to several thousand species, is presented as an alternative to it. In the literature there is no single point of view about the density of microorganism colonization of the human digestive system. According to [3], the relative content of microorganisms (cells/mL) in different parts of the gastrointestinal tract is duodenum, 101–103; jejunum and ileum, 104–107; cecum, 108; and large intestine, 1011–1012. A large number of publications give the relative content of microorganisms in the range of 102–1013, while the maximum values are recorded in the cecum and transverse colon.
The specificity of food digestion is due to the variety of enzymes capable of carrying out similar biochemical transformations, if not entirely, then at least of its many components, due to intestinal microbiota. The synthesis of specific proteins, including enzymes, is due to the presence of various nucleotide DNA sequences. The diversity of these sequences in a complex system consisting of hundreds, or even thousands, of individual species of microorganisms is significantly higher than that of human. The lifetime of a particular microorganism, depending on the immune response of the host organism, correlates with the function that promotes or interferes with its vital activity. The production of specific microorganism killer proteins is not observed in the case of symbiosis. Processes of synthesis of interleukins and phagocytosis are immediately activated in the alternative situation [4]. A big array of metagenomic studies of human intestinal microbiota collected in recent years in various information repositories, such as the National Center for Biotechnology Information (NCBI).
The role of microbiota is quite significant already at the stage of primary processing of nutrients. For example, in [5], the fact is given that only bacteroids of the
The species composition of the microbiota is specific for each person and depends on many factors, such as age, diet, use of antibiotics, etc. We can talk about two components of the microbiota—obligate or transient. A self-organizing ecosystem with the dominance of some species of microorganisms and the oppression of others arises in a normally functioning organism. The classification and systematization of information on the species and genetic diversity of the microbiota of the human body were carried out independently by two scientific communities in the United States and the European Union, which resulted in the appearance of two databases: Human Microbiome Project (HMP) [7] and Metagenomics of the Human Intestinal Tract (MetaHIT) [8].
Extensive information on the composition of the intestinal microbiota of a healthy person is contained in the literature. These studies indicate the dominance of several genera of strict anaerobes, and the main ones are
Part of the gastrointestinal tract | The dominant species composition of the microbiota |
---|---|
Oral cavity | |
Throat, esophagus | |
Stomach | |
Small intestine | |
Cecum | |
Rising gut | |
Colon |
Differences in the composition of the microbiota throughout the gastrointestinal tract (adapted from [9]).
A huge number of types of microorganisms perform the biochemical functions which we call the “conveyor” of the microbiota [10]. The diversity of species with different biochemical activity provides coordinated work of the microbiota. The final metabolite formation depends on many factors: the quality and quantity of substrate (food components); the function of the stomach, pancreas, liver, and gallbladder; bowel motility; etc. definitely influence the metabolism of microbiota. The normal biotransformation of any of the substrates in the intestinal lumen takes place sequentially [10]. Biochemistry of deep food transformation is in many respects similar to the metabolic characteristic of microorganisms. The main part of the individual amino acids that come from food after the cleavage of polypeptides is further spent on the synthesis of its own proteins, which are necessary for the functioning of the body. Residual amino acids can be transformed into other substances of a non-protein nature, performing a number of important functions not related to digestion or the building function.
This trend is most pronounced for aromatic amino acids such as phenylalanine, tyrosine, and tryptophan. The transformations of the phenylalanine-tyrosine pair occurring in the liver are contained in the human metabolome database (Figure 3). Phenylalanine and tyrosine are interchangeable in terms of metabolism. Phenylalanine is transformed into tyrosine under the action of a complex compound of Fe2+ ions with phenylalanine-4-hydroxylase with the participation of L-erythrotetrahydrobiopretin. Then both amino acids are transformed into 4-hydroxyphenylpyruvic acid, and then, by successive transformations, they are transformed into acetoacetic and fumaric acids—components of the Krebs cycle under the action of the same enzymes with the participation of the same substances [11]. There is no direct conversion of phenylpyruvic acid to 4-hydroxyphenylpyruvic acid in this metabolism scheme.
Normal metabolism of phenylalanine and tyrosine in the liver. Enzymes (coenzymes): (1) phenylalanine-4-hydroxylase (Fe2+); (2) aspartate aminotransferase, cytoplasmic tyrosine aminotransferase; (3) L-amino-acid oxidase (FAD); (4) 4-hydroxyphenylpyruvate dioxygenase (Fe3+); (5) homogentisate 1,2-dioxygenase; (6) maleylacetoacetate isomerase; (7) fumarylacetoacetase (according to the HMDB).
The pathway of tyrosine processing, namely, its biotransformation in tyramine further into three directions—dopamine, homovanillin, and dopachinone—is important for the normal functioning of human mental activity (Figure 4). All biochemical transformations that make up these metabolic pathways occur with the direct action of enzymes. However, enzymes for not all reactions are listed in the HMDB. The label “??” (Figure 4) refers to the absence of data on the enzyme. The pathway reactions can be divided into two types: “traditional” and “unusual.”
Tyrosine metabolism. Enzymes (coenzymes): (1) aromatic-L-amino-acid decarboxylase, (Pyridoxal-5′-phosphate); (2) tyrosinase (Cu2+); (3) amiloride-sensitive amine oxidase [copper-containing] (Cu2+, Ca2+, topaquinone); (4) dopamine beta-hydroxylase (Cu2+, pyrroloquinoline, quinone); (5) aldehyde dehydrogenase (dimeric NADP-preferring); (6) amine oxidase [flavin-containing] A (FAD); (7) aldehyde dehydrogenase,(dimeric NADP-preferring); (8) catechol O-methyltransferase (Mg2+) (according to the HMDB).
The first type is rather trivial transformations, such as the conversion of an aldehyde to the corresponding carboxylic acid, for example, homovanillin to homovanillic acid. Such transformations are well known in classical organic chemistry. These reactions do not require enzymes; it is enough to have an oxidizing agent, such as molecular oxygen, hydrogen peroxide, reactive oxygen species, etc. The situation is different in the case of the formation of nitrogen-containing heterocycles formed from aromatic amino acids. The information about enzyme in HMDB is not available for the key dopachinone conversion reaction to leukodopachrome. A detailed study of the mechanism of this reaction, contained in [12], shows that nitric oxide (I) takes an active part in it. This fact is complicated only by understanding the base of interactions. Many reactions of tyrosine metabolism are supported by a complex of copper ions with tyrosinase, well known in the biochemistry of microorganisms and used in biotechnology (see, e.g., [13]).
A significant part of the reactions given in Figure 4, with a sufficient degree of confidence, occurs with the participation of enzymes of exogenous (microbiological) origin generated by the microbiota. The formation of metabolites not only with the benzene but also with the indole ring occurs as a result of tyrosine biotransformation, including the participation of microbial enzymes.
Indoles, including those synthesized using human microbiota enzymes, play an important role in metabolism. Such physiologically important substances as serotonin, tryptamine, and derivatives of quinic acid belong to them (Figure 5). Many of the compounds involved in the indole metabolism are able to pass through the blood–brain barrier. About 95% of tryptophan enters the brain as a conjugate with kynurenine compounds, whose final metabolic products are kinuric and quinolinic acids, 3-hydroxykynurenine [14].
Simplified scheme of normal tryptophan metabolism. Enzymes (coenzymes): (1) tryptophan 5-hydroxylase (Fe2+); (2) tryptophan 2,3-dioxygenase (heme); (3) aromatic-L-amino-acid decarboxylase (pyridoxal-5′-phosphate); (4) indolethylamine N-methyltransferase; (5) kynurenine formamidase; (6) kynurenine 3-monooxygenase (FAD); (7) aldehyde dehydrogenase, mitochondrial (NAD); (8) aldehyde dehydrogenase, mitochondrial or aldehyde oxidase (FAD, molybdopterin, 2Fe-2S); (9) kynureninase (pyrophosphate); (10) acetylserotonin O-methyltransferase (S-Adenosyl methionine) (according to the HMDB).
Reactions associated with the presence of endogenous enzymes and enzymes of microbial origin are in a state of dynamic equilibrium with the normal functioning of biochemical processes in the body. Microbiota metabolism is able to quickly adjust in a direction that helps to maintain homeostasis with moderate deviations (abnormalities with dietary errors, travels with changing time zones, etc.). The dynamic metabolism of the “invisible organ” is provided by the potential of the metabolic pathways, such as catecholamine biosynthesis (Figure 6) with participation of numerous species of microorganisms.
Catecholamine biosynthesis. Enzymes (coenzymes): (1) tyrosine 3-monooxygenase (Fe2+); (2) aromatic-L-amino-acid decarboxylase (pyridoxal-5′-phosphate); (3) dopamine beta-hydroxylase (Cu2+, pyrroloquinoline, quinone); (4) phenylethanolamine N-methyltransferase) (according to the HMDB).
Microbiota metabolism can also be seriously affected if the disorders are systemic under the influence of adverse external factors (e.g., massive antimicrobial therapy, severe poisoning, hypoxia, blood loss, etc.). These disorders can manifest themselves clinically by developing a critical state, which often puts the existence of the organism (its life) at risk.
Disturbances in the normal functioning of the gastrointestinal tract are largely due to changes in the digestion processes associated with the state of the microbiota. As noted above, the microbiota composition depends on the heredity and health of the host, climate, nutrition, bad habits, etc. A system itself is able to return to a state of homeostasis in the case of mild disorders. The microbiota has mechanisms to adapt to the effects of antibacterial substances. Antibiotics are originally the products of bacteria which they use as competitive advantage in the conditions of nutrient substrate deficiency in their habitat. However, significant changes in species composition may be developed under the influence of broad-spectrum antibacterial drugs, since the massive use of antibiotics (xenobiotics) is violent and anti-biological and can disrupt biochemical processes.
The microbiota is involved in the transformation of xenobiotics and provides a range of reactions including acetylation, deacylation, decarboxylation, dehydroxylation, demethylation, etc. under the influence of low-quality products and synthetic drugs [15]. Modern possibilities of metabolic methods allow an extensive study of another important function of the microbiota—detoxification of the host organism, which maintains its normal state longer in the conditions of retention and self-repairing of the microbiota.
Disorders of the microbial products of short-chain fatty acids SCFA (acetic, propionic, butyric) are most thoroughly studied as a result of the suppression of the normal functioning of anaerobic bacteria. Normally, SCFA requires enterocytes as the main source of energy, respectively; their deficiency contributes to the violation of mucosal trophism, reduction of reparative processes, development of ulcers, and inflammation. Persistent indigestion disorders and chronic gastroenterological diseases are the clinical manifestations of serious changes in the species composition and dysfunction of the microbiota.
Different genera of anaerobic bacteria are called responsible for the production of SCFA. For example, large amount of carbohydrate dissimilation butyrate from dissimilation is associated with some
In his review, Nyangale et al. rightly noted that several members of the microbiota have been linked with diseases mainly affecting the gut, lake inflammatory bowel disease, such as ulcerative colitis, Crohn’s disease, colorectal cancer, and irritable bowel syndrome, although mechanisms involved are still not yet fully understood [16]. The authors consider the possibilities of metabolite analysis to assess the metabolic activity of the microbiota, to measure volatile and nonvolatile metabolite in biological samples, and to give metabolic pathways the contribution of microbiota to which it is most pronounced. These pathways include also the transformation of glucose and amino acids into SCFA, amino acid, microbial degradation of tyrosine to
A metabolite composition, determined in the feces, may indicate the composition of microbiota and its changes associated with the use of antibiotics [17]. The use of chemometric approaches in relation to the primary mass spectral data of the samples under study allows one to reliably find the differences between patients with inflamed intestines and the control group. The authors consider that changes in the microbiota phenotype cause this kind of deviations. The ratio of the species composition of microbiota—obligate or transient—significantly affects the metabolite composition that enters the circulatory system from the bowel. Thus, the role of
In such acquired endocrinological diseases as obesity, type 2 diabetes (not related to heredity) can be attributed to pathological conditions due to metabolic disorders involving the microbiota. Microbiota can influence the development of diabetes [19]. Changes in the microbiological composition—dysbacteriosis—caused, for example, by the use of antibiotics, may contribute to an increase in insulin dysfunction, a long-term consequence of which is the development of type 2 diabetes. Due diet may ensure opportune correction of the microbiota and prevent further development of the disease. In a similar study for type 2 diabetes, cited in [20], the authors come to analogous conclusions. The authors agree that function is more important than taxonomy when discussing the role of microbiota in the development of metabolic disorders and diseases of the gastrointestinal tract [21].
In the future, methods of diagnosing gastrointestinal diseases and methods of treatment through the modulation of the microbiota based on information about intermediate metabolites and end products of microbial biodegradation of various compounds can be constructed and developed.
Changes in the human body due to microbiota metabolism can affect cells and tissues and contribute to the development of benign and malignant tumors. The biochemistry and physiology of oncological processes is not completely clear, but certain metabolic shifts can be fixed instrumentally for some types of oncological diseases [22, 23]. The successful search for links between the patterns of normal functioning of the microbiota and the biochemistry of carcinogenesis is detailed in recent reviews [24, 25]. This indicates the prospects of such concept and allows us to call the microbiota “a key orchestrator of cancer therapy.”
Most of the data on the correlation between a microbiota and cancer tumors is in the gastroenterology [26, 27, 28, 29, 30, 31]. Such intestinal microorganisms as
The analysis of statistical data shows that there is an activation of the biosynthesis of fatty acids against the background of inhibition of the biosynthesis of amino acids and glycan in patients with colorectal cancer compared with the control group [26]. Statistically significant differences in the levels of metabolites of microbial origin, namely, an increase in the relative concentrations of phenylacetic, isobutyric, valeric, isovaleric acids, and hexose-phosphates with a simultaneous decrease in taurine, glutamine, β-alanine, isoleucine, galactose, xylose, glycerol, methanol, ornithine, guanidine, choline acid, and its derivatives, 4-aminohippuric acid, have been identified in a recent paper [32].
Certainty is not currently attainable regarding the use of volatile fatty acids as markers of oncology. Reducing the levels of SCFA (acetic, butyric), secondary bile acids, concomitant increase in amino acids (leucine, valine, proline, serine) valeric, isobutyric, isovaleric acid can be associated with the activity of enzymatic systems of
An alternative concept is that volatile fatty acids, for example, butyric acid, may have a protective effect, which slows down the development of large intestine malignancies. Butyrate-producing bacteria contained in the microbiota of the gastrointestinal tract, such as
A treatment of large amounts of information on substances of bacterial origin potentially capable of being included in human metabolism allows us to distinguish six groups of compounds, based on the profile of which early diagnosis of colorectal cancer can be built [29]. There are short-chain fatty acids, bile acids, indoles, cresols, phenolic (phenyl-containing fatty) acids, and polyamines. Analysis of literature data [27] shows that under the influence of microbiota, changes in the directions of chemical transformation of glucose, fats, and amino acids are possible.
The metabolic profile, largely formed by the microbiota, was used as a diagnostic method for cancer not directly related to the gastrointestinal tract. Statistically significant differences in the content of substances involved in the metabolism of glycerol lipids and retinol and ways of ethylbenzene degradation can be used to diagnose bladder cancer. Such metabolites are actively produced and/or absorbed with the participation of enzymes of
A change in the metabolic profile of amino acids such as valine, cysteine, tyrosine, and 6-hydroxynicotinic acid can be used as a method for diagnosing oral cancer [37]. Substances of microbial origin and components of the metabolism of
The metabolites produced by the microbiota of the upper respiratory tract and lungs may influence the development of oncological processes in them. Three types of bacteria,
However, waste products of bacteria can contribute to the development of breast cancer [22, 40, 41, 42]. The waste products of bacteria of the gastrointestinal tract can contribute to the development of malignant tumors of any other location: lung cancer [38, 39], bladder [36], pancreas [38], including hormone-dependent forms of breast cancer [22, 38, 40, 41, 42], and prostate cancer [43].
Statistically significant correlations between the levels of secondary bile acids and the incidence of breast cancer were found in [22]. The authors believe that lithocholic acid, which is a product of the metabolism of microorganisms, is able to limit the proliferation of breast cancer cells both in vitro and in vivo by activating the TGR5 receptor. Changes in the metabolism of hormones, cysteine, and methionine and the biosynthesis of fatty acids associated with breast cancer were noted in a similar study [41], but there is no definite connection between them. The search for low-molecular markers of breast cancer, carried out in [42], allowed identification of 12 compounds (amino acids, organic acids, and nucleosides) that pretend to this role. These compounds are included in the metabolism of amino acid and nucleoside metabolism.
Microbiota metabolites are able to act as accelerants and inhibitors of oncological processes. Now a scientific search in this field of knowledge is in the stage of intensive development and accumulation of a critical amount of information. The use of metabolomic approaches in combination with modern methods of statistical processing of large amounts of data undoubtedly contributes to the development of fundamental and applied medicine in the field of diagnosis and treatment of oncological diseases.
Some substances that form the amino acid metabolism can overcome the hemato-encephalic barrier and have a direct effect on the brain (Figure 7) [14, 44, 45, 46]. A search for such low-molecular compounds, quantitative determination, and their ratios can serve as the basis for the development of methods for early diagnosis, including cognitive and mental disorders [47]. It is important to note that metabolites can directly enter the region of the medulla, with blood through arteria vertebralis-arteria spinalis, bypassing the hemato-encephalic barrier, and that critical vital centers of respiration and circulation are located there.
Scheme of amino acid metabolite transport in the brain.
It is unlikely that metabolites of microbial biotransformation of amino acids are the direct cause of mental or neurological diseases. At the same time, numerous experimental studies indicate the existence of a direct “intestine-microbiota-brain” link. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system [48].
The authors in literature sources traditionally attend to the aromatic amino acid tryptophan metabolism mainly due to its relationship with the synthesis of serotonin (5-HT) and melatonin [49]. Tryptophan biotransformation in humans can occur in different ways: either with the participation of endogenous enzymes that are synthesized by the intestinal cell wall or with the participation of bacterial enzymes. Accordingly, the ratios of end products of tryptophan metabolism will differ. This is easily seen by comparing the enzymes and metabolic products of tryptophan in Figures 5 and 8.
Tryptophan metabolism. Enzymes: (1) indoleamine deoxygenase or tryptophan deoxygenase; (2) formidase; (3) kynurenine aminotransferase; (4) kynureninase; (5) kynurenine-3-monooxygenase; (6) kynureninase; (7) 3- hydroxyanthranilate 3,4-dioxygenase; (8) 2-amino-3- carboxymuconate-semialdehyde decarboxylase (according to [
The traditional view is that the amino acid tryptophan is used primarily for protein synthesis or the formation of serotonin and melatonin. However, more than 90% of tryptophan was found to be metabolized into N-formyl-kynurenine followed by kynurenine (Figure 8) [50]. The presence of anthranilic and 3-hydroxyanthranilic acids attracts particular attention as tryptophan metabolites. This pathway is not presented in mammalian metabolism. Such reactions of indole compounds are possible only with the participation of microbiota enzymatic systems. This also applies to picolinic and quinolinic acids, the formation of which is associated with the opening of the indole ring, which can occur exclusively in the process of microbial biotransformation.
A decrease of tryptophan, xanthurenic, 3-hydroxyanthranilic, and quinolinic acids in the blood was recorded in the case of clinical occurrences of Alzheimer’s disease. The same metabolites are given in [51] as potential markers of Alzheimer’s disease. It can be assumed that one of the Alzheimer’s disease triggers is a chronic deficiency of these substances.
Now there are two alternative hypotheses in the literature regarding products of tryptophan metabolism and their influence on the development of schizophrenia. One of them postulates that a chronic tryptophan deficiency results in failure of catabolism products, such as 3-hydroxykynurenine, quinolinic, picolinic, xanthurenic, kinureric, and anthranilic acids. Some authors maintain that such deficiency stipulates the psychosomatic symptoms of schizophrenia [52]. Other authors come to the opposite conclusion based on the analysis of statistical data [53]. They indicate a direct correlation of clinical manifestations of schizophrenia with an increased content of kynurenic acid in the cerebrospinal fluid relative to the control group. Such conflicting data emphasize once again the peculiarities of the metabolic approach. You should not limit yourself to searching and measuring one or two metabolites during clinical trials; it is important to evaluate the complex metabolic profile, to compare the indicators with positive and negative dynamics. In addition, other mechanisms that are not related to the metabolism of neurotransmitters may be the basis of mental and neurologic disorders.
Thus, attempts to search for low-molecular markers of autism [54] and depressive disorder [55] were unsuccessful. But the data indicating the potential role of the metabolism of aromatic amino acids were discovered in such a mental disorder as anorexia nervosa. Levels of tryptophan and phenylalanine were significantly reduced in patients compared with the healthy ones.
Changes in the distribution of the tryptophan metabolism products, such as kynurenine, 3-hydroxy kynurenine, kynurenic, and anthranilic acids, are observed in patients with symptoms of Parkinson’s disease [56]. Low levels of norepinephrine, dopamine, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid in the blood are fixed in these patients relative to the control group [57].
The failure of aromatic L-amino acid decarboxylase in combination with reduced levels of important metabolites such as serotonin, dopamine, and catecholamines leads to disruptions in the normal functioning of the whole organism, including brain activity. Crisis of oculomotor function along with muscular hypotonia and dystonia is observed in combination with other neurological syndromes in a similar state [58]. A decrease in the blood concentrations of homovanillic, 5-hydroxyindoleacetic acids, and 3-
Scientists have used metabolomics to gain new knowledge about the significance of the role that bacteria play in complex regulatory processes of higher nervous activity. Understanding the potential for managing this process cannot leave psychiatrists, neurologists, and neurorehabilitation specialists indifferent [59, 60, 61]. This fact is due to the relevance and high frequency of pathology of the nervous system. Prospects for the correction of microbiota metabolism for neurorehabilitation and the demand for this scientific search for new solutions in this area cannot be overestimated.
One of the areas discussed in the literature is the transformation of the species composition of the patient’s microbiota to eliminate the deficiency of certain microorganisms. This idea has a scientific ground that many bacteria from the human microbiota in the in vitro study revealed the ability to produce hormones and neurotransmitters, that is, the presence of appropriate enzyme systems. These data are summarized in the reviews [44, 62] and in brief form are presented in Table 2.
Hormone, neurotransmitter | Bacteria |
---|---|
Norepinephrine | |
Dopamine | |
Dopamine precursor (DOPA) | |
Serotonin | |
Histamine | |
γ-Aminobutyric acid | |
Tyramine |
Certain reports indicate that the treatment with large doses of
Neurorehabilitation of patients in modern clinics is considered as a component of acute cerebral therapy and starts from the earliest periods after injuries, strokes, and brain operations, even at the stage of the patient’s stay in the intensive care unit. This is a multicomponent and long-term process aimed not only at saving lives but also at restoring motor activity, correcting neuro-endocrine, cognitive impairments, and emotional status. Different methods of monitoring the effectiveness of intensive care and the rehabilitation of the functional state of patients with various brain injuries are used [65].
The authors of this chapter believe that neurorehabilitation can be significantly enriched with a set of targeted measures aimed at correcting disorders in the development of which metabolic products associated with microbiota are actively involved. Our accumulated data on the magnitude of changes in the profile of microbiota metabolites and their connection with the course and outcome of the disease in patients with lesions of the central nervous system indicate the possibility of their use in choosing tactics for managing patients with this pathology. This complex may include several areas: (i) the first is the additional introduction into the body of substances that are associated with a shortage of other clinical manifestations of pathology. This can be achieved by nutritional correction or dietary supplements, including those obtained using industrial microbiology methods, as well as the administration of parenteral preparations containing the necessary metabolites of microbial origin. (ii) The second is the suppression of the metabolic activity of those types of bacteria in the composition of the microbiota, which in excess produce “unwanted” metabolites, through the selective use of antibacterial drugs with an appropriate mechanism of action. (iii) The third is the elimination of excess unwanted metabolites in the systemic circulation through the targeted use of extracorporeal blood purification procedures with filters/sorbents that remove specific substances.
Of course, the use of modern metabolic methods for an objective assessment of the dynamics of the profile of metabolites in parallel with the monitoring of the psychosomatic state, functions of the damaged brain, spasticity level, motor skills, etc. is necessary for the successful implementation of the above directions in a particular patient. But above all, reliable data on key microbial metabolites, the level of which must be monitored in patients in the process of neurorehabilitation to on must be obtained. For example, metabolites associated with the development of septic shock (p-HPhAA) [66, 67] and death (PhA, p-HPhLA) [10] were earlier established for patients with sepsis. At the same time, another metabolite—PhPA—was a characteristic for the metabolic profile of a healthy person. The study of metabolome is conducted using the GC–MS method for patients with affection of the central nervous system of various etiologies [68]. Currently, the purpose of this study is to detect microbial metabolites associated with changes in the neurological status of patients in the process of neurorehabilitation. Preliminary results indicate a number of significant features, for example, positive neurological and psychosomatic dynamics is associated with the appearance and accumulation of the metabolite p-HBA in the intestine and the patient’s blood, which is not observed in other groups of patients. The composition of the microbiota in patients with severe neurosomatic pathology using the method of metagenomic sequencing of the 16S pRNA is under study. Correlations with microbial blood metabolites are also being studied. Preliminary data demonstrate significant differences when comparing various patient groups [69]. The results of the multicenter study will serve as the basis for the development and objective evaluation of the effectiveness of the above technologies in the process of neurorehabilitation.
A new level of knowledge about the role of the microbiota in the human body was made possible by metabolomics. In the coming years, this will lead to new solutions in the diagnosis of many “difficult” diseases. Methods of active control of metabolic processes that will subordinate the dysfunction of the “invisible organ” to the benefit of the host will be found. It will lead to the increase in the effectiveness of treatment and successful rehabilitation of patients. In particular, in the field of neurorehabilitation, clinical studies are currently aimed at finding such methods for correcting the metabolism of microbiota that will achieve a balance of low-molecular metabolites as signaling molecules of microbiota to restore brain function.
This work was supported by the Russian Science Foundation Grant № 15–15-00110-P.
IntechOpen’s Academic Editors and Authors have received funding for their work through many well-known funders, including: the European Commission, Bill and Melinda Gates Foundation, Wellcome Trust, Chinese Academy of Sciences, Natural Science Foundation of China (NSFC), CGIAR Consortium of International Agricultural Research Centers, National Institute of Health (NIH), National Science Foundation (NSF), National Aeronautics and Space Administration (NASA), National Institute of Standards and Technology (NIST), German Research Foundation (DFG), Research Councils United Kingdom (RCUK), Oswaldo Cruz Foundation, Austrian Science Fund (FWF), Foundation for Science and Technology (FCT), Australian Research Council (ARC).
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