RESUMO
The concept of inflammatory bowel disease (IBD), which encompasses Crohn's disease and ulcerative colitis, represents a complex and growing global health concern resulting from a multifactorial etiology. Both dysfunctional autophagy and dysbiosis contribute to IBD, with their combined effects exacerbating the related inflammatory condition. As a result, the existing interconnection between gut microbiota, autophagy, and the host's immune system is a decisive factor in the occurrence of IBD. The factors that influence the gut microbiota and their impact are another important point in this regard. Based on this initial perspective, this manuscript briefly highlighted the intricate interplay between the gut microbiota, autophagy, and IBD pathogenesis. In addition, it also addressed the potential targeting of the microbiota and modulating autophagic pathways for IBD therapy and proposed suggestions for future research within a more specific and expanded context. Further studies are warranted to explore restoring microbial balance and regulating autophagy mechanisms, which may offer new therapeutic avenues for IBD management and to delve into personalized treatment to alleviate the related burden.
Assuntos
Autofagia , Disbiose , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/imunologia , Disbiose/imunologia , Doença de Crohn/microbiologia , Doença de Crohn/imunologia , Colite Ulcerativa/microbiologia , Colite Ulcerativa/imunologia , Animais , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/imunologiaRESUMO
Inflammatory bowel disease (IBD) is the consequence of a complex interplay between environmental factors, like dietary habits, that alter intestinal microbiota in response to luminal antigens in genetically susceptible individuals. Epigenetics represents an auspicious area for the discovery of how environmental factors influence the pathogenesis of inflammation, prognosis, and response to therapy. Consequently, it relates to gene expression control in response to environmental influences. The increasing number of patients with IBD globally is indicative of the negative effects of a food supply rich in trans and saturated fats, refined sugars, starches and additives, as well as other environmental factors like sedentarism and excess bodyweight, influencing the promotion of gene expression and increasing DNA hypomethylation in IBD. As many genetic variants are now associated with Crohn's disease (CD), new therapeutic strategies targeting modifiable environmental triggers, such as the implementation of an anti-inflammatory diet that involves the removal of potential food antigens, are of growing interest in the current literature. Diet, as a strong epigenetic factor in the pathogenesis of inflammatory disorders like IBD, provides novel insights into the pathophysiology of intestinal and extraintestinal inflammatory disorders.
Assuntos
Metilação de DNA , Dieta , Epigênese Genética , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/imunologia , Dieta/efeitos adversos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Comportamento Alimentar , Predisposição Genética para DoençaRESUMO
Fecal Microbiota Transplant (FMT) has shown some success in treating inflammatory bowel diseases (IBD). There is emerging evidence that host engraftment of donor taxa is a tenet of successful FMT. We undertook a double-blind, randomized, placebo-controlled pilot study to characterize the response to FMT in children and young adults with mild to moderate active Crohn's disease (CD) and ulcerative colitis (UC). Subjects with CD or UC were randomized to receive antibiotics and weekly FMT or placebo in addition to baseline medications. We enrolled 15 subjects aged 14-29 years. Four subjects had CD, and 11 had UC. Subjects exhibited a wide range of microbial diversity and donor engraftment. Specifically, engraftment ranged from 26 to 90% at week 2 and 3-92% at 2 months. Consistent with the current literature, increases over time of both alpha diversity (p < 0.05) and donor engraftment (p < 0.05) correlated with improved clinical response. We discovered that the post-antibiotic but pre-FMT time point was rich in microbial correlates of eventual engraftment. Greater residual alpha diversity after antibiotic treatment was positively correlated with engraftment and subsequent clinical response. Interestingly, a transient rise in the relative abundance of Lactobacillus was also positively correlated with engraftment, a finding that we recapitulated with our analysis of another FMT trial.
Assuntos
Transplante de Microbiota Fecal , Lactobacillus , Humanos , Transplante de Microbiota Fecal/métodos , Adulto , Adolescente , Feminino , Masculino , Adulto Jovem , Método Duplo-Cego , Doenças Inflamatórias Intestinais/terapia , Doenças Inflamatórias Intestinais/microbiologia , Microbioma Gastrointestinal , Projetos Piloto , Fezes/microbiologia , Resultado do Tratamento , Doença de Crohn/terapia , Doença de Crohn/microbiologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Colite Ulcerativa/terapia , Colite Ulcerativa/microbiologiaRESUMO
BACKGROUND: Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. RESULTS: Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/- host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. CONCLUSIONS: Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. Video Abstract.
Assuntos
Modelos Animais de Doenças , Disbiose , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Interleucina-10 , Animais , Humanos , Camundongos , Doenças Inflamatórias Intestinais/microbiologia , Disbiose/microbiologia , Interleucina-10/genética , Colite/microbiologia , Fezes/microbiologia , Colo/microbiologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Feminino , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Inflamação , MasculinoRESUMO
Recent research indicates that the microbiome has a significant impact on the progression of inflammatory bowel disease (IBD) and that creating therapies that change its composition could positively impact the outcomes of IBD treatment. This review summarizes the results of extensive studies that examined IBD patients undergoing several therapies, including anti-TNF medication, vedolizumab, ustekinumab, probiotics, and fecal microbiota transplantation (FMT), and the alterations in their gut microbiota's composition and function. The objective was to investigate the variety and effectiveness of microbial species in order to discover new biomarkers or therapeutic targets that could improve the outcome of treatment for these patients. This research aimed to offer useful insights into personalized medicine techniques for managing IBD. Beneficial bacteria such as Faecalibacterium prausnitzii and Roseburia have been consistently linked to favorable clinical outcomes, whereas pathogenic bacteria such as Escherichia coli and Clostridioides difficile are associated with worsening disease conditions. Although many studies have examined the role of gut microbiota in IBD, there is still a need for more targeted research on the connection between specific microbial communities and treatment outcomes. This study sought to address this gap by exploring the intricate relationship between the gut microbiota composition and the effectiveness of IBD medications.
Assuntos
Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/terapia , Transplante de Microbiota Fecal/métodos , Resultado do Tratamento , Probióticos/uso terapêutico , Anticorpos Monoclonais HumanizadosRESUMO
BACKGROUND: Current therapy for patients suffering from inflammatory bowel diseases (IBD) is focused on inflammatory mechanisms exclusively and not the dysbiotic microbiota, despite growing evidence implicating a role for intestinal microbes in disease. MAIN BODY: Ongoing research into the intestinal microbiota of IBD patients, using new technologies and/or deeper application of existing ones, has identified a number of microorganisms whose properties and behaviors warrant consideration as causative factors in disease. Such studies have implicated both bacteria and fungi in the pathogenesis of disease. Some of these organisms manifest mechanisms that should be amenable to therapeutic intervention via either conventional or novel drug discovery platforms. Of particular note is a deeper characterization of microbial derived proteases and their destructive potential. CONCLUSION: Given the steady progress on the mechanistic role of the microbiota in inflammatory diseases, it is reasonable to anticipate a future in which therapeutics targeting microbial derived pathogenic factors play an important role in improving the lives of IBD patients.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Bactérias/efeitos dos fármacos , Bactérias/metabolismoRESUMO
Inflammatory bowel disease (IBD) is an idiopathic and persistent inflammatory illness of the bowels, leading to a substantial burden on both society and patients due to its high incidence and recurrence. The pathogenesis of IBD is multifaceted, partly attributed to the imbalance of immune responses toward the gut microbiota. There is a correlation between the severity of the disease and the imbalance in the oral microbiota, which has been discovered in recent research highlighting the role of oral microbes in the development of IBD. In addition, various oral conditions, such as angular cheilitis and periodontitis, are common extraintestinal manifestations (EIMs) of IBD and are associated with the severity of colonic inflammation. However, it is still unclear exactly how the oral microbiota contributes to the pathogenesis of IBD. This review sheds light on the probable causal involvement of oral microbiota in intestinal inflammation by providing an overview of the evidence, developments, and future directions regarding the relationship between oral microbiota and IBD. Changes in the oral microbiota can serve as markers for IBD, aiding in early diagnosis and predicting disease progression. Promising advances in probiotic-mediated oral microbiome modification and antibiotic-targeted eradication of specific oral pathogens hold potential to prevent IBD recurrence.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Boca , Humanos , Microbioma Gastrointestinal/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/etiologia , Boca/microbiologia , Boca/imunologia , Animais , Disbiose/imunologia , Probióticos/uso terapêuticoRESUMO
Alzheimer's disease is the most common cause of dementia globally. The pathogenesis is multifactorial and includes deposition of amyloid-ß in the central nervous system, presence of intraneuronal neurofibrillary tangles and a decreased amount of synapses. It remains uncertain what causes the progression of the disease. Nowadays, it is suggested that the brain is connected to the gastrointestinal tract, especially the enteric nervous system and gut microbiome. Studies have found a positive association between AD and gastrointestinal diseases such as periodontitis, Helicobacter pylori infection, inflammatory bowel disease and microbiome disorders. H. pylori and its metabolites can enter the CNS via the oropharyngeal olfactory pathway and may predispose to the onset and progression of AD. Periodontitis may cause systemic inflammation of low severity with high levels of pro-inflammatory cytokines and neutrophils. Moreover, lipopolysaccharide from oral bacteria accompanies beta-amyloid in plaques that form in the brain. Increased intestinal permeability in IBS leads to neuronal inflammation from transference. Chronic inflammation may lead to beta-amyloid plaque formation in the intestinal tract that spreads to the brain via the vagus nerve. The microbiome plays an important role in many bodily functions, such as nutrient absorption and vitamin production, but it is also an important factor in the development of many diseases, including Alzheimer's disease. Both the quantity and diversity of the microbiome change significantly in patients with AD and even in people in the preclinical stage of the disease, when symptoms are not yet present. The microbiome influences the functioning of the central nervous system through, among other things, the microbiota-gut-brain axis. Given the involvement of the microbiome in the pathogenesis of AD, antibiotic therapy, probiotics and prebiotics, and faecal transplantation are being considered as possible therapeutic options.
Assuntos
Doença de Alzheimer , Gastroenteropatias , Microbioma Gastrointestinal , Humanos , Doença de Alzheimer/microbiologia , Gastroenteropatias/microbiologia , Eixo Encéfalo-Intestino/fisiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/microbiologia , Periodontite/microbiologia , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/metabolismo , Helicobacter pylori , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , Encéfalo/metabolismoRESUMO
Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease of the intestinal tract. The complex pathophysiological mechanisms of IBD include genetic susceptibility, environmental factors, and abnormal immune response of the gut microbiota. Gut microbiota forms a metabolic organ that contributes to human health by performing various physiological functions. The development of IBD is closely linked to the imbalance of gut microbiota. In IBD patients, this imbalance is mainly characterized by an increased abundance of pro-inflammatory microorganisms, specifically enteropathogenic bacteria. Pyroptosis is a form of programmed cell death that can be initiated by microbial infection or host factors. It occurs mostly after intracellular infection with bacteria or pathogens. Other than cell death, its primary effect is to release inflammatory mediators that trigger an inflammatory response in the host. Pyroptosis is an important component of innate immunity and can protect against intracellular risk factors via the inflammatory response. However, excessive activation can cause disease. Previous studies of IBD have indicated a complex relationship between gut microbiota and pyroptosis. Some enteropathogenic bacteria can activate the host's immune system to clear infected cells. This inhibits the proliferation of enteropathogenic bacteria by inducing pyroptosis and restoring the balance of gut microbiota. However, the initial inflammatory response and damage to the integrity of the intestinal barrier are crucial factors that elicit the onset of IBD and favor its progression. This review summarizes research on the role of several common enteropathogenic bacteria in the development of IBD through their induction of host cell pyroptosis. A better understanding of the complex interactions between gut microbiota and pyroptosis should lead to the identification of new targets and treatment options for IBD.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Piroptose , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/imunologia , Microbioma Gastrointestinal/fisiologia , Animais , Imunidade InataRESUMO
BACKGROUND: The gut virome has been implicated in inflammatory bowel disease (IBD), yet a full understanding of the gut virome in IBD patients, especially across diverse geographic populations, is lacking. RESULTS: In this study, we conducted a comprehensive gut virome-wide association study in a Chinese cohort of 71 IBD patients (15 with Crohn's disease and 56 with ulcerative colitis) and 77 healthy controls via viral-like particle (VLP) and bulk virome sequencing of their feces. By utilizing an integrated gut virus catalog tailored to the IBD virome, we revealed fundamental alterations in the gut virome in IBD patients. These characterized 139 differentially abundant viral signatures, including elevated phages predicted to infect Escherichia, Klebsiella, Enterococcus_B, Streptococcus, and Veillonella species, as well as IBD-depleted phages targeting Prevotella, Ruminococcus_E, Bifidobacterium, and Blautia species. Remarkably, these viral signatures demonstrated high consistency across diverse populations such as those in Europe and the USA, emphasizing their significance and broad relevance in the disease context. Furthermore, fecal virome transplantation experiments verified that the colonization of these IBD-characterized viruses can modulate experimental colitis in mouse models. CONCLUSIONS: Building upon these insights into the IBD gut virome, we identified potential biomarkers for prognosis and therapy in IBD patients, laying the foundation for further exploration of viromes in related conditions. Video Abstract.
Assuntos
Fezes , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Viroma , Humanos , Microbioma Gastrointestinal/genética , Animais , Fezes/virologia , Fezes/microbiologia , Camundongos , Doenças Inflamatórias Intestinais/virologia , Doenças Inflamatórias Intestinais/microbiologia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Doença de Crohn/virologia , Doença de Crohn/microbiologia , Bacteriófagos/genética , Bacteriófagos/isolamento & purificação , Colite Ulcerativa/virologia , Colite Ulcerativa/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , China , Transplante de Microbiota Fecal , Estudos de Casos e Controles , Vírus/classificação , Vírus/isolamento & purificação , Vírus/genéticaRESUMO
The interwoven relationship between gut microbiota and the epigenetic landscape constitutes a pivotal axis in understanding human health and disease. Governed by a myriad of dietary, genetic, and environmental influences, the gut microbiota orchestrates a sophisticated metabolic interplay, shaping nutrient utilization, immune responses, and defenses against pathogens. Recent strides in genomics and metabolomics have shed light on the intricate connections between these microbial influencers and the host's physiological dynamics, presenting a dynamic panorama across diverse disease spectra. DNA methylation and histone modifications, as key players in epigenetics, intricately align with the dynamic orchestration of the gut microbiota. This seamless collaboration, notably evident in conditions like inflammatory bowel disease and obesity, has captured the attention of researchers, prompting an exploration of its nuanced choreography. Nevertheless, challenges abound. Analyzing data is intricate due to the multifaceted nature of the gut microbiota and the limitations of current analytical methods. This underscores the need for a multidisciplinary approach, where diverse disciplines converge to pave innovative research pathways. The integration of insights from microbiome and epigenome studies assumes paramount importance in unraveling the complexities of this intricate partnership. Deciphering the synchronized interactions within this collaboration offers a deeper understanding of these delicate interplays, potentially heralding revolutionary strides in treatment modalities and strategies for enhancing public health.
Assuntos
Epigênese Genética , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiologia , Metilação de DNA , Obesidade/microbiologia , Obesidade/genética , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/genéticaRESUMO
Inflammatory bowel diseases (IBDs), such as Crohn's disease (CD) and ulcerative colitis (UC), are chronic diseases of the digestive system with a multifactorial and not fully understood etiology. There is research suggesting that they may be initiated by genetic, immunological, and lifestyle factors. In turn, all of these factors play an important role in the modulation of intestinal microflora, and a significant proportion of IBD patients struggle with intestinal dysbiosis, which leads to the conclusion that intestinal microflora disorders may significantly increase the risk of developing IBD. Additionally, in IBD patients, Toll-like receptors (TLRs) produced by intestinal epithelial cells and dendritic cells treat intestinal bacterial antigens as pathogens, which causes a disruption of the immune response, resulting in the development of an inflammatory process. This may result in the occurrence of intestinal dysbiosis, which IBD patients are significantly vulnerable to. In this study, we reviewed scientific studies (in particular, systematic reviews with meta-analyses, being studies with the highest level of evidence) regarding the microflora of patients with IBD vs. the microflora in healthy people, and the use of various strains in IBD therapy.
Assuntos
Disbiose , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/imunologia , Doença de Crohn/microbiologia , Doença de Crohn/imunologia , Probióticos/uso terapêutico , Colite Ulcerativa/microbiologia , Colite Ulcerativa/imunologiaRESUMO
BACKGROUND: Toll-like receptors (TLRs) are a family of fundamental pattern recognition receptors in the innate immune system, constituting the first line of defense against endogenous and exogenous antigens. The gut microbiota, a collection of commensal microorganisms in the intestine, is a major source of exogenous antigens. The components and metabolites of the gut microbiota interact with specific TLRs to contribute to whole-body immune and metabolic homeostasis. OBJECTIVE: This review aims to summarize the interaction between the gut microbiota and TLR signaling pathways and to enumerate the role of microbiota dysbiosis-induced TLR signaling pathways in obesity, inflammatory bowel disease (IBD), and colorectal cancer (CRC). RESULTS: Through the recognition of TLRs, the microbiota facilitates the development of both the innate and adaptive immune systems, while the immune system monitors dynamic changes in the commensal bacteria to maintain the balance of the host-microorganism symbiosis. Dysbiosis of the gut microbiota can induce a cascade of inflammatory and metabolic responses mediated by TLR signaling pathways, potentially resulting in various metabolic and inflammatory diseases. CONCLUSION: Understanding the crosstalk between TLRs and the gut microbiota contributes to potential therapeutic applications in related diseases, offering new avenues for treatment strategies in conditions like obesity, IBD, and CRC.
Assuntos
Disbiose , Microbioma Gastrointestinal , Homeostase , Doenças Inflamatórias Intestinais , Transdução de Sinais , Receptores Toll-Like , Humanos , Microbioma Gastrointestinal/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismo , Receptores Toll-Like/imunologia , Homeostase/imunologia , Animais , Disbiose/imunologia , Disbiose/microbiologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , Obesidade/imunologia , Obesidade/microbiologia , Obesidade/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/metabolismoRESUMO
Investigating the gut microbiome and metabolome frequently requires faecal samples, which can be difficult to obtain. Previous studies have shown that rectal swabs are comparable to faecal samples for analysing gut microbiota composition and key metabolites. In this study, 3D printed rectal swabs were compared with conventional flocked swabs and faecal samples, due to the potential advantages 3D printing as a technique offers for swab production and development. 16S rRNA gene sequencing, qPCR and metabolite profiling (using 1H-NMR spectroscopy) were performed on swab and faecal samples from healthy participants. Faecal calprotectin and total protein analysis were performed on samples from inflammatory bowel disease (IBD) patients. There were no significant differences between both swab types and faecal samples when assessing key measures of alpha and beta diversity, and differences in the abundance of major phyla. There was a strong correlation between both swab types and faecal samples for all combined metabolites detected by NMR. In IBD patients, there was no significant difference in faecal calprotectin and total protein levels between both swab types and faecal samples. These data lead us to conclude that 3D printed swabs are equivalent to flocked swabs for the analysis of the gut microbiome, metabolome and inflammation.
Assuntos
Fezes , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Metaboloma , Impressão Tridimensional , RNA Ribossômico 16S , Humanos , Fezes/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , RNA Ribossômico 16S/genética , Masculino , Feminino , Adulto , Reto/microbiologia , Reto/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Complexo Antígeno L1 Leucocitário/análise , Inflamação/microbiologia , Inflamação/metabolismo , Pessoa de Meia-Idade , Manejo de Espécimes/métodosRESUMO
The gut microbiota is a complex ecosystem, home to hundreds of bacterial species and a vast repository of enzymes capable of metabolising a wide range of pharmaceuticals. Several drugs have been shown to affect negatively the composition and function of the gut microbial ecosystem. Janus Kinase (JAK) inhibitors and Sphingosine-1-phosphate (S1P) receptor modulators are drugs recently approved for inflammatory bowel disease through an immediate release formulation and would potentially benefit from colonic targeted delivery to enhance the local drug concentration at the diseased site. However, their impact on the human gut microbiota and susceptibility to bacterial metabolism remain unexplored. With the use of calorimetric, optical density measurements, and metagenomics next-generation sequencing, we show that JAK inhibitors (tofacitinib citrate, baricitinib, filgotinib) have a minor impact on the composition of the human gut microbiota, while ozanimod exerts a significant antimicrobial effect, leading to a prevalence of the Enterococcus genus and a markedly different metabolic landscape when compared to the untreated microbiota. Moreover, ozanimod, unlike the JAK inhibitors, is the only drug subject to enzymatic degradation by the human gut microbiota sourced from six healthy donors. Overall, given the crucial role of the gut microbiome in health, screening assays to investigate the interaction of drugs with the microbiota should be encouraged for the pharmaceutical industry as a standard in the drug discovery and development process.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Inibidores de Janus Quinases , Moduladores do Receptor de Esfingosina 1 Fosfato , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Inibidores de Janus Quinases/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , Pirazóis/farmacologia , Colo/microbiologia , Colo/metabolismo , Colo/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/administração & dosagem , Purinas , Azetidinas/farmacologia , Azetidinas/administração & dosagem , Compostos de Benzil/farmacologia , Compostos de Benzil/administração & dosagem , Piperidinas/farmacologia , Piperidinas/administração & dosagem , Pirimidinas/farmacologia , Pirimidinas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Oxidiazóis/farmacologia , Oxidiazóis/administração & dosagem , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Pirróis/farmacologia , Pirróis/administração & dosagem , Indanos/farmacologia , Indanos/administração & dosagem , Piridinas , TriazóisRESUMO
Antimicrobial proteins contribute to host-microbiota interactions and are associated with inflammatory bowel disease (IBD), but our understanding on antimicrobial protein diversity and functions remains incomplete. Ribonuclease 4 (Rnase4) is a potential antimicrobial protein with no known function in the intestines. Here we find that RNASE4 is expressed in intestinal epithelial cells (IEC) including Paneth and goblet cells, and is detectable in human and mouse stool. Results from Rnase4-deficient mice and recombinant protein suggest that Rnase4 kills Parasutterella to modulate intestinal microbiome, thereby enhancing indoleamine-2,3-dioxygenase 1 (IDO1) expression and subsequently kynurenic and xanthurenic acid production in IECs to reduce colitis susceptibility. Furthermore, deceased RNASE4 levels are observed in the intestinal tissues and stool from patients with IBD, correlating with increased stool Parasutterella. Our results thus implicate Rnase4 as an intestinal antimicrobial protein regulating gut microbiota and metabolite homeostasis, and as a potential diagnostic biomarker and therapeutic target for IBD.
Assuntos
Microbioma Gastrointestinal , Homeostase , Doenças Inflamatórias Intestinais , Camundongos Endogâmicos C57BL , Animais , Feminino , Humanos , Masculino , Camundongos , Peptídeos Antimicrobianos/metabolismo , Colite/microbiologia , Colite/metabolismo , Colite/induzido quimicamente , Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Intestinos/microbiologia , Camundongos Knockout , Ribonucleases/metabolismoRESUMO
The human gut flora comprises a dynamic network of bacterial species that coexist in a finely tuned equilibrium. The interaction with intestinal bacteria profoundly influences the host's development, metabolism, immunity, and overall health. Furthermore, dysbiosis, a disruption of the gut microbiota, can induce a variety of diseases, not exclusively associated with the intestinal tract. The increased consumption of animal protein, high-fat and high-sugar diets in Western countries has been implicated in the rise of chronic and inflammatory illnesses associated with dysbiosis. In particular, this diet leads to the overgrowth of sulfide-producing bacteria, known as sulfidogenic bacteria, which has been linked to inflammatory bowel diseases and colorectal cancer, among other disorders. Sulfidogenic bacteria include sulfate-reducing bacteria (Desulfovibrio spp.) and Bilophila wadsworthia among others, which convert organic and inorganic sulfur compounds to sulfide through the dissimilatory sulfite reduction pathway. At high concentrations, sulfide is cytotoxic and disrupts the integrity of the intestinal epithelium and mucus barrier, triggering inflammation. Besides producing sulfide, B. wadsworthia has revealed significant pathogenic potential, demonstrated in the ability to cause infection, adhere to intestinal cells, promote inflammation, and compromise the integrity of the colonic mucus layer. This review delves into the mechanisms by which taurine and sulfide-driven gut dysbiosis contribute to the pathogenesis of sulfidogenic bacteria, and discusses the role of these gut microbes, particularly B. wadsworthia, in human diseases.
Assuntos
Disbiose , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiologia , Disbiose/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/metabolismo , Sulfetos/metabolismo , Desulfovibrio/metabolismo , Bilophila/metabolismo , Taurina/metabolismo , Animais , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/metabolismo , Bactérias/metabolismo , Bactérias/genéticaRESUMO
Inflammatory bowel diseases (IBD) are chronic, incurable inflammatory condition of the gut. They comprise Crohn's disease and ulcerative colitis. Crohn's disease (CD) may affect any tract of the gastrointestinal (GI) tract and is a transmural inflammatory condition; ulcerative colitis (UC), on the other hand, is limited to the mucosal layer of the rectum and colon. Treatment options available for both IBD are notoriously loaded with potentially serious side effects and risks. Although the pathogenesis of IBD involves a complex interaction between genetic, environmental, microbial and immunological factors, there is evidence that the interplay between the microbiota and the GI mucosa has a preponderant role. It is therefore no surprise that in recent years, a growing interest for effective and safer alternatives has focused on the potential role of prebiotics and-especially-probiotics.The mechanisms of action underlying the potential benefits of probiotics in IBD have been largely and quite extensively investigated in vitro and in vivo experiments. In terms of clinical evidence, the results of trials in the induction of remission of active CD or the maintenance of its remission with probiotics have been so far largely disappointing, to the point that their use in this disease cannot be at present recommended.On the contrary, for the treatment as well as for maintenance therapy of UC, there is clinical evidence of efficacy for some specific strains or multi-strain preparations.It is evident that this is a rapidly evolving and promising field; more data are very likely to yield a better understanding on what strains and in what doses should be used in different specific clinical settings, as we expect new and exciting developments of precision and even personalized therapy by the fast-growing field of probiogenomics.
Assuntos
Colite Ulcerativa , Probióticos , Humanos , Probióticos/uso terapêutico , Colite Ulcerativa/terapia , Colite Ulcerativa/microbiologia , Doenças Inflamatórias Intestinais/terapia , Doenças Inflamatórias Intestinais/microbiologia , Doença de Crohn/terapia , Doença de Crohn/microbiologia , Doença de Crohn/imunologia , Microbioma Gastrointestinal , Animais , Resultado do TratamentoRESUMO
The incidence of chronic inflammatory diseases (CIDs) is dramatically increasing in the developed world, resulting in an increased burden of disease in childhood. Currently, there are limited effective strategies for treating or preventing these conditions. To date, myriads of cross-sectional studies have described alterations in the composition of the gut microbiota in a variety of disease states, after the disease has already occurred. We suggest that to mechanically link these microbiome changes with disease pathogenesis, a prospective cohort design is needed to capture changes that precede or coincide with disease onset and symptoms. In addition, these prospective studies must integrate microbiological, metagenomic, meta transcriptomic and metabolomic data with minimal and standardized clinical and environmental metadata that allow to correctly compare and interpret the results of the analysis of the human microbiota in order to build a system-level model of the interactions between the host and the development of the disease. The creation of new biological computational models thus constructed will allow us to finally move from the detection of simple elements of "association" to the identification of elements of real "causality" allowing to provide a mechanistic approach to the exploration of the development of CIDs.This can only be done when these diseases are studied as complex biological networks. In this chapter we discuss the current knowledge regarding the contribution of the microbiome to CID in childhood, focusing on celiac disease and inflammatory bowel disease, with the overall aim of identifying pathways to shift research from descriptive to mechanistic approaches. We then examine how some components of the microbiota, through epigenetic reprogramming, can start the march from genetic predisposition to clinical expression of CIDs, thus opening up new possibilities for intervention, through microbiota therapy targeting the manipulation of the composition and function of the microbiota, for future applications of precision medicine and primary prevention.
Assuntos
Doença Celíaca , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Probióticos , Humanos , Doença Celíaca/microbiologia , Doença Celíaca/genética , Doença Celíaca/prevenção & controle , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/prevenção & controle , Probióticos/uso terapêuticoRESUMO
Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBDs). To understand how microbial-metabolic circuits contribute to intestinal injury, we disrupt mitochondrial function in the epithelium by deleting the mitochondrial chaperone, heat shock protein 60 (Hsp60Δ/ΔIEC). This metabolic perturbation causes self-resolving tissue injury. Regeneration is disrupted in the absence of the aryl hydrocarbon receptor (Hsp60Δ/ΔIEC;AhR-/-) involved in intestinal homeostasis or inflammatory regulator interleukin (IL)-10 (Hsp60Δ/ΔIEC;Il10-/-), causing IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60Δ/ΔIEC mice, highlighting bacterial control of metabolic injury. Colonizing GF Hsp60Δ/ΔIEC mice with the synthetic community OMM12 reveals expansion of metabolically flexible Bacteroides, and B. caecimuris mono-colonization recapitulates the injury. Transcriptional profiling of the metabolically impaired epithelium reveals gene signatures involved in oxidative stress (Ido1, Nos2, Duox2). These signatures are observed in samples from Crohn's disease patients, distinguishing active from inactive inflammation. Thus, mitochondrial perturbation of the epithelium causes microbiota-dependent injury with discriminative inflammatory gene profiles relevant for IBD.