Intestinal Colonization Research Articles

Sex- and site-specific associations of circulating lipocalin 2 and incident colorectal cancer: Results from the EPIC cohort.

Experimental research has uncovered lipocalin 2 (LCN2) as a novel biomarker implicated in the modulation of intestinal inflammation, metabolic homeostasis, and colon carcinogenesis. However, evidence from human research has been scant. We, therefore, explored the association of pre-diagnostic circulating LCN2 concentrations with incident colorectal cancer (CRC) in a nested case-control study within the in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. LCN2 was measured in 1267 incident CRC cases matched to 1267 controls using incidence density sampling. Conditional logistic regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) according to tumor subsite and sex. Weighted Cox proportional hazard regression was used to explore associations by adiposity status. In multivariable-adjusted analyses, the IRR [95% CI] per doubling in LCN2 concentration was 1.16 [0.98-1.37] for CRC overall, 1.26 [1.00-1.59] for colon cancer, and 1.08 [0.85-1.38] for rectal cancer. The association for colon cancer was more pronounced in women (IRR [95% CI], 1.66 [1.20-2.30]) and for proximal colon cancer (IRR [95% CI], 1.96 [1.15-3.34]), whereas no association was seen in men and distal colon cancer. The association for colon cancer was positive in individuals with high waist circumference (hazard ratio [95% CI], 1.69 [1.52-1.88]) and inverse in individuals with low waist circumference (hazard ratio [95% CI], 0.86 [0.76-0.98], P interaction<0.01). Overall, these data suggest that pre-diagnostic LCN2 concentrations were positively associated with colon cancer, particularly occurring in the proximal colon, in women and among individuals with abdominal adiposity.

Shrimp Intestinal Microbiota Homeostasis: Dynamic Interplay Between the Microbiota and Host Immunity

ABSTRACTThe shrimp intestine harbors a microbiota that has pivotal roles for host's physiology. Imbalance of shrimp intestinal microbiota has been shown closely related to the occurrence of diseases. The morphological and biological features of the shrimp intestine are considered suboptimal for stable microbial colonization, making the intestinal microbiota composition highly susceptible to the impact of environmental changes or stressors, and particularly unstable. Therefore, the relative unsteadiness of the microbiota composition represents a continuous threat to host survival. Shrimp intestinal microbiota homeostasis is achieved through a dynamic interplay between the microbiota and the host's innate immunity. The shrimp intestine possesses effective innate immune mechanisms that can suppress the uncontrolled proliferation of microbiota components, and simultaneously protect the microbiota from elimination. The mechanism(s) by which the microbial components and the intestinal innate immunity interact with each other to achieve homeostasis represents an interesting interplay between host and microbiota. This review summarizes the current knowledge about intestinal microbiota colonization in shrimp, as well as the intricate mechanisms employed by the intestinal immune system to regulate this microbiota. Moreover, the potential intervention strategies to promote and protect shrimp intestinal homeostasis by modulating the microbiota are also discussed. Thus, this review seeks to comprehensively analyze the current information and contribute to a deeper understanding of the complex interplay between the shrimp intestinal microbiota and innate immunity in maintaining shrimp intestinal homeostasis and overall health. This enhanced understanding may potentially open new avenues for aquaculture management and disease mitigation strategies, ultimately benefiting the shrimp farming industry.

Fecal tryptophan metabolite profiling in newborns in relation to microbiota and antibiotic treatment

In the first days of life, the newborns’ intestinal microbiota develops simultaneously with the intestinal gut barrier and follows intestinal immunity. The mode of delivery shows significant impact on microbial development and, thus, the initiation of the tryptophan catabolism pathway. Further antibiotics (ATB) treatment of mothers before or during delivery affects the microbial and tryptophan metabolite composition of stool of the caesarean- and vaginal-delivered newborns. The determination of microbiome and levels of tryptophan microbial metabolites in meconium and stool can characterize intestinal colonization of a newborn. From 134 samples from the Central European Longitudinal Studies of Parents and Children: The Next Generation (CELSPAC: TNG) cohort study, 16S rRNA gene sequencing was performed, and microbial tryptophan metabolites were quantified using ultra-high-performance liquid chromatography with triple-quadrupole mass spectrometry. Microbial diversity and concentrations of tryptophan metabolites were significantly higher in stool compared to meconium. Treatment of mothers with ATB before or during delivery affects metabolite composition and microbial diversity in stool of vaginal- and caesarean-delivered newborns. Correlation of microbial and metabolite composition shows significant positive correlations of indol-3-lactic acid, N-acetyl-tryptophan and indol-3-acetic acid with Bifidobacterium, Bacteroides and Peptoclostridium. The positive effect of vaginal delivery on newborns’ microbiome development is degraded when mother is treated with ATB before or during delivery.Key points• Antibiotic treatment diminishes the positive effects of vaginal delivery.• Antibiotic treatment affects metabolite and microbial composition in newborns.• Bifidobacterium and Peptoclostridium could be the producer of indole-lactic acid.

Refining the gut colonization Zophobas morio larvae model using an oral administration of multidrug-resistant Escherichia coli

The darkling beetle Zophobas morio can be implemented as an alternative in vivo model to study different intestinal colonization aspects. Recently, we showed that its larvae can be colonized by multidrug-resistant Escherichia coli strains administered via contaminated food (for 7 days) for a total experimental duration of 28 days. In the present work, we aimed to shorten the model to 14 days (T14) by administering the previously used CTX-M-15 ESBL-producing ST131 Escherichia coli strain Ec-4901.28 via a single oral administration (5 µL dose of 108 CFU/mL) , using a blunt 26s-gauge needle connected to a 250 μL gastight syringe. Force-feeding was performed either without or with (larvae placed on ice for 10 minutes before injection) anesthesia. In addition, phage-treated larvae were orally injected with 10 µL of INTESTI bacteriophage cocktail (∼105-6 PFU/mL) on days 4 (T4) and 7 (T7) . Growth curve analyses showed that, while larvae rapidly became colonized with Ec-4901.28 (T1, ∼106-7 CFU/mL) , only those anesthetized maintained a high bacterial load (∼102-3vs. ∼105-6 CFU/mL) and survival rate (76% vs. 99%; P<0.001) by T14. Moreover, bacteriophage administration to anesthetized larvae significantly reduced the bacterial count of INTESTI-susceptible Ec-4901.28 at T14 (5.17 × 105vs. 2.26 × 104, for non-treated and phage-treated larvae, respectively; P=0.04) . The methodological refinements applied to establish the intestinal colonization model simplify the use of Z. morio larvae, facilitate prompt evaluation of novel decolonization approaches and reduce experiments involving vertebrate animals in accordance with the Replacement, Reduction and Refinement principles.

Is intestinal colonization with multidrug-resistant Enterobacterales associated with higher rates of nosocomial Enterobacterales bloodstream infections?

ObjectiveIntestinal colonization with multidrug-resistant Enterobacterales (MDRE-IC) increases the risk of MDRE bloodstream infection (MDRE-BSI). However, its impact on the overall risk of nosocomial Enterobacterales bloodstream infections (nE-BSI) remains unclear. This study aimed to determine this risk and identify associated factors in hospitalized patients. Design and methodsThis retrospective cohort study at a 3200-bed tertiary institution included patients hospitalized in 2019 who underwent MDRE rectal swab (RS) screening. Inclusion criteria were age ≥18 years, first RS in 2019, follow-up ≥7 days, and E-BSIs >48 hours post-RS. The primary outcome was the first nE-BSI during follow-up period, analysed using a Cox model. ResultsAmong 7006 patients, 817 (11.9%) had MDRE-IC. Most were male and primarily hospitalized in acute wards. nE-BSIs occurred in 433 (6.1%) patients and was more frequent in MDRE-IC patients compared to non-colonized group (aHR = 1.78, 95%CI: 1.40-2.26). Intestinal colonization with ESBL-producing and carbapenemase-resistant Enterobacterales showed similar risks for E-BSI onset: aHR = 1.73 (95%CI: 1.33-2.24) and aHR = 2.02 (95%CI: 1.27-3.22), respectively. ConclusionIn hospitalized patients, MDRE-IC is associated with a higher rate of nE-BSI compared to those without MDRE-IC, underscoring the urgent need for improved infection prevention and control measures, as well as optimized antibiotic use to mitigate this risk.

DegS regulates the aerobic metabolism of Vibrio cholerae via the ArcA-isocitrate dehydrogenase pathway for growth and intestinal colonization

DegS regulates the aerobic metabolism of Vibrio cholerae via the ArcA-isocitrate dehydrogenase pathway for growth and intestinal colonization

Unraveling Cecal Alterations in Clostridioides difficile Colonized Mice through Comprehensive Metabolic Profiling.

The disruption of gut microbiota caused by antibiotics favors the intestinal colonization of Clostridioides difficile - a Gram-positive, spore-forming anaerobic bacterium that causes potentially fatal gastrointestinal infections. In an endeavor to elucidate the complexities of the gut-brain axis in the context of Clostridium difficile infection (CDI), a murine model has been used to investigate the potential effects of antibiotic administration and subsequent colonization by C. difficile, as well as the impact of three different 10-day treatments (metronidazole, probiotics, and fecal microbiota transplantation), on the cecal metabolome for the first time. This follows our previous research which highlighted the metabolic effect of CDI and these treatments in the brain and employs the same four different metabolomics-based methods (targeted GC-MS/MS, targeted HILIC-MS/MS, untargeted RP-LC-HRMS/MS and untargeted GC-MS). A total of 286 unique metabolites have been identified in the mouse cecal profiles and statistical analysis revealed that CDI, as well as the subsequent treatments, significantly alters cecal metabolites and lipids implicated in various biochemical pathways centered around amino acid metabolism, glycerophospholipid metabolism, and central carbon metabolism. To our knowledge, this study represents the first exploration of the effects of C. difficile-induced colitis and potential treatments on the cecal tissue metabolome.

Evaluation of the effect of nano-encapsulated Lippia origanoides essential oil extract on Salmonella serovar Enteritidis as a natural alternative to antibiotics in the poultry industry

The purpose of the present research was to evaluate the bactericidal activity of a formulation of thymol chemotype of Lippia origanoides essential oils (LOEOs) nano-encapsulated in maltodextrin against Salmonella ser. Enteritidis (SE) in an in vitro crop assay and in a prophylactic broiler chicken model using three low doses of the product: 75 ppm, 150 ppm, and 300 ppm. Two trials of each assay were conducted. Day-of-hatch male Cobb-Vantress broiler chickens were randomly allotted to one of four groups: G1) positive control group; G2) 75 ppm LOEOs group; G3) 150 ppm LOEOs group; G4) 300 ppm LOEOs group. Chicks were fed and watered ad libitum in heated brooder batteries in a controlled, age-appropriate environment. On day seven of age, all chickens were orally gavaged with 108 colony-forming units (CFU) of SE. Chickens were euthanized by exposure to CO2 for 24 hours after the SE challenge. Recovery of SE was evaluated in the liver, spleen, and ceca (including cecal tonsils). None of the three microencapsulated LOEOs doses changed SE concentration (p&gt;0.05) in the in vitro crop assay. Similarly, no significant differences in SE were observed in the organ and intestinal colonization in broiler chicken trials. Therefore, the low concentrations of the nano-encapsulated LOEOs used do not reduce SE concentration in different poultry models. Further studies are needed to optimize the formulation, delivery, models, and concentration of essential oils to control Salmonella infections in broiler chickens effectively.

Influence of genotype on carcass composition, metric traits of the digestive system and leg bones of laying hens after the egg-production season

Context The genotype of laying hens is one of the most important factors influencing their carcass composition and anatomical features. Aims The aim of the present study was to compare two genotypes of laying hens, Lohmann Brown and Lohmann White, after the laying period. Methods The experimental material consisted of 26 carcasses obtained after slaughtering spent laying hens at the age of 83 weeks. Key results The genotype of the birds had a significant (P &lt; 0.05) effect on carcass weight, and the proportion (%) of the breast muscle, leg muscle and gizzard weight. Significant correlations were also found between bodyweight and the weight of the stomach, proventriculus, liver and spleen. The origin of the laying hens also had a significant impact on the length of the sections on intestinal segments, namely, jejunum, ileum and colon. Significant differences in the correlations between bodyweight and length of duodenum, jejunum and rectum were also found. The compared hybrids of laying hens differed significantly in the dimensions of the femur and tibia. Lohmann Brown (LB) hens were characterized by higher greatest length, medial length, smallest breadth of the corpus, and greatest breadth of the distal end of the femur compared with Lohmann White (LW) hens. Dimensions of the tibia greatest length, axial length, smallest breadth of the corpus, greatest breadth of the distal end and greatest depth of the distal end in LB hens were also significantly (P &lt; 0.05) higher than those in LW hens. Conclusions The results showed that the genotype of laying hens tested after the laying period influenced carcass weight and muscle percentage, as well as differentiated the birds in terms of dimensions of individual segments of the digestive tract, femur, and tibia bones. Implications The results of this research may be useful for consumers of laying hen carcasses and people interested in poultry anatomy.

Candida tropicalis-derived vitamin B3 exerts protective effects against intestinal inflammation by promoting IL-17A/IL-22-dependent epithelial barrier function

ABSTRACT Candida tropicalis-a prevalent gut commensal fungus in healthy individuals – contributes to intestinal health and disease. However, how commensal C. tropicalis influences intestinal homeostasis and barrier function is poorly understood. Here, we demonstrated that the reference strain of C. tropicalis (MYA-3404) ameliorated intestinal inflammation in murine models of chemically induced colitis and bacterial infection. Intestinal colonization of C. tropicalis robustly upregulated the expression of IL-17A and IL-22 to increase barrier function and promote proliferation of intestinal epithelial cells in the mouse colon. Metabolomics analysis of fecal samples from mice colonized with C. tropicalis revealed alterations in vitamin B3 metabolism, promoting conversion of nicotinamide to nicotinic acid. Although nicotinamide worsened colitis, treatment with nicotinic acid alleviated disease symptoms and enhanced epithelial proliferation and Th17 cell differentiation. Oral gavage of C. tropicalis mitigated nicotinamide-induced intestinal dysfunction in experimental colitis. Blockade of nicotinic acid production with nicotinamidase inhibitors lowered the protective effects against colitis in mice treated with C. tropicalis. Notably, a clinical C. tropicalis strain isolated from patients with candidemia lacked the protective effects against murine colitis observed with the reference strain. Together, our results highlight a novel role for C. tropicalis in resolving intestinal inflammation through the modulation of vitamin B3 metabolism.

Characterization of Yeast Isolated from the Gut Microbiota of Tunisian Children with Autism Spectrum Disorder

Research on the microbiota–gut–brain axis in autism has primarily focused on bacteria, with limited attention to fungi. There is a growing interest in understanding the involvement of fungi, particularly Candida, in patients with autism spectrum disorder. The aim of this study was to assess the prevalence, antifungal susceptibility profiles and virulence factors of Candida isolates from the guts of Tunisian children with autism. Twenty-eight children with autism and forty-six controls were enrolled. Candida isolates from the faecal samples were identified using biochemical and molecular methods; antifungal susceptibility testing was determined by the EUCAST broth microdilution method and virulence factors, including biofilm formation, cell surface hydrophobicity and phospholipase and proteinase activities, were assessed in vitro. As a result, Candida was detected in 13 children with autism (46.4%) and 14 control children (30.4%). Candida albicans was found to be the most common species isolate in the faeces of both groups of children. Antifungal susceptibility profiles showed that one Candida isolate was resistant to amphotericin B and anidulafungin (3.7%), six were resistant to micafungin (22.2%) and five were resistant to fluconazole (18.5%). All Candida isolates were biofilm producers. Of the twenty-seven isolates, only four showed phospholipase activity (14.8%), eight showed aspartyl-proteinase activity (29.6%) and nine were hydrophobic (33.3%). These results highlight the presence of Candida in the guts of children with autism, as well as the ability to express multiple virulence factors and the antifungal resistance, and they emphasize the need for further studies to confirm intestinal Candida colonization and its potential role in autism.

Gestational diabetes exacerbates intrauterine microbial exposure induced intestinal microbiota change in offspring contributing to increased immune response.

maternal health during pregnancy can affect the intestinal microbial community of offspring, but currently the impact of intrauterine environmental changes resulting from gestational diabetes mellitus (GDM) on the microbiota of offspring as well as its interaction with the immune system remains unclear. to explore the impact of intrauterine microbial exposure during pregnancy of gestational diabetes mellitus on the development of neonate's intestinal microbiota and activation of immune responses. Levels of lipopolysaccharides in cord blood from GDM and expression of microbial recognition-related proteins in the placenta were measured. To evaluate embryonic intestinal colonization, pregnant mice with GDM were administered with labeled Escherichia coli or Lactobacillus. The intestinal colonization of pups was analyzed through 16S rRNA gene sequencing and labeled microbial culture. Additionally, memory T lymphocyte and dendritic cell co-culture experiments were conducted to elucidate the immune memory of intestinal microbes during the embryonic stages. Gestational diabetes mellitus led to elevated umbilical cord blood LPS level and increased GFP labeled Escherichia coli in the offspring's intestine after gestational microbial exposure. The mouse model of GDM exhibited increased immune markers including TLR4, TLR5, IL-22 and IL-23 in the placenta and a recall response from memory T cells in offspring's intestines, with similar observations found in human experiments. Furthermore, reduced intestinal microbiome diversity and an increased ratio of Firmicutes/Bacteroidetes was found in GDM progeny, with the stability of bacterial colonization been interfered. Our investigation has revealed a noteworthy correlation between gestational diabetes and intrauterine microbial exposure, as well as alterations in the neonatal microbiota and activation of immune responses. These findings highlight the gestational diabetes's role on offspring's gut microbiota and immune system interactions with early-life pathogen exposure.

Vibrio cholerae virulence is blocked by chitosan oligosaccharide-mediated inhibition of ChsR activity.

Vibrio cholerae causes cholera, an important cause of death worldwide. A fuller understanding of how virulence is regulated offers the potential for developing virulence inhibitors, regarded as efficient therapeutic alternatives for cholera treatment. Here we show using competitive infections of wild-type and mutant bacteria that the regulator of chitosan utilization, ChsR, increases V. cholerae virulence in vivo. Mechanistically, RNA sequencing, chromatin immunoprecipitation with sequencing and molecular biology approaches revealed that ChsR directly upregulated the expression of the virulence regulator, TcpP, which promoted expression of the cholera toxin and the toxin co-regulated pilus, in response to low O2 levels in the small intestine. We also found that chitosan degradation products inhibit the ChsR-tcpP promoter interaction. Consistently, administration of chitosan oligosaccharide, particularly when delivered via sodium alginate microsphere carriers, reduced V. cholerae intestinal colonization and disease severity in mice by blocking the chsR-mediated pathway. These data reveal the potential of chitosan oligosaccharide as supplemental therapy for cholera treatment and prevention.

Epigallocatechin gallate protects mice from Salmonella enterica ser. Typhimurium infection by modulating bacterial virulence through quorum sensing inhibition.

Salmonella enterica ser. Typhimurium is a common pathogen that poses a considerable public health threat, contributing to severe gastrointestinal diseases and widespread foodborne illnesses. The virulence of S. Typhimurium is regulated by quorum sensing (QS) and the type III secretion system (T3SS). This study investigated the inhibitory effects and anti-QS activity of epigallocatechin gallate (EGCG), which is a bioactive ingredient found in green tea, on the virulence of S. Typhimurium. In vitro bacterial experiments demonstrated that EGCG inhibited the production of autoinducers, biofilm formation, and flagellar activity by downregulating the expression of AI-1, AI-2, Salmonella pathogenicity islands (SPI)-1, SPI-2, and genes related to flagella, fimbriae, and curli fibers. In a mouse model of S. Typhimurium-induced enteritis, EGCG considerably reduced intestinal colonization by S. Typhimurium and alleviated intestinal damage. In conclusion, EGCG protects the intestines of mice infected with S. Typhimurium by inhibiting QS-induced virulence gene expression, demonstrating its potential as a therapeutic agent for controlling S. Typhimurium infections.

Surveillance of travel-associated isolates elucidates the diversity of non-pandemic Vibrio cholerae.

Vibrio cholerae is a Gram-negative bacterium found in aquatic environments and is the aetiological agent of cholera, characterized by acute watery diarrhoea and severe dehydration. Cholera presents a significant global health burden of an estimated 1.3-5 million annual cases, with the current pandemic caused by a toxigenic lineage of the O1 El Tor biotype called seventh pandemic El Tor (7PET) that is still ongoing. Whilst it is known that non-7PET lineages can cause sporadic disease, little is known about the transmission of these non-epidemic lineages. Thirty-four V. cholerae isolates were obtained from travellers returning from Indonesia to Australia between 2005 and 2017. These were whole genome sequenced, placed into a global phylogenetic context with 883 isolates, and screened for known genes associated with antimicrobial resistance and virulence. This analysis revealed that 30 isolates fell within non-7PET lineages and four within the 7PET lineage. Both 7PET and non-7PET isolates carried genes for resistance to antibiotics that are commonly used in cholera treatment such as tetracyclines and fluoroquinolones. Diverse virulence factors were also present in non-7PET isolates, with two isolates notably carrying toxin-coregulated pilus genes, which are primarily responsible for intestinal colonization in 7PET V. cholerae. This study demonstrates the role of travel in long-range carriage of epidemic and non-epidemic lineages of V. cholerae, and how sentinel travel surveillance can enrich our knowledge of V. cholerae diversity, reveal new biology about the spread of diverse lineages with differing disease potential and illuminate disease presence in endemic regions with limited surveillance data.

Exploring the impact of sEH inhibition on intestinal cell differentiation and Colon Cancer: Insights from TPPU treatment

Inhibition of soluble epoxide hydrolase (sEH) appears to be promising for the treatment of many diseases. Studies have focused on the beneficial effects of epoxyeicosatrienoic acids (EETs), which are sEH substrates. However, our recent studies have shown that the sEH activity is crucial for the proper intestinal cell differentiation. In this recent study, we investigated the impact of TPPU, an inhibitor of sEH, on the colon cancer cell lines Caco2 and HT-29. We analysed the changes in the expression of the cytoskeletal protein ezrin and the phosphorylated protein kinase p38 (p-p38). Our results showed a decrease in ezrin expression in differentiated cells and an increase in p-p38 expression after TPPU treatment. Immunocytochemical staining revealed a higher staining intensity of p-p38 in the nuclei of HT-29 cells following TPPU treatment. Immunohistochemical staining was performed on human samples of normal colon tissue, grade 2 tumours, and embryonal/foetal tissues. The staining intensity of ezrin in tumours was reduced in the surface area compared to the crypts. Additionally, we observed the translocation of p-p38 expression from the cytoplasm to the nucleus during differentiation. The tumour samples exhibited higher levels of p-p38 in the cytoplasm, similar to normal undifferentiated tissue. To observe the disruption of the cytoskeleton after TPPU treatment, confocal microscopy was used. It was found that β-actin associated with ezrin forms clusters under the plasma membranes. All of these results are significant because sEH inhibitors are being tested in clinical trials, but they could cause an unexpected adverse effects.

Cyclic-di-GMP modulates lapA-mediated biofilm formation of Hafnia paralvei to enhance its intestinal colonization and injury

The formation of biofilm by pathogen promotes its colonization, posing significant threats to the environment and the health of humans and animals. The mechanism by which c-di-GMP regulates biofilm formation and its impact on pathogen colonization and intestinal injury has not been fully characterized. Here, we found that overexpressing the phosphodiesterases encoding gene adrB in Hafnia paralvei Z11 reduced c-di-GMP levels, leading to a decrease in outer membrane proteins (OMPs) content and the declining adhesion, as well as a lower level of biofilm formation. Conversely, overexpressing the OMPs-encoding gene lapA significantly enhanced adhesion and biofilm formation. Furthermore, overexpression of adrB exhibited a lower colonization ability in the loach intestine, whereas overexpression of lapA in strain Z11::pBBR1MCS-adrB significantly promoted its colonization in the loach intestine, and caused damage to intestinal barrier integrity, inducing host oxidative stress and the elevated expression level of inflammation-related genes. Thus, this study reveals that c-di-GMP regulates lapA-mediated biofilm formation of H. paralvei Z11, which promotes its intestinal colonization and damage to loach intestines, enhancing our understanding of pathogen-induced intestinal colonization and damage strategies.

Inhibition of intestinal inflammation and fibrosis by Scutellaria Baicalensis georgi and Boswellia serrata in human epithelial cells and fibroblasts.

Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, manifests with chronic intestinal inflammation and frequent sequential fibrosis. Current pharmacological therapies may show harmful side effects and are not useful for prevention or resolution of fibrosis. Thus, the use of alternative therapies is emerging as a novel useful approach. Previous results suggest that Scutellaria baicalensis Georgi (SBG) and Boswellia serrata (BS) display anti-inflammatory properties. The aim of this study was to investigate in intestinal epithelial cells and fibroblasts the anti-inflammatory and anti-fibrotic potential of SBG and BS, alone or in combination. Human colorectal adenocarcinoma cells (HT29), human intestinal epithelial cells (HIEC6) and human colon fibroblasts (CCD-18Co) were used. Cells were pretreated with SBG and BS and then exposed to pro-inflammatory and pro-fibrotic cytokines. SBG and BS extracts significantly decreased pro-inflammatory cytokine expression and improved epithelial restitution in HT29 and HIEC6 cells. Besides, fibrotic marker expression, including SNAIL, ACTA2, ZNF281, was strongly reduced. Colon myofibroblasts treated with SBG and BS showed a significant decrease of fibrotic markers as well. SBG and BS extracts significantly reduce inflammation and impair fibrosis in intestinal epithelial cells and colon myofibroblasts. No cooperative effect is observed.

Efficacy and safety of apraglutide in short bowel syndrome with intestinal failure and colon–in–continuity: A multicenter, open-label, metabolic balance study

BackgroundApraglutide is a novel long-acting GLP-2 analog in development for short bowel syndrome with intestinal failure (SBS-IF). This multicenter, open-label, phase 2 study in SBS-IF and colon-in-continuity (CiC) investigates the safety and efficacy of apraglutide. MethodsThis was a 52-week phase 2 metabolic balance study (MBS) in 9 adult patients with SBS-IF-CiC receiving once-weekly subcutaneous apraglutide injections. Safety was the primary endpoint. Secondary endpoints included changes in absorption parameters (MBS at baseline, after 4 weeks with stable parenteral support (PS), and 48 weeks), PS needs (48-week PS adjustment period based on monthly 48-hour fluid balances) and intestinal morphology and motility (static and cine MRI at baseline and 4, 24 and 48 weeks). ResultsPS volume decreased by -4702mL/week (-52%; p<0.001) at week 52. Seven patients (78%) achieved ≥1 day off PS at week 52. At 4 weeks, fecal output was reduced by 253 g/day (p=0.013). At 48 weeks, increases in wet weight absorption by 316 g/day (p=0.039), energy absorption by 1134 kJ/day (p=0.041) and carbohydrate absorption by 56.1 g/day (p= 0.024) were observed. Moreover, small bowel length increased from 29.7 to 40.7 cm (p=0.012), duodenal wall thickness increased by 0.8 mm (p=0.02) and motility in the proximal colon was reduced (p=0.031). A total of 127 adverse events was reported, which were mostly mild to moderate. ConclusionApraglutide had an acceptable safety profile and was associated with significant reductions in PS needs and days off PS, improvements in intestinal absorption, and structural and functional intestinal changes in patients with SBS-IF-CiC.ClinicalTrials.gov, Number NCT04964986

Improving the growth and intestinal colonization of Escherichia coli Nissle 1917 by strengthening its oligopeptides importation ability

Escherichia coli Nissle 1917 (EcN), the probiotic featured with well-established safety in different host, is emerging as a favored chassis for the construction of engineered probiotics for disease treatment. However, limited by the low intestinal colonization ability of EcN, repeated administration is required to maximize the health benefits of the EcN-derived engineered probiotics. Here, using fecal metabolites as "metabolites pool", we developed a metabolomic strategy to characterize the comprehensive metabolic profile of EcN. Compared with Prevotella copri DSM 18205 (P. copri), one of the dominant microbes in gut flora, EcN exhibited minor growth advantage under the fecal metabolites-containing condition for its lower metabolic capability towards fecal metabolites. Further study indicated that EcN lacked the ability to import the oligopeptides containing more than two amino acids. The shortage of oligopeptides-derived amino acids might limit the growth of EcN by restricting its purine metabolism. Assisted with the bioinformatic and qRT-PCR analyses, we identified a tripeptides-specific importer Pc-OPT in P. copri, which was mainly distributed in genera Prevotella and Bacteroides. Overexpression of Pc-OPT improved the tripeptides importation of EcN and promoted its growth and intestinal colonization. Notably, 16S rRNA gene amplicon sequencing results indicated that strengthening the oligopeptides importation ability of EcN might promote its intestinal colonization by adjusting the gut microbial composition. Our study reveals that the growth and intestinal colonization of EcN is limited by its insufficient oligopeptides importation and paves road for promoting the efficacy of the EcN-derived synthetic probiotics by improving their intestinal colonization ability.