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1.
Mohammad I. El Mouzan Harland S. Winter Assad A. Assiri Kirill S. Korolev Ahmad A. Al Sarkhy Scot E. Dowd Mohammad A. Al Mofarreh Rajita Menon 《Gut pathogens》2018,10(1):49
Background
The role of microbiota in Crohn’s disease (CD) is increasingly recognized. However, most of the reports are from Western populations. Considering the possible variation from other populations, the aim of this study was to describe the microbiota profile in children with CD in Saudi Arabia, a non-Western developing country population.Results
Significantly more abundant genera in children with CD included Fusobacterium, Peptostreptococcus, Psychrobacter, and Acinetobacter; whereas the most significantly-depleted genera included Roseburia, Clostridium, Ruminococcus, Ruminoclostridium, Intestinibacter, Mitsuokella, Megasphaera, Streptococcus, Lactobacillus, Turicibacter, and Paludibacter. Alpha diversity was significantly reduced in stool (p?=?0.03) but not in mucosa (p?=?0.31). Beta diversity showed significant difference in community composition between control and CD samples (p?=?0.03).Conclusion
In this developing country, we found a pattern of microbiota in children with CD similar to Western literature, suggesting a role of recent dietary lifestyle changes in this population on microbiota structure.2.
Xiuli Xiao Wenbo Long Tingyu Huang Tian Xia Rupei Ye Yong Liu Hanan Long 《Digestive diseases and sciences》2018,63(11):2923-2929
Background
Multiple factors including host–microbiota interaction could contribute to the conversion of healthy mucosa to sporadic precancerous lesions. An imbalance of the gut microbiota may be a cause or consequence of this process.Aim
The goal was to investigate and analyze the composition of gut microbiota during the genesis of precancerous lesions of colorectal cancer.Methods
To analyze the composition of gut microbiota in the genesis of precancerous lesions, a rat model of 1, 2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) was established. The feces of these rats and healthy rats were collected for 16S rRNA sequencing.Results
The diversity and density of the rat intestinal microbiota were significantly different between ACF-bearing and non-bearing group. ACF were induced in rats treated with DMH and showed increased expression of the inflammatory cytokines IL-6, IL-8, and TNF-α. Firmicutes was the most predominant phylum in both ACF-bearing and non-bearing group, followed by Bacteroidetes. Interestingly, although the density of Bacteroidetes decreased from the fifth week to the 17th week in both groups, it was significantly reduced in ACF-bearing group at the 13th week (P?<?0.01). At the genus level, no significant difference was observed in the most predominant genus, Lactobacillus. Instead, Bacteroides and Prevotella were significantly less abundant (P?<?0.01), while Akkermansia was significantly more abundant (P?<?0.05) in ACF-bearing group at the 13th week.Conclusion
Imbalance of the intestinal microbiota existed between ACF-bearing and non-bearing rats, which could be used as biomarker to predict the genesis of precancerous lesions in the gut.3.
Omar Youssef Leo Lahti Arto Kokkola Tiina Karla Milja Tikkanen Homa Ehsan Monika Carpelan-Holmström Selja Koskensalo Tom Böhling Hilpi Rautelin Pauli Puolakkainen Sakari Knuutila Virinder Sarhadi 《Digestive diseases and sciences》2018,63(11):2950-2958
Background
Microbial ecosystems that inhabit the human gut form central component of our physiology and metabolism, regulating and modulating both health and disease. Changes or disturbances in the composition and activity of this gut microbiota can result in altered immunity, inflammation, and even cancer.Aim
To compare the composition and diversity of gut microbiota in stool samples from patient groups based on the site of neoplasm in the gastrointestinal tract (GIT) and to assess the possible contribution of the bacterial composition to tumorigenesis.Methods
We studied gut microbiota by16S RNA gene sequencing from stool DNA of 83 patients, who were diagnosed with different GIT neoplasms, and 13 healthy individuals.Results
As compared to healthy individuals, stools of patients with stomach neoplasms had elevated levels of Enterobacteriaceae, and those with rectal neoplasms had lower levels of Bifidobacteriaceae. Lower abundance of Lactobacillaceae was seen in patients with colon neoplasms. Abundance of Lactobacillaceae was higher in stools of GIT patients sampled after cancer treatment compared to samples collected before start of any treatment. In addition to site-specific differences, higher abundances of Ruminococcus, Subdoligranulum and lower abundances of Lachnoclostridium and Oscillibacter were observed in overall GIT neoplasms as compared to healthy controlsConclusion
Our study demonstrates that the alterations in gut microbiota vary according to the site of GIT neoplasm. The observed lower abundance of two common families, Lactobacillaceae and Bifidobacteriaceae, and the increased abundance of Enterobacteriaceae could provide indicators of compromised gut health and potentially facilitate GIT disease monitoring.4.
Purpose
There is a high incidence of abnormal sphenoid sinus changes in patients with pituitary apoplexy (PA). Their pathophysiology is currently unexplored and may reflect an inflammatory or infective process. In this preliminary study, we characterised the microbiota of sphenoid sinus mucosa in patients with PA and compared findings to a control group of surgically treated non-functioning pituitary adenomas (NFPAs).Methods
In this prospective observational study of patients undergoing trans-sphenoidal surgery for PA or NFPA, sphenoid sinus mucosal specimens were microbiologically profiled through PCR-cloning of the 16S rRNA gene.Results
Ten patients (five with PA and five with NFPAs) with a mean age of 51 years (range 23–71) were included. Differences in the sphenoid sinus microbiota of the PA and NFPA groups were observed. Four PA patients harboured Enterobacteriaceae (Enterobacter spp., N = 3; Escherichia coli, N = 1). In contrast, patients with NFPAs had a sinus microbiota more representative of health, including Staphylococcus epidermidis (N = 2) or Corynebacterium spp. (N = 2).Conclusions
PA may be associated with an abnormal sphenoid sinus microbiota that is similar to that seen in patients with sphenoid sinusitis.5.
Zhou Feng Wenmin Long Binhan Hao Ding Ding Xiaoqing Ma Liping Zhao Xiaoyan Pang 《Gut pathogens》2017,9(1):59
Background
Bilophila wadsworthia is a major member of sulfidogenic bacteria in human gut, it was originally recovered from different clinical specimens of intra-abdominal infections and recently was reported potentially linked to different chronic metabolic disorders. However, there is still insufficient understanding on its detailed function and mechanism to date.Methods
A B. wadsworthia strain was isolated from fresh feces of a latent autoimmune diabetes in adults patient and we investigated its pathogenicity by oral administration to specific-pathogen-free mice. Tissue samples and serum were collected after sacrifice. Stool samples were collected at different time points to profile the gut microbiota.Results
Bilophila wadsworthia infection resulted in the reduction of body weight and fat mass, apparent hepatosplenomegaly and elevated serum inflammatory factors, including serum amyloid A and interleukin-6, while without significant change of the overall gut microbiota structure.Conclusions
These results demonstrated that higher amount of B. wadsworthia caused systemic inflammatory response in SPF mice, which adds new evidence to the pathogenicity of this bacterium and implied its potential role to the chronic inflammation related metabolic diseases like diabetes.6.
Anne Ørnholt Kier Julie Midtgaard Karin Sørig Hougaard Anja Berggreen Gunhild Bukh Renata Baronaite Hansen Lene Dreyer 《Clinical rheumatology》2016,35(8):1957-1965
Objective
Half of patients with systemic lupus erythematosus (SLE) consider fatigue to be the most disabling disease symptom. To develop and promote strategies to prevent and control fatigue, this study aimed to describe how women with SLE manage the experience of fatigue.Methods
Four focus groups were conducted with 27 women with SLE, and data were analyzed by means of framework analysis. Two patient representatives with SLE were part of the investigator team.Results
The analysis revealed three main themes (i.e., learning how to be open about fatigue, learning to listen to the body, and learning to accept fatigue) and six sub-themes (i.e., the search for recognition, legitimization, planning and prioritizing, the body’s limits and self-indulgence, adjusting life to comply with resources, and acceptance of dependence).Conclusion
Fatigue is the controlling element in everyday life of women with SLE. Patients try to integrate fatigue into their everyday lives by attempting to control it and meet the challenges of structure and planning. This study indicates a need for clinicians to acknowledge patients’ fatigue, including supporting patients’ own resources, offering information, and conversation about fatigue, as well as involving patients’ relatives.7.
Mitsuaki Ishioka Kouichi Miura Shinichiro Minami Yoichiro Shimura Hirohide Ohnishi 《Digestive diseases and sciences》2017,62(2):396-406
Background
Although several types of diet have been used in experimental steatohepatitis models, comparison of gut microbiota and immunological alterations in the gut among diets has not yet been performed.Aim
We attempted to clarify the difference in the gut environment between mice administrated several experimental diets.Methods
Male wild-type mice were fed a high-fat (HF) diet, a choline-deficient amino acid-defined (CDAA) diet, and a methionine-choline-deficient (MCD) diet for 8 weeks. We compared the severity of steatohepatitis, the composition of gut microbiota, and the intestinal expression of interleukin (IL)-17, an immune modulator.Results
Steatohepatitis was most severe in the mice fed the CDAA diet, followed by the MCD diet, and the HF diet. Analysis of gut microbiota showed that the composition of the Firmicutes phylum differed markedly at order level between the mice fed the CDAA and HF diet. The CDAA diet increased the abundance of Clostridiales, while the HF diet increased that of lactate-producing bacteria. In addition, the CDAA diet decreased the abundance of lactate-producing bacteria and antiinflammatory bacterium Parabacteroides goldsteinii in the phylum Bacteroidetes. In CDAA-fed mice, IL-17 levels were increased in ileum as well as portal vein. In addition, the CDAA diet also elevated hepatic expression of chemokines, downstream targets of IL-17.Conclusions
The composition of gut microbiota and IL-17 expression varied considerably between mice administrated different experimental diets to induce steatohepatitis.8.
9.
Shu-Ying Tseng Kwong-Chung Tung Jan-Fang Cheng Yi-Hsuan Lee Zong-Yen Wu Yu-Kai Hong Shi-Yu Chen Yao-Ting Huang Po-Yu Liu 《Gut pathogens》2018,10(1):38
Background
Shewanella algae has been recognized as an emerging human pathogen. However, not much is known about the mechanism of its pathogenesis and its adaptation to a special niche such as the hepatobiliary tract.Results
In this study, we isolated the S. algae ACCC strain from human bile and performed whole genome sequencing. S. algae ACCC consists of a circular 4,743,354-bp chromosome with a GC content of 53.08%, within 4080 protein coding sequences. The genome of strain ACCC contains a number of candidate genes which have been reported to be associated with bile adaption, including htpB, exbBD, wecA, galU, adeFGH and phoPQ regulon.Conclusions
Our results highlight the association of S. algae with a rare disease profile. Further studies are needed to shed light on the evolution of pathogenesis and the niche adaptation of S. algae.10.
Purpose of Review
The microbiome is the term that describes the microbial ecosystem that cohabits an organism such as humans. The microbiome has been implicated in a long list of immune-mediated diseases which include rheumatoid arthritis, ankylosing spondylitis, and even gout. The mechanisms to account for this effect are multiple. The clinical implications from observations on the microbiome and disease are broad.Recent Findings
A growing number of microbiota constituents such as Prevotella copri, Porphyromonas gingivalis, and Collinsella have been correlated or causally related to rheumatic disease. The microbiome has a marked effect on the immune system. Our understanding of immune pathways modulated by the microbiota such as the induction of T helper 17 (Th17) cells and secretory immunoglobulin A (IgA) responses to segmented filamentous bacteria continues to expand. In addition to the gut microbiome, bacterial communities of other sites such as the mouth, lung, and skin have also been associated with the pathogenesis of rheumatic diseases.Summary
Strategies to alter the microbiome or to alter the immune activation from the microbiome might play a role in the future therapy for rheumatic diseases.11.
Background
Intestinal Behçet’s disease (BD) can cause acute lower gastrointestinal bleeding, which is sometimes fatal.Aim
We aimed to identify the risk factors and outcomes of acute lower gastrointestinal bleeding and factors associated with rebleeding in intestinal BD patients.Methods
Of the total of 588 intestinal BD patients, we retrospectively reviewed the medical records of 66 (11.2%) patients with acute lower gastrointestinal bleeding and compared them with those of 132 matched patients without bleeding.Results
The baseline characteristics were comparable between the bleeding group (n = 66) and the non-bleeding group (n = 132). On multivariate analysis, the independent factors significantly associated with lower gastrointestinal bleeding were older age (>52 years) (hazard ratio [HR] 2.2, 95% confidence interval [CI] 1.058–4.684, p = 0.035) and a nodular ulcer margin (HR 7.1, 95% CI 2.084–24.189, p = 0.002). Rebleeding occurred in 23 patients (34.8%). Female patients (p = 0.044) and those with previous use of corticosteroids or azathioprine (p = 0.034) were more likely to develop rebleeding. On multivariate analysis, only use of steroids or azathioprine was significantly associated with rebleeding (HR 3.2, 95% CI 1.070–9.462, p = 0.037).Conclusions
Age >52 years and the presence of a nodular margin of the ulcer were found to be related to increased risk of bleeding in patients with intestinal BD. Rebleeding is not uncommon and not effectively prevented with currently available medications. Further studies are warranted to identify effective measures to decrease rebleeding in intestinal BD.12.
Cornelia Lass-Flörl Astrid Mayr Maria Aigner Michaela Lackner Dorothea Orth-Höller 《Infection》2018,46(5):701-704
Purpose
To determine the burden of antifungal resistance in fungi over the last 10 years.Methods
Performance of a semi-nationwide surveillance on antifungal resistance.Results
We observed a low frequency of azole resistance in Aspergillus fumigatus, a moderate increase of echinocandin resistance in yeasts, and a stable amphotericin B activity in yeasts and molds. Posaconazole resistance in Aspergillus terreus occurred in a few isolates.Conclusion
The burden of resistance in fungi seems to be low in Tyrol, Austria.13.
Mariko Hojo Takashi Asahara Akihito Nagahara Tsutomu Takeda Kohei Matsumoto Hiroya Ueyama Kenshi Matsumoto Daisuke Asaoka Takuya Takahashi Koji Nomoto Yuichiro Yamashiro Sumio Watanabe 《Digestive diseases and sciences》2018,63(11):2940-2949
Background
Recently, problems associated with proton pump inhibitor (PPI) use have begun to surface. PPIs influence the gut microbiota; therefore, PPI use may increase the risk of enteric infections and cause bacterial translocation. In this study, we investigated fecal microbiota composition, fecal organic acid concentrations and pH, and gut bacteria in the blood of the same patients before and after PPI use.Methods
Twenty patients with reflux esophagitis based on endoscopic examination received 8 weeks of treatment with PPIs. To analyze fecal microbiota composition and gut bacteria in blood and organic acid concentrations, 16S and 23S rRNA-targeted quantitative RT-PCR and high-performance liquid chromatography were conducted.Results
Lactobacillus species were significantly increased at both 4 and 8 weeks after PPI treatment compared with bacterial counts before treatment (P?=?0.011 and P?=?0.002, respectively). Among Lactobacillus spp., counts of the L. gasseri subgroup, L. fermentum, the L. reuteri subgroup, and the L. ruminis subgroup were significantly increased at 4 and 8 weeks after treatment compared with counts before treatment. Streptococcus species were also significantly increased at 4 and 8 weeks after PPI treatment compared with counts before treatment (P?<?0.01 and P?<?0.001, respectively). There was no significant difference in the total organic acid concentrations before and after PPI treatment. Detection rates of bacteria in blood before and after PPI treatment were 22 and 28%, respectively, with no significant differences.Conclusions
Our quantitative RT-PCR results showed that gut dysbiosis was caused by PPI use, corroborating previous results obtained by metagenomic analysis.14.
Marta Olivares Audrey M. Neyrinck Sarah A. Pötgens Martin Beaumont Nuria Salazar Patrice D. Cani Laure B. Bindels Nathalie M. Delzenne 《Diabetologia》2018,61(8):1838-1848
Aims/hypothesis
Dipeptidyl peptidase 4 (DPP-4) inhibitors are agents designed to increase the half-life of incretins. Although they are administered orally, little is known about their effects on the gut microbiota and functions, despite the fact that some bacteria present in the gut microbiota exhibit DPP-4-like activity. Our objective was to study the impact of the DPP-4 inhibitor vildagliptin on gut functions and the intestinal ecosystem in a murine model of obesity induced by a Western diet (WD).Methods
Twenty seven male C57BL/6J mice were randomised to receive a control diet, a WD (45% kJ from fat and 17% kJ from sucrose) or a WD + vildagliptin (0.6 mg/ml in drinking water) for 8 weeks.Results
Vildagliptin significantly reduced DPP-4 activity in the caecal content and faeces. Vildagliptin impacted on the composition of the gut microbiota and its metabolic activity. It mainly decreased Oscillibacter spp. (a direct effect independent of DPP-4 activity was shown on cultured O. valericigenes), increased Lactobacillus spp. and propionate, and reduced the ligands of Toll-like receptors 2 and 4. Vildagliptin protected against the reductions in crypt depth and ileal expression of antimicrobial peptides induced by the WD. In the liver, the expression of immune cell populations (Cd3g and Cd11c [also known as Itgax]) and cytokines was decreased in the WD + vildagliptin-fed mice compared with the WD-fed group. Ex vivo exposure of precision-cut liver slices to vildagliptin showed that this response was not related to a direct effect of the drug on the liver tissue.Conclusions/interpretation
Our study is the first to consider the DPP-4-like activity of the gut microbiota as a target of DPP-4 inhibition. We propose that vildagliptin exerts beneficial effects at the intestinal level in association with modulation of gut microbiota, with consequences for hepatic immunity. If relevant in humans, this could open new therapeutic uses of DPP-4 inhibition to tackle gut dysfunctions in different pathophysiological contexts.Data availability
The sequences used for analysis can be found in the MG-RAST database under the project name MYNEWGUT3.15.
Liying Liu Lili Lin Linna Zheng Hui Tang Xinzhong Fan Nianguo Xue Min Li Min Liu Xianyao Li 《Gut pathogens》2018,10(1):34
Background
Salmonella enterica, serovar Enteritidis (S. Enteritidis), an important zoonotic foodborne pathogen, can affect the microbiota of the chicken intestine and cause many enteric diseases, such as acute gastroenteritis. The gut microbiota contributes to the development and function of the host immune system and competes with pathogenic microbes. The interaction between S. Enteritidis and the host cecal microbiota is still not fully understood. We investigated the microbiome composition in both treated and control groups through 16S ribosomal RNA (rRNA) gene sequencing at 1, 3, 7, 14, 21, 28, and 35 days post-S. Enteritidis inoculation (dpi) in the current study.Results
Chao1 richness and Shannon diversity significantly increased with chicken development in both the treated and control groups (P?<?0.05). The Chao1 index was significantly lower in the treated group than that in the control group at 14 dpi (P?<?0.05). Phyla Proteobacteria and Firmicutes were most dominant at 1 and 3 dpi. S. Enteritidis inoculation influenced cecal microbiota mainly at 7 and 14 dpi. S. Enteritidis inoculation significantly altered the relative abundance of 18 genera at different time points (P?<?0.05) with relative abundance significantly changed after 14 dpi. The abundance of those genera changed dramatically between 28 and 35 dpi in the treated group compared to control group. Positive correlations existed between Bacillus and Blautia and between Coprococcus and Flavonifractor following S. Enteritidis inoculation.Conclusions
Our results indicated that both development and S. Enteritidis have effect on chicken cecal microbiota profiles. S. Enteritidis inoculation in young chicks influences the cecal microbiota mainly at 7 and 14 dpi. The cecal microbiota exhibited immunity to S. Enteritidis inoculation at 28 dpi. These findings will provide basic knowledge of the role that chicken cecal microbiota play in response to S. Enteritidis inoculation.16.
Vincent Blasco-Baque Berengère Coupé Aurelie Fabre Sandra Handgraaf Pierre Gourdy Jean-François Arnal Michael Courtney Carole Schuster-Klein Beatrice Guardiola François Tercé Rémy Burcelin Matteo Serino 《Diabetologia》2017,60(4):690-700
Aims/hypothesis
Despite the current pandemic of metabolic diseases, our understanding of the diverse nature of the development of metabolic alterations in people who eat a high-fat diet (HFD) is still poor. We recently demonstrated a cardio-metabolic adaptation in mice fed an HFD, which was characterised by a specific gut and periodontal microbiota profile. Since the severity of hepatic disease is characterised by specific microRNA (miRNA) signatures and the gut microbiota is a key driver of both hepatic disease and miRNA expression, we analysed the expression of three hepatic miRNA and studied their correlation with hepatic triacylglycerol content and gut microbiota.Methods
Two cohorts of C57BL/6 4-week-old wild-type (WT) male mice (n?=?62 and n?=?96) were fed an HFD for 3 months to provide a model of metabolic adaptation. Additionally 8-week-old C57BL/6 mice, either WT or of different genotypes, with diverse gut microbiota (ob/ob, Nod1, Cd14 knockout [Cd14KO] and Nod2) or without gut microbiota (axenic mice) were fed a normal chow diet. Following which, glycaemic index, body weight, blood glucose levels and hepatic triacylglycerol levels were measured. Gut (caecum) microbiota taxa were analysed by pyrosequencing. To analyse hepatic miRNA expression, real-time PCR was performed on total extracted miRNA samples. Data were analysed using two-way ANOVA followed by the Dunnett’s post hoc test, or by the unpaired Student’s t test. A cluster analysis and multivariate analyses were also performed.Results
Our results demonstrated that the expression of miR-181a, miR-666 and miR-21 in primary murine hepatocytes is controlled by lipopolysaccharide in a dose-dependent manner. Of the gut microbiota, Firmicutes were positively correlated and Proteobacteria and Bacteroides acidifaciens were negatively correlated with liver triacylglycerol levels. Furthermore, the relative abundance of Firmicutes was negatively correlated with hepatic expression of miR-666 and miR-21. In contrast, the relative abundance of B. acidifaciens was positively correlated with miR-21.Conclusions/interpretation
We propose the involvement of hepatic miRNA, liver triacylglycerols and gut microbiota as a new triad that underlies the molecular mechanisms by which gut microbiota governs hepatic pathophysiology during metabolic adaptation to HFD.17.
Takeshi Kimura Atsushi Uda Tomoyuki Sakaue Kazuhiko Yamashita Tatsuya Nishioka Sho Nishimura Kei Ebisawa Manabu Nagata Goh Ohji Tatsuya Nakamura Chihiro Koike Mari Kusuki Takeshi Ioroi Akira Mukai Yasuhisa Abe Hiroyuki Yoshida Midori Hirai Soichi Arakawa Ikuko Yano Kentaro Iwata Issei Tokimatsu 《Infection》2018,46(2):215-224
Objective
To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on antibiotic use, antimicrobial-resistant bacteria, and clinical outcomes.Design
Before–after study.Setting
National university hospital with 934 beds.Intervention
Implementation in March 2010 of a comprehensive ASPs including, among other strategies, weekly prospective audit and feedback with multidisciplinary collaboration.Methods
The primary outcome was the use of antipseudomonal antibiotics as measured by the monthly mean days of therapy per 1000 patient days each year. Secondary outcomes included overall antibiotic use and that of each antibiotic class, susceptibility of Pseudomonas aeruginosa, the proportion of patients isolated methicillin-resistant Staphylococcus aureus (MRSA) among all patients isolated S. aureus, the incidence of MRSA, and the 30-day mortality attributable to bacteremia.Results
The mean monthly use of antipseudomonal antibiotics significantly decreased in 2011 and after as compared with 2009. Susceptibility to levofloxacin was significantly increased from 2009 to 2016 (P = 0.01 for trend). Its susceptibility to other antibiotics remained over 84% and did not change significantly during the study period. The proportion of patients isolated MRSA and the incidence of MRSA decreased significantly from 2009 to 2016 (P < 0.001 and = 0.02 for trend, respectively). There were no significant changes in the 30-day mortality attributable to bacteremia during the study period (P = 0.57 for trend).Conclusion
The comprehensive ASPs had long-term efficacy for reducing the use of the targeted broad-spectrum antibiotics, maintaining the antibiotic susceptibility of P. aeruginosa, and decreasing the prevalence of MRSA, without adversely affecting clinical outcome.18.
Antony Cougnoux Miyad Movassaghi Jaqueline A. Picache James R. Iben Fatemeh Navid Alexander Salman Kyle Martin Nicole Y. Farhat Celine Cluzeau Wei-Chia Tseng Kathryn Burkert Caitlin Sojka Christopher A. Wassif Niamh X. Cawley Richard Bonnet Forbes D. Porter 《Digestive diseases and sciences》2018,63(4):870-880
Background
Niemann–Pick disease, type C (NPC) is a rare lysosomal storage disorder characterized by progressive neurodegeneration, splenomegaly, hepatomegaly, and early death. NPC is caused by mutations in either the NPC1 or NPC2 gene. Impaired NPC function leads to defective intracellular transport of unesterified cholesterol and its accumulation in late endosomes and lysosomes. A high frequency of Crohn disease has been reported in NPC1 patients, suggesting that gastrointestinal tract pathology may become a more prominent clinical issue if effective therapies are developed to slow the neurodegeneration. The Npc1 nih mouse model on a BALB/c background replicates the hepatic and neurological disease observed in NPC1 patients. Thus, we sought to characterize the gastrointestinal tract pathology in this model to determine whether it can serve as a model of Crohn disease in NPC1.Methods
We analyzed the gastrointestinal tract and isolated macrophages of BALB/cJ cNctr-Npc1m1N/J (Npc1?/?) mouse model to determine whether there was any Crohn-like pathology or inflammatory cell activation. We also evaluated temporal changes in the microbiota by 16S rRNA sequencing of fecal samples to determine whether there were changes consistent with Crohn disease.Results
Relative to controls, Npc1 mutant mice demonstrate increased inflammation and crypt abscesses in the gastrointestinal tract; however, the observed pathological changes are significantly less than those observed in other Crohn disease mouse models. Analysis of Npc1 mutant macrophages demonstrated an increased response to lipopolysaccharides and delayed bactericidal activity; both of which are pathological features of Crohn disease. Analysis of the bacterial microbiota does not mimic what is reported in Crohn disease in either human or mouse models. We did observe significant increases in cyanobacteria and epsilon-proteobacteria. The increase in epsilon-proteobacteria may be related to altered cholesterol homeostasis since cholesterol is known to promote growth of this bacterial subgroup.Conclusions
Macrophage dysfunction in the BALB/c Npc1?/? mouse is similar to that observed in other Crohn disease models. However, neither the degree of pathology nor the microbiota changes are typical of Crohn disease. Thus, this mouse model is not a good model system for Crohn disease pathology reported in NPC1 patients.19.