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Inflammatory bowel diseases (IBDs) are a group of chronic gastrointestinal inflammatory diseases with unknown etiology. There is a combination of well documented factors in their pathogenesis, including intestinal microbiota dysbiosis. The symbiotic microbiota plays important functions in the host, and the loss of beneficial microbes could favor the expansion of microbial pathobionts. In particular, the bloom of potentially harmful Proteobacteria, especially Enterobacteriaceae, has been described as enhancing the inflammatory response, as observed in IBDs. Herein, we seek to investigate the contribution of Enterobacteriaceae to IBD pathogenesis whilst considering the continuous expansion of the literature and data. Despite the mechanism of their expansion still remaining unclear, their expansion could be correlated with the increase in nitrate and oxygen levels in the inflamed gut and with the bile acid dysmetabolism described in IBD patients. Furthermore, in several Enterobacteriaceae studies conducted at a species level, it has been suggested that some adherent-invasive Escherichia coli (AIEC) play an important role in IBD pathogenesis. Overall, this review highlights the pivotal role played by Enterobacteriaceae in gut dysbiosis associated with IBD pathogenesis and progression.

Antimicrobial Blue Light (aBL) can be used to control the growth of pathogens in several applicative fields, from sanitization of inert surfaces to human skin treatment and from industry to food. Though the mechanism of action is still unknown, it has been hypothesized that specific wavelengths can activate potential endogenous photosensitizers in microbial cytoplasm and/or envelope. In turn, this photooxidative stress could induce inactivation of macromolecules resulting in bacterial killing. In this work, we investigated the effect of radiometric parameters of light at 410 nm on Escherichia coli K-12 MG1655, a strain rather tolerant to blue light irradiation. Interestingly, by changing the radiometric parameters of aBL protocol, different rates of killing were observed. Irradiation at 100 J/cm2 caused a variable antimicrobial effect depending on the irradiance values. We observed an “irradiance effect”: namely, at higher irradiance values, the inhibitory effect is reduced. On the other hand, at increasing fluences the bactericidal rate increases. In addition, the shift from continuous to pulsed light could enhance the antimicrobial activity of protocols using higher irradiance values. Taken together, these results underline the importance of defining radiometric parameters to ensure the efficacy of aBL treatments and emphasize the importance of further research into the aBL mechanism.

The relevance of veterinary reservoirs extends into food production, as illustrated byHabib et al., who reported widespread MDR and toxigenic methicillin-resistant Staphylococcus aureus (MRSA) strains in retail meat and produce in the United Arab Emirates, emphasizing the One Health implications of AMR and the potential for community exposure. [...]longitudinal studies, such as that fromZhu et al., can provide an essential perspective to enhance our understanding of AMR evolution and population dynamics. The studies demonstrate that resistance emerges through adaptation to intracellular lifestyle and diverse genetic mechanisms, including plasmid-mediated gene acquisition, point mutations, efflux operons, and genome-scale rearrangements.

Efflux pumps of the resistance-nodulation-cell-division (RND) family increase antibiotic resistance in many bacterial pathogens, representing candidate targets for the development of antibiotic adjuvants. RND pumps have also been proposed to contribute to bacterial infection, implying that efflux pump inhibitors (EPIs) could also act as anti-virulence drugs. Nevertheless, EPIs are usually investigated only for their properties as antibiotic adjuvants, while their potential anti-virulence activity is seldom taken into account. In this study it is shown that RND efflux pumps contribute to Pseudomonas aeruginosa PAO1 pathogenicity in an insect model of infection, and that the well-characterized EPI Phe-Arg-β-naphthylamide (PAβN) is able to reduce in vivo virulence of the P . aeruginosa PAO1 laboratory strain, as well as of clinical isolates. The production of quorum sensing (QS) molecules and of QS-dependent virulence phenotypes is differentially affected by PAβN, depending on the strain. Transcriptomic and phenotypic analyses showed that the protection exerted by PAβN from P . aeruginosa PAO1 infection in vivo correlates with the down-regulation of key virulence genes ( e . g . genes involved in iron and phosphate starvation). Since PAβN impacts P . aeruginosa virulence, anti-virulence properties of EPIs are worthy to be explored, taking into account possible strain-specificity of their activity.

Ulcerative colitis (UC) is a multifactorial chronic inflammatory bowel disease (IBD) that affects the large intestine with superficial mucosal inflammation. A dysbiotic gut microbial profile has been associated with UC. Our study aimed to characterize the UC gut bacterial, fungal, and metabolic fingerprints by omic approaches. The 16S rRNA- and ITS2-based metataxonomics and gas chromatography-mass spectrometry/solid phase microextraction (GC-MS/SPME) metabolomic analysis were performed on stool samples of 53 UC patients and 37 healthy subjects (CTRL). Univariate and multivariate approaches were applied to separated and integrated omic data, to define microbiota, mycobiota, and metabolic signatures in UC. The interaction between gut bacteria and fungi was investigated by network analysis. In the UC cohort, we reported the increase of , , Enterobacteriaceae, TM7-3, , , , , , , Gemellaceae, and phenylethyl alcohol; and we also reported the decrease of ; Ruminococcaceae; ; ; ; ; ; ; ; ; ; hexadecane; cyclopentadecane; 5-hepten-2-ol, 6 methyl; 3-carene; caryophyllene; p-Cresol; 2-butenal; indole, 3-methyl-; 6-methyl-3,5-heptadiene-2-one; 5-octadecene; and 5-hepten-2-one, 6 methyl. The integration of the multi-omic data confirmed the presence of a distinctive bacterial, fungal, and metabolic fingerprint in UC gut microbiota. Moreover, the network analysis highlighted bacterial and fungal synergistic and/or divergent interkingdom interactions. In this study, we identified intestinal bacterial, fungal, and metabolic UC-associated biomarkers. Furthermore, evidence on the relationships between bacterial and fungal ecosystems provides a comprehensive perspective on intestinal dysbiosis and ecological interactions between microorganisms in the framework of UC.

Background Inflammatory bowel diseases are chronic disabling conditions with a complex and multifactorial etiology, still incompletely understood. OCTN1, an organic cation transporter, could have a role in modulating the inflammatory response, and some genetic polymorphisms of this molecule have been associated with increased risk of inflammatory bowel diseases. Until now, limited information exists on its potential in predicting/modulating patient’s response to therapies. The aim of this study was to evaluate the role of OCTN1 in modifying gut microbiota and mucosal immunity in response to infliximab therapy in murine colitis. Methods A dextran sodium sulphate model of colitis was used to assess the clinical efficacy of infliximab administered intravenously in ocnt1 gene knockout mice and their C57BL/6 controls. Stool, colon, and mesenteric lymph node samples were collected to evaluate differences in gut microbiota composition, histology, and T cell populations, respectively. Results Octn1-/- influences the microbiota profile and is associated with a worse dysbiosis in mice with colitis. Infliximab treatment attenuates colitis-associated dysbiosis, with an increase of bacterial richness and evenness in both strains. In comparison with wild type, octn1-/- mice have milder disease and a higher baseline percentage of Treg, Tmemory, Th2 and Th17 cells. Conclusions Our data support the murine model to study OCTN1 genetic contribution to inflammatory bowel diseases. This could be the first step towards the recognition of this membrane transporter as a biomarker in inflammatory conditions and a predictor of response to therapies. Lay Summary In this article, we evaluated the role of OCTN1, an organic cation transporter, in modifying gut microbiota and immune T cell populations, as well as its effects on experimental colitis and the response to infliximab treatment.

In Crohn’s disease (CD) patients, the adherent-invasive Escherichia coli (AIEC) pathovar contributes to the chronic inflammation typical of the disease via its ability to invade gut epithelial cells and to survive in macrophages. We show that, in the AIEC strain LF82, inactivation of the pyrD gene, encoding dihydroorotate dehydrogenase (DHOD), an enzyme of the de novo pyrimidine biosynthetic pathway, completely abolished its ability of to grow in a macrophage environment-mimicking culture medium. In addition, pyrD inactivation reduced flagellar motility and strongly affected biofilm formation by downregulating transcription of both type 1 fimbriae and curli subunit genes. Thus, the pyrD gene appears to be essential for several cellular processes involved in AIEC virulence. Interestingly, vidofludimus (VF), a DHOD inhibitor, has been proposed as an effective drug in CD treatment. Despite displaying a potentially similar binding mode for both human and E. coli DHOD in computational molecular docking experiments, VF showed no activity on either growth or virulence-related processes in LF82. Altogether, our results suggest that the crucial role played by the pyrD gene in AIEC virulence, and the presence of structural differences between E. coli and human DHOD allowing for the design of specific inhibitors, make E. coli DHOD a promising target for therapeutical strategies aiming at counteracting chronic inflammation in CD by acting selectively on its bacterial triggers.

Abstract Background Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis, often associated with inflammatory bowel diseases. Recent evidence ascribes, together with immunologic and environmental components, a significant role to the intestinal microbiota or its molecules in the PSC pathogenesis. Methods By metagenomic sequencing of 16S rRNA and ITS2 loci, we describe the fecal microbiota and mycobiota of 26 pediatric patients affected by PSC and concomitant ulcerative colitis (PSC-UC), 27 patients without PSC but with UC (UC), and 26 healthy subjects (CTRLs). Results Compared with CTRL, the bacterial and fungal gut dysbiosis was evident for both PSC-UC and UC groups; in particular, Streptococcus, Saccharomyces, Sporobolomyces, Tilletiopsis, and Debaryomyces appeared increased in PSC-UC, whereas Klebsiella, Haemophilus, Enterococcus Collinsella, Piptoporus, Candida, and Hyphodontia in UC. In both patient groups, Akkermansia, Bacteroides, Parabacteroides, Oscillospira, Meyerozyma and Malassezia were decreased. Co-occurrence analysis evidenced the lowest number of nodes and edges for fungi networks compared with bacteria. Finally, we identified a specific patient profile, based on liver function tests, bacterial and fungal signatures, that is able to distinguish PSC-UC from UC patients. Conclusions We describe the gut microbiota and mycobiota dysbiosis associated to PSC-UC disease. Our results evidenced a gut imbalance, with the reduction of gut commensal microorganisms with stated anti-inflammatory properties (ie, Akkermansia, Bacteroides, Parabacteroides, Oscillospira, Meyerozyma, and Malassezia) and the increase of pathobionts (ie, Streptococcus, Saccharomyces, and Debaryomyces) that could be involved in PSC progression. Altogether, these events may concur in the pathophysiology of PSC in the framework of UC. Lay Summary In this study, we report the gut microbiota and mycobiota dysbiosis in pediatric patients affected by primary sclerosing cholangitis (PSC) associated with ulcerative colitis (UC), with an increase in pro-inflammatory pathobionts and a reduction in anti-inflammatory commensals.

Objectives: Biofilm increases bacterial antibiotic tolerance, posing a challenge for treating biofilm-associated infections in clinical settings. 5-fluorocytosine (5-FC), an FDA-approved antifungal and antitumor drug, has been shown to inhibit virulence factor production and biofilm formation in Gram-negative bacteria. This work aims to determine whether 5-FC antivirulence and antibiofilm activity are preserved in clinical E. coli isolates and to test possible synergies with antibiotics in treating preformed biofilm. Methods: 5-FC ability to inhibit biofilm formation, disrupt mature biofilm, and modulate virulence determinants was tested on uropathogenic E. coli (UPEC) clinical strains using the Crystal Violet-based biofilm adhesion and minimum biofilm eradication concentration assays. Gene expression was measured by RT-qPCR. The effect on bacterial viability within preformed biofilm was monitored using fluorescein diacetate and by determining colony-forming units in biofilm treated with or without 5-FC and specific antibiotics. Bladder epithelial cell cultures were used to assess the effect of 5-FC on UPEC adherence and cytotoxicity. Results: 5-FC inhibited biofilm formation in all tested UPEC strains. Gene expression analysis suggested that 5-FC concurrently inhibits the expression of genes encoding curli fibers, a major adhesion factor in E. coli, as well as other virulence determinants such as secreted toxins and type I and P fimbriae. Accordingly, 5-FC reduced UPEC adherence to epithelial cells and promoted host cell survival. Although 5-FC could not disrupt preformed biofilm, combining 5-FC with β-lactams drastically reduced the viability of biofilm-resident bacteria. Conclusions: 5-FC shows antibiofilm and antivirulence activity against uropathogenic E. coli strains by reducing the expression of several virulence factors and the overall UPEC pathogenic potential. In combination with β-lactams, 5-FC eradicates bacteria within mature biofilms, which are known to be highly refractory to antibiotic treatment. Our data suggest that 5-FC is an excellent candidate for preventing and treating bacterial infections associated with recalcitrant biofilms.Competing Interest StatementThe authors have declared no competing interest.

Obesity, whose prevalence is pandemic and continuing to increase, is a major preventable and modifiable risk factor for diabetes and cardiovascular diseases, as well as for cancer. Furthermore, epidemiological studies have shown that obesity is a negative independent prognostic factor for several oncological outcomes, including overall and cancer-specific survival, for several site-specific cancers as well as for all cancers combined. Yet, a recently growing body of evidence suggests that sometimes overweight and obesity may associate with better outcomes, and that immunotherapy may show improved response among obese patients compared with patients with a normal weight. The so-called ‘obesity paradox’ has been reported in several advanced cancer as well as in other diseases, albeit the mechanisms behind this unexpected relationship are still not clear. Aim of this review is to explore the expected as well as the paradoxical relationship between obesity and cancer prognosis, with a particular emphasis on the effects of cancer therapies in obese people.