Ubiquitin-specific proteases in inflammatory bowel disease-related signalling pathway regulation

The exact pathogenesis of inflammatory bowel disease (IBD), a chronic gastrointestinal inflammatory disease comprising Crohn’s disease and ulcerative colitis, remains unclear. Studies on ubiquitination, which regulates the degradation of inflammation signalling pathway molecules, and deubiquitination have provided novel insights. Targeting the ubiquitin-specific protease (USP) family of deubiquitinases elucidates IBD signalling pathway mechanisms and possibly, IBD therapeutic solutions. Here, we characterised USPs as chief regulators of pro-inflammatory signalling pathways, including nuclear factor-κB and transforming growth factor-β; analysed the relationship between USPs and IBD pathogenesis in terms of genetic susceptibility, intestinal epithelial barrier, immunity, and gut microbiota; and discussed future research prospects.Subject terms: Inflammatory bowel disease, Ubiquitylation     

肠道微生物群落与炎症性肠病关系研究进展

目的炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC）,以持续性肠道非特异性炎症为特征,通常反复发作、迁延不愈,临床上仍无特效性的治疗手段。IBD确切的发病机制尚不清楚,涉及免疫、环境及遗传等因素,这些因素共同诱导肠道炎症、黏膜损伤和修复。肠道微生物群落及其代谢产物、宿主基因易感性及肠道黏膜免疫三方面共同参与了IBD的发病机制。本文从消化道微生态角度出发,对目前IBD相关的肠道微生物群落研究现状、宿主-微生物间免疫应答及益生菌治疗等内容进行探讨。     

Efficacy of Probiotics-Based Interventions as Therapy for Inflammatory Bowel Disease: A Recent Update

Probiotics such as Lactobacillus spp. play an important role in human health as they embark beneficial effect on the human gastrointestinal microflora composition and immune system. Dysbiosis in the gastrointestinal microbial composition has been identified as a major contributor to chronic inflammatory conditions, such as inflammatory bowel disease (IBD). Higher prevalence of IBD is often recorded in most of the developed Western countries, but recent data has shown an increase in previously regarded as lower risk regions, such as Japan, Malaysia, Singapore, and India. Although the IBD etiology remains a subject of speculation, the disease is likely to have developed because of interaction between extrinsic environmental elements; the host’s immune system, and the gut microbial composition. Compared to conventional treatments, probiotics and probiotic-based interventions including the introduction of specific prebiotics, symbiotic and postbiotic products had been demonstrated as more promising therapeutic measures. The present review discusses the association between gut dysbiosis, the pathogenesis of IBD, and risk factors leading to gut dysbiosis. In addition, it discusses recent studies focused on the alteration of the gastrointestinal microbiome as an effective therapy for IBD. The impact of the COVID-19 pandemic and other viral infections on IBD are also discussed in this review. Clinical and animal-based studies have shown that probiotic-based therapies can restore the gastrointestinal microbiota balance and reduce gut inflammations. Therefore, this review also assesses the status quo of these microbial-based therapies for the treatment of IBD. A better understanding of the mechanisms of their actions on modulating altered gut microbiota is required to enhance the effectiveness of the IBD therapeutics.     

Extracellular Vesicles Derived from Gut Microbiota,Especially Akkermansia muciniphila,Protect the Progression of Dextran Sulfate Sodium-Induced Colitis

Gut microbiota play an important part in the pathogenesis of mucosal inflammation, such as inflammatory bowel disease (IBD). However, owing to the complexity of the gut microbiota, our understanding of the roles of commensal and pathogenic bacteria in the maintenance of immune homeostasis in the gut is evolving only slowly. Here, we evaluated the role of gut microbiota and their secreting extracellular vesicles (EV) in the development of mucosal inflammation in the gut. Experimental IBD model was established by oral application of dextran sulfate sodium (DSS) to C57BL/6 mice. The composition of gut microbiota and bacteria-derived EV in stools was evaluated by metagenome sequencing using bacterial common primer of 16S rDNA. Metagenomics in the IBD mouse model showed that the change in stool EV composition was more drastic, compared to the change of bacterial composition. Oral DSS application decreased the composition of EV from Akkermansia muciniphila and Bacteroides acidifaciens in stools, whereas increased EV from TM7 phylum, especially from species DQ777900_s and AJ400239_s. In vitro pretreatment of A. muciniphila-derived EV ameliorated the production of a pro-inflammatory cytokine IL-6 from colon epithelial cells induced by Escherichia coli EV. Additionally, oral application of A. muciniphila EV also protected DSS-induced IBD phenotypes, such as body weight loss, colon length, and inflammatory cell infiltration of colon wall. Our data provides insight into the role of gut microbiota-derived EV in regulation of intestinal immunity and homeostasis, and A. muciniphila-derived EV have protective effects in the development of DSS-induced colitis.     

Dysbiosis of Salivary Microbiota in Inflammatory Bowel Disease and Its Association With Oral Immunological Biomarkers

Analysis of microbiota in various biological and environmental samples under a variety of conditions has recently become more practical due to remarkable advances in next-generation sequencing. Changes leading to specific biological states including some of the more complex diseases can now be characterized with relative ease. It is known that gut microbiota is involved in the pathogenesis of inflammatory bowel disease (IBD), mainly Crohn''s disease and ulcerative colitis, exhibiting symptoms in the gastrointestinal tract. Recent studies also showed increased frequency of oral manifestations among IBD patients, indicating aberrations in the oral microbiota. Based on these observations, we analyzed the composition of salivary microbiota of 35 IBD patients by 454 pyrosequencing of the bacterial 16S rRNA gene and compared it with that of 24 healthy controls (HCs). The results showed that Bacteroidetes was significantly increased with a concurrent decrease in Proteobacteria in the salivary microbiota of IBD patients. The dominant genera, Streptococcus, Prevotella, Neisseria, Haemophilus, Veillonella, and Gemella, were found to largely contribute to dysbiosis (dysbacteriosis) observed in the salivary microbiota of IBD patients. Analysis of immunological biomarkers in the saliva of IBD patients showed elevated levels of many inflammatory cytokines and immunoglobulin A, and a lower lysozyme level. A strong correlation was shown between lysozyme and IL-1β levels and the relative abundance of Streptococcus, Prevotella, Haemophilus and Veillonella. Our data demonstrate that dysbiosis of salivary microbiota is associated with inflammatory responses in IBD patients, suggesting that it is possibly linked to dysbiosis of their gut microbiota.     

Current understanding of microbiota- and dietary-therapies for treating inflammatory bowel disease

Inflammatory bowel disease (IBD) is a result of chronic inflammation caused, in some part, by dysbiosis of intestinal microbiota, mainly commensal bacteria. Gut dysbiosis can be caused by multiple factors, including abnormal immune responses which might be related to genetic susceptibility, infection, western dietary habits, and administration of antibiotics. Consequently, the disease itself is characterized as having multiple causes, etiologies, and severities. Recent studies have identified >200 IBD risk loci in the host. It has been postulated that gut microbiota interact with these risk loci resulting in dysbiosis, and this subsequently leads to the development of IBD. Typical gut microbiota in IBD patients are characterized with decrease in species richness and many of the commensal, and beneficial, fecal bacteria such as Firmicutes and Bacteroidetes and an increase or bloom of Proteobacteria. However, at this time, cause and effect relationships have not been rigorously established. While treatments of IBD usually includes medications such as corticosteroids, 5-aminosalicylates, antibiotics, immunomodulators, and anti-TNF agents, restoration of gut dysbiosis seems to be a safer and more sustainable approach. Bacteriotherapies (now called microbiota therapies) and dietary interventions are effective way to modulate gut microbiota. In this review, we summarize factors involved in IBD and studies attempted to treat IBD with probiotics. We also discuss the potential use of microbiota therapies as one promising approach in treating IBD. As therapies based on the modulation of gut microbiota becomes more common, future studies should include individual gut microbiota differences to develop personalized therapy for IBD.     

The multifaceted role of CARD9 in inflammatory bowel disease

Inflammatory bowel disease (IBD) involves a dysregulated immune response to the gut microbiota. Emerging evidence has demonstrated that dysfunctions in caspase recruitment domain‐containing protein 9 (CARD9) may contribute to the pathogenesis of IBD. Interestingly, an allelic series of Card9 variants have both a common predisposing and rare protective function in IBD patients. In this review, we provide mechanistic insights into the role of the CARD9 adaptor molecule in intestinal inflammation and determine a potential CARD9‐targeting therapeutic approach against IBD.     

Mind-altering with the gut: Modulation of the gut-brain axis with probiotics

It is increasingly evident that bidirectional interactions exist among the gastrointestinal tract, the enteric nervous system, and the central nervous system. Recent preclinical and clinical trials have shown that gut microbiota plays an important role in these gut-brain interactions. Furthermore, alterations in gut microbiota composition may be associated with pathogenesis of various neurological disorders, including stress, autism, depression, Parkinson’s disease, and Alzheimer’s disease. Therefore, the concepts of the microbiota-gut-brain axis is emerging. Here, we review the role of gut microbiota in bidirectional interactions between the gut and the brain, including neural, immune-mediated, and metabolic mechanisms. We highlight recent advances in the understanding of probiotic modulation of neurological and neuropsychiatric disorders via the gut-brain axis.     

Functional effects of gut microbiota-derived metabolites in Alzheimer's disease

The precise causation of Alzheimer's disease (AD) is unknown, and the factors that contribute to its etiology are highly complicated. Numerous research has been conducted to investigate the potential impact of various factors to the risk of AD development or prevention against it. A growing body of evidence suggests to the importance of the gut microbiota-brain axis in the modulation of AD, which is characterized by altered gut microbiota composition. These changes can alter the production of microbial-derived metabolites, which may play a detrimental role in disease progression by being involved in cognitive decline, neurodegeneration, neuroinflammation, and accumulation of Aβ and tau. The focus of this review is on the relationship between the key metabolic products of the gut microbiota and AD pathogenesis in the brain. Understanding the action of microbial metabolites can open up new avenues for the development of AD treatment targets.     

Pediococcus pentosaceus LI05 alleviates DSS-induced colitis by modulating immunological profiles,the gut microbiota and short-chain fatty acid levels in a mouse model

The gut microbiota is considered a key factor in pathogenesis and progression of inflammatory bowel disease (IBD). The bacterium Pediococcus pentosaceus LI05 alleviated host inflammation by maintaining the gut epithelial integrity, modulating the host immunity, gut microbiota and metabolism, but its effect on IBD remains unclear. The present study aimed to investigate the role and mechanisms of P. pentosaceus LI05. Mice were administered P. pentosaceus LI05 or phosphate-buffered saline once daily by oral gavage for 14 days, and colitis was induced by providing mice 2% DSS-containing drinking water for 7 days. P. pentosaceus LI05 ameliorated colitis in mice and reduced the body weight loss, disease activity index (DAI) scores, colon length shortening, intestinal permeability and the proinflammatory cytokine levels. Furthermore, a significantly altered gut microbiota composition with increased diversity and short-chain fatty acid (SCFA) production was observed in mice treated with P. pentosaceus LI05. Several genera, including Akkermansia and Faecalibacterium, were differentially enriched in the P. pentosaceus LI05-treated mice and were negatively correlated with colitis indices and positively correlated with gut barrier markers and SCFA levels. The P. pentosaceus LI05 treatment alleviated intestinal inflammation by maintaining the intestinal epithelial integrity and modulating the immunological profiles, gut microbiome and metabolite composition. Based on our findings, P. pentosaceus LI05 might be applied as potential preparation to ameliorate colitis.     

The fungal microbiota of de-novo paediatric inflammatory bowel disease

Inflammatory bowel disease (IBD) is characterised by an inappropriate chronic immune response against resident gut microbes. This may be on account of distinct changes in the gut microbiota termed as dysbiosis. The role of fungi in this altered luminal environment has been scarcely reported. We studied the fungal microbiome in de-novo paediatric IBD patients utilising next generation sequencing and compared with adult disease and normal controls. We report a distinct difference in fungal species with Ascomycota predominating in control subjects compared to Basidiomycota dominance in children with IBD, which could be as a result of altered tolerance in these patients.     

肠道微生物群与脱发的相关性研究进展

随着年轻人群脱发比例的逐年增加,头发健康问题日益受到关注。脱发会影响人们的生活质量,并对心理和社交生活产生巨大影响。近年来,对肠道微生物群的生理功能性研究已不再仅仅局限于胃肠道。研究表明肠道和肠道微生物群与皮肤有密切关系,提示“肠-皮肤轴”的存在。本文在已有的“肠-皮肤轴”研究现状基础上,总结近年来文献资料,探讨肠道微生物群与脱发之间可能的联系和潜在机制,为脱发的发病机制和治疗靶点提供新的认识和观点。     

Intestinal anti-inflammatory effect of the probiotic Saccharomyces boulardii in DSS-induced colitis in mice: Impact on microRNAs expression and gut microbiota composition

The beneficial effects exerted by probiotics in inflammatory bowel disease (IBD) are well known, although their exact mechanisms have not been fully elucidated, and only few studies have focused on their impact on selected miRNAs and the gut microbiota composition. Therefore, our aim was to correlate the intestinal anti-inflammatory activity of the probiotic Saccharomyces boulardii in the dextran sodium sulphate (DSS) model of mouse colitis and the changes induced in miRNA expression and gut microbiota populations. Probiotic was given orally (5×10⁹ CFU) to C57BL/6 mice for 26 days. After 2 weeks, the colitis was induced adding DSS to the drinking water. Mice were scored daily using a Disease Activity Index (DAI). After sacrifice, the colonic specimens were evaluated by determining the expression of inflammatory markers and micro-RNAs by qRT-PCR. Moreover, changes in microbiota populations were evaluated by pyrosequencing. Probiotic ameliorated the colonic damage induced by DSS, as evidenced by lower DAI values and colonic weight/length compared with untreated mice. The treatment modified the colonic expression of different inflammatory markers and the epithelial integrity proteins, and induced changes in micro-RNAs expression. Moreover, microbiota characterization showed that probiotic treatment increased bacterial diversity, thus ameliorating the dysbiosis produced by DSS-colitis. Saccharomyces boulardii exerted intestinal anti-inflammatory effects in DSS-mouse colitis, through the modulation in the immune response, involving modification of altered miRNA expression, being associated to the improvement of the inflammation-associated dysbiosis in the intestinal lumen, which could be of great interest to control the complex pathogenesis of IBD.     

Neuropathy in COVID-19 associated with dysbiosis-related inflammation

Although COVID-19 affects mainly lungs with a hyperactive and imbalanced immune response, gastrointestinal and neurological symptoms such as diarrhea and neuropathic pains have been described as well in patients with COVID-19. Studies indicate that gut–lung axis maintains host homeostasis and disease development with the association of immune system, and gut microbiota is involved in the COVID-19 severity in patients with extrapulmonary conditions. Gut microbiota dysbiosis impairs the gut permeability resulting in translocation of gut microbes and their metabolites into the circulatory system and induce systemic inflammation which, in turn, can affect distal organs such as the brain. Moreover, gut microbiota maintains the availability of tryptophan for kynurenine pathway, which is important for both central nervous and gastrointestinal system in regulating inflammation. SARS-CoV-2 infection disturbs the gut microbiota and leads to immune dysfunction with generalized inflammation. It has been known that cytokines and microbial products crossing the blood-brain barrier induce the neuroinflammation, which contributes to the pathophysiology of neurodegenerative diseases including neuropathies. Therefore, we believe that both gut–lung and gut–brain axes are involved in COVID-19 severity and extrapulmonary complications. Furthermore, gut microbial dysbiosis could be the reason of the neurologic complications seen in severe COVID-19 patients with the association of dysbiosis-related neuroinflammation. This review will provide valuable insights into the role of gut microbiota dysbiosis and dysbiosis-related inflammation on the neuropathy in COVID-19 patients and the disease severity.     

Mouse models for the study of Crohn's disease

Crohn's Disease (CD) is a chronic inflammatory bowel disease (IBD) that can affect any portion of the gastrointestinal tract and can cause significant morbidity. A variety of animal models of both acute and chronic intestinal inflammation have been developed to investigate disease pathogenesis and novel treatment modalities. These include chemically induced, genetically manipulated and immune-mediated models of gut inflammation, each of which possesses similarities to human IBD and offers unique advantages for studying specific aspects of disease pathogenesis. However, the majority of these models are characterized by colitis and, unlike human CD, do not involve the small intestine. More recently, murine models of chronic ileal inflammation have been characterized that spontaneously develop and closely resemble human CD with regard to disease location, histologic features and clinical response to therapy. Two mouse models of experimental ileitis will be discussed in this review: the TNF DeltaARE and SAMP1/YitFc strains. Studies using these new models might provide important insight into the pathogenesis of human CD and test the efficacy of potential therapies to treat this devastating disease.     

肠道菌群及其代谢产物对心肌纤维化影响与治疗的研究进展

心肌纤维化是多种心血管疾病,如冠心病、心肌梗死和心力衰竭等的终末期表现和主要致病因素。研究发现,免疫和炎症过程在心肌纤维化的发病机制中起决定性作用。近年来,人们发现肠道微生物在心肌纤维化的发病机制和发展中起着至关重要的作用。肠道菌群的失调可导致微生物的代谢产物转移到血液循环中,如短链脂肪酸、脂多糖和氧化三甲胺等。这些代谢物直接或间接地诱导组织损伤免疫和激活全身炎症反应,进而影响心肌纤维化。如何改变肠道菌群来改善心肌纤维化已成为当前的研究重点,包括饮食干预、使用抗生素、补充益生菌和益生元,以及粪便微生物群移植等。本综述旨在回顾肠道菌群及其代谢产物与心肌纤维化的相互作用,介绍通过干预肠道菌群改善心肌纤维化的研究进展,为心肌纤维化的治疗提供新思路。     

The microbiome in inflammatory bowel diseases:from pathogenesis to therapy

Inflammatory bowel disease(IBD)has become a global disease with accelerating incidence worldwide in the 21st century while its accurate etiology remains unclear.In the past decade,gut microbiota dysbiosis has con-sistently been associated with IBD.Although many IBD-associated dysbiosis have not been proven to be a cause or an effect of IBD,it is often hypothesized that at least some of alteration in microbiome is protective or causative.In this article,we selectively reviewed the hypothesis supported by both association studies in human and pathogenesis studies in biological models.Specifically,we reviewed the potential protective bac-terial pathways and species against IBD,as well as the potential causative bacterial pathways and species of IBD.We also reviewed the potential roles of some members of mycobiome and virome in IBD.Lastly,we covered the current status of therapeutic approaches targeting microbiome,which is a promising strategy to alleviate and cure this inflammatory disease.     

Suppression of inflammation by helminths: a role for the gut microbiota?

Multiple recent investigations have highlighted the promise of helminth-based therapies for the treatment of inflammatory disorders of the intestinal tract of humans, including inflammatory bowel disease and coeliac disease. However, the mechanisms by which helminths regulate immune responses, leading to the amelioration of symptoms of chronic inflammation are unknown. Given the pivotal roles of the intestinal microbiota in the pathogenesis of these disorders, it has been hypothesized that helminth-induced modifications of the gut commensal flora may be responsible for the therapeutic properties of gastrointestinal parasites. In this article, we review recent progress in the elucidation of host–parasite–microbiota interactions in both animal models of chronic inflammation and humans, and provide a working hypothesis of the role of the gut microbiota in helminth-induced suppression of inflammation.     

Altered gut microbiome in FUT2 loss-of-function mutants in support of personalized medicine for inflammatory bowel diseases

The FUT2 loss-of-function mutations are highly prevalent and are associated with inflammatory bowel disease (IBD).To investigate the impact of FUT2 loss-of-function mutation on the gut microbiota in patients with IBD,81 endoscopically confirmed IBD patients were genotyped and divided into 3 groups:homozygous for functional FUT2 genes (SeSe),with one copy of non-functional FUT2 gene (Sese),or homozygous for non-functional FUT2 genes (sese).Escherichia,which attaches to fucosylated glycoconjugates,was the only abundant genus exhibiting decreased abundance in sese patients.Compared with SeSe or Sese patients,sese patients exhibited higher abundance in CD8~+inducing Alistipe and Phascolarctobacterium and Th17 inducing Erysipelotrichaceae UCG-003.Counter-intuitively,butyrate-producing bacteria were more abundant in sese patients.Consistently,metabolomics analysis found higher levels of butyrate in sese patients.Our data support the hypothesis that FUT2 loss-of-function mutation participates in the IBD pathogenesis by decreasing binding sites for adherent bacteria and thus altering the gut microbiota.Decreased abundances of adherent bacteria may allow the overgrowth of bacteria that induce inflammatory T cells,leading to intestinal inflammation.As FUT2 loss-of-function mutations are highly prevalent,the identification of T cell inducing bacteria in sese patients could be valuable for the development of personalized microbial intervention for IBD.