Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a chronic and relapsing inflammatory disorder of the intestine. Although its incidence is increasing globally, ...the precise etiology remains unclear and a cure for IBD has yet to be discovered. The most accepted hypothesis of IBD pathogenesis is that complex interactions between genetics, environmental factors, and the host immune system lead to aberrant immune responses and chronic intestinal inflammation. The human gut harbors a complex and abundant aggregation of microbes, collectively referred to as the gut microbiota. The gut microbiota has physiological functions associated with nutrition, the immune system, and defense of the host. Recent advances in next-generation sequencing technology have identified alteration of the composition and function of the gut microbiota, which is referred to as dysbiosis, in IBD. Clinical and experimental data suggest dysbiosis may play a pivotal role in the pathogenesis of IBD. This review is focused on the physiological function of the gut microbiota and the association between the gut microbiota and pathogenesis in IBD. In addition, we review the therapeutic options for manipulating the altered gut microbiota, such as probiotics and fecal microbiota transplantation.
Background
The mucosa-associated gut microbiota directly modulates epithelial and mucosal function. In this study, we investigated the mucosa-associated microbial community in patients with ...inflammatory bowel disease (IBD), using endoscopic brush samples.
Methods
A total of 174 mucus samples from 43 patients with ulcerative colitis (UC), 26 with Crohn’s disease (CD) and 14 non-IBD controls were obtained by gentle brushing of mucosal surfaces using endoscopic cytology brushes. The gut microbiome was analyzed using 16S rRNA gene sequencing.
Results
There were no significant differences in microbial structure among different anatomical sites (the ileum, cecum and sigmoid colon) within individuals. There was, however, a significant difference in microbial structure between CD, UC and non-IBD controls. The difference between CD and non-IBD controls was more marked than that between UC patients and non-IBD controls. α-Diversity was significantly lower in UC and CD patients than non-IBD controls. When comparing CD patients with non-IBD controls, the phylum
Proteobacteria
was significantly increased and the phyla
Firmicutes
and
Bacteroidetes
were significantly reduced. These included a significant increase in the genera
Escherichia
,
Ruminococcus
(
R. gnavus
),
Cetobacterium
,
Actinobacillus
and
Enterococcus
, and a significant decrease in the genera
Faecalibacterium
,
Coprococcus
,
Prevotella
and
Roseburia
. Comparisons between CD and UC patients revealed a greater abundance of the genera
Escherichia, Ruminococcus
(
R. gnavus
)
, Clostridium, Cetobacterium, Peptostreptococcus
in CD patients, and the genera
Faecalibacterium
,
Blautia
,
Bifidobacterium
,
Roseburia
and
Citrobacter
in UC patients.
Conclusions
Mucosa-associated dysbiosis was identified in IBD patients. CD and UC may be distinguishable from the mucosa-associated microbial community structure.
Interleukin-33 (IL-33), IL-36, and IL-38 are members of the IL-1 cytokine family. The expression of each cytokine has been reported to be increased in the inflamed mucosa of patients with ...inflammatory bowel disease (IBD). IL-33 and IL-36 have been studied for pro- and anti-inflammatory functions, and IL-38 has been characterized as an anti-inflammatory cytokine by antagonizing the IL-36 receptor (IL-36R). IL-33 is a nuclear cytokine constitutively expressed by certain cell types such as epithelial, endothelial, and fibroblast-like cells and released on necrotic cell death. IL-33 mainly induces type 2 immune response through its receptor suppression tumorigenicity 2 (ST2) from Th2 cells and type 2 innate lymphoid cells (ILC2s), but also by stimulating Th1 cells, regulatory T cells, and CD8
+
T cells. IL-36 cytokines consist of three agonists: IL-36α, IL-36β, and IL-36γ, and two receptor antagonists: IL-36R antagonist (IL-36Ra) and IL-38. All IL-36 cytokines bind to the IL-36R complex and exert various functions through NF-κB and mitogen-activated protein kinase (MAPK) pathways in inflammatory settings. IL-33 and IL-36 also play a crucial role in intestinal fibrosis characteristic manifestation of CD. In this review, we focused on the current understanding of the pro- and anti-inflammatory roles of IL-33, IL-36, and IL38 in experimental colitis and IBD patients.
Curcumin is a hydrophobic polyphenol derived from turmeric, a traditional Indian spice. Curcumin exhibits various biological functions, but its clinical application is limited due to its poor ...absorbability after oral administration. A newly developed nanoparticle curcumin shows improved absorbability in vivo. In this study, we examined the effects of nanoparticle curcumin (named Theracurmin) on experimental colitis in mice.
BALB/c mice were fed with 3% dextran sulfate sodium (DSS) in water. Mucosal cytokine expression and lymphocyte subpopulation were analyzed by real-time PCR and flow cytometry, respectively. The profile of the gut microbiota was analyzed by real-time PCR.
Treatment with nanoparticle curcumin significantly attenuated body weight loss, disease activity index, histological colitis score and significantly improved mucosal permeability. Immunoblot analysis showed that NF-κB activation in colonic epithelial cells was significantly suppressed by treatment with nanoparticle curcumin. Mucosal mRNA expression of inflammatory mediators was significantly suppressed by treatment with nanoparticle curcumin. Treatment with nanoparticle curcumin increased the abundance of butyrate-producing bacteria and fecal butyrate level. This was accompanied by increased expansion of CD4+ Foxp3+ regulatory T cells and CD103+ CD8α- regulatory dendritic cells in the colonic mucosa.
Treatment with nanoparticle curcumin suppressed the development of DSS-induced colitis potentially via modulation of gut microbial structure. These responses were associated with induction of mucosal immune cells with regulatory properties. Nanoparticle curcumin is one of the promising candidates as a therapeutic option for the treatment of IBD.
Altered gut microbial ecology contributes to the development of metabolic diseases including obesity. In this study, we performed 16S rRNA sequence analysis of the gut microbiota profiles of obese ...and lean Japanese populations. The V3–V4 hypervariable regions of 16S rRNA of fecal samples from 10 obese and 10 lean volunteers were sequenced using the Illumina MiSeqTMII system. The average body mass index of the obese and lean group were 38.1 and 16.6 kg/m2, respectively (p<0.01). The Shannon diversity index was significantly higher in the lean group than in the obese group (p<0.01). The phyla Firmicutes and Fusobacteria were significantly more abundant in obese people than in lean people. The abundance of the phylum Bacteroidetes and the Bacteroidetes/Firmicutes ratio were not different between the obese and lean groups. The genera Alistipes, Anaerococcus, Corpococcus, Fusobacterium and Parvimonas increased significantly in obese people, and the genera Bacteroides, Desulfovibrio, Faecalibacterium, Lachnoanaerobaculum and Olsenella increased significantly in lean people. Bacteria species possessing anti-inflammatory properties, such as Faecalibacterium prausnitzii, increased significantly in lean people, but bacteria species possessing pro-inflammatory properties increased in obese people. Obesity-associated gut microbiota in the Japanese population was different from that in Western people.
The trichloromethyl group is an important functionality. It is a useful synthetic moiety and appears in the structures of natural and biologically active compounds; hence, developing synthetic ...methods for its introduction into structural motifs is an important objective. Herein, we report an efficient chemistry for the trichloromethylations and cycloaminations of olefin. These reactions are realized in a single step and triggered by the addition of the trichloromethyl radical, generated from bromotrichloromethane by photoredox catalysis, to a double bond, with the resulting intermediate trapped through intramolecular reaction with an amino group. This process facilitates the construction of N‐heterocycles having trichloromethyl units and tetrasubstituted carbons from simple compounds under mild conditions.
The trichloromethyl group is an important functionality as it appears in the structures of biologically active compounds. The trichloromethylative olefin cycloaminations are reported. These reactions are triggered by the addition of the trichloromethyl radical, generated from bromotrichloromethane by photoredox catalysis, to a double bond. This process facilitates the construction of N‐heterocycles having trichloromethyl units.
A total synthesis of (±)‐lundurines A and B is described. These natural products have a unique hexacyclic skeleton which includes a cyclopropane‐fused indoline. A stereospecific construction of the ...pentasubstituted cyclopropane core was achieved, by radical cyclization using SmI2, with perfect stereoselectivity. Cyclizations to give seven‐ and five‐membered heterocycles, under palladium and ruthenium catalysis, respectively, accomplished the total syntheses. The late‐stage construction of the F ring by ring‐closing metathesis enabled access to the title compounds from a spiroindoline intermediate which is a common structure of other kopsia alkaloids.
To the core: The total synthesis of (±)‐lundurines A and B is described. One of the key reactions is a SmI2‐mediated cyclopropanation, which delivered the core structure with perfect stereocontrol of the quaternary carbon centers. Palladium‐ and ruthenium‐catalyzed cyclizations were also effective for constructing seven‐ and five‐membered heterocycles, respectively, to complete the total syntheses.
The global alteration of the gut microbial community (dysbiosis) plays an important role in the pathogenesis of inflammatory bowel diseases (IBDs). However, bacterial species that characterize ...dysbiosis in IBD remain unclear. In this study, we assessed the alteration of the fecal microbiota profile in patients with Crohn's disease (CD) using 16S rRNA sequencing.
Fecal samples from 10 inactive CD patients and 10 healthy individuals were subjected to 16S rRNA sequencing. The V3-V4 hypervariable regions of 16S rRNA were sequenced by the Illumina MiSeq™II system. The average of 62,201 reads per CD sample was significantly lower than the average of 73,716 reads per control sample. The genera Bacteroides, Eubacterium, Faecalibacterium and Ruminococcus significantly decreased in CD patients as compared to healthy controls. In contrast, the genera Actinomyces and Bifidobacterium significantly increased in CD patients. At the species level, butyrate-producing bacterial species, such as Blautia faecis, Roseburia inulinivorans, Ruminococcus torques, Clostridium lavalense, Bacteroides uniformis and Faecalibacterium prausnitzii were significantly reduced in CD patients as compared to healthy individuals (p < 0.05). These results of 16S rRNA sequencing were confirmed in additional CD patients (n = 68) and in healthy controls (n = 46) using quantitative PCR. The abundance of Roseburia inulinivorans and Ruminococcus torques was significantly lower in C-reactive protein (CRP)-positive CD patients as compared to CRP-negative CD patients (p < 0.05).
The dysbiosis of CD patients is characterized by reduced abundance of multiple butyrate-producing bacteria species.
The relationship between skeletal muscle volume and the prognosis of patients with inflammatory bowel disease (IBD) remains undetermined. We conducted a retrospective study of 72 IBD patients who ...were admitted to the hospital due to disease exacerbation. We enrolled IBD patients who had undergone abdominal computed tomography and assessed the nutritional indices, such as the Onodera's prognostic nutritional index (O-PNI) and the controlling nutritional status (CONUT) index. The L3 skeletal muscle index (SMI), which is the ratio of the cross-sectional area of skeletal muscles at the level of the third lumbar (L3) vertebra to the height squared, was used to identify sarcopenia. Sarcopenia, defined as a low SMI, was observed in 42% of all IBD patients (37% with Crohn's disease (CD) and 48% with ulcerative colitis (UC)). In UC patients, the O-PNI and CONUT values, height, and albumin levels were significantly lower than in CD patients. The SMI strongly correlated with sex, body weight, albumin level, and O-PNI in IBD patients. Multivariate analysis using the Cox regression model demonstrated that the presence of sarcopenia (P = 0.015) and disease type (CD or UC) (P = 0.007) were significant factors predicting intestinal resection. The cumulative operation-free survival rate was significantly lower for sarcopenic patients than in all IBD patients (P = 0.003) and a stratified analysis of CD patients (P = 0.001) using the Kaplan-Meier method and log-rank test. The L3 skeletal muscle area is a prognostic factor for intestinal resection in patients with CD.
A new approach to cyclooctabindole through formal 5+3 cycloaddition was developed. This methodology was realized by using an indole derivative as a C5 unit and a cyclopropane derivative as a C3 unit. ...These two units have both donor and acceptor properties. Two carbon–carbon bonds were formed stepwise by the successive addition of a Lewis acidic catalyst and a Brønsted base. The reaction could be performed as a one‐pot process. Optically active cyclooctabindole was also synthesized by using this methodology with a chiral cyclopropane as a C3 substrate.
A new approach to cyclooctabindole through formal 5+3 cycloaddition was developed. This methodology was realized by using an indole derivative as a C5 unit and a cyclopropane derivative as a C3 unit. Two carbon–carbon bonds were formed stepwise by the addition of a Lewis acidic catalyst and a Brønsted base. The reaction could be performed as a one‐pot process.
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