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Pharmaceuticals can directly inhibit the growth of gut bacteria, but the degree to which such interactions manifest in complex community settings is an open question. Here, we compared the effects of 30 drugs on a 32-species synthetic community with their effects on each community member in isolation. While most individual drug-species interactions remained the same in the community context, communal behaviors emerged in 26% of all tested cases. Cross-protection during which drug-sensitive species were protected in community was 6 times more frequent than cross-sensitization, the converse phenomenon. Cross-protection decreased and cross-sensitization increased at higher drug concentrations, suggesting that the resilience of microbial communities can collapse when perturbations get stronger. By metabolically profiling drug-treated communities, we showed that both drug biotransformation and bioaccumulation contribute mechanistically to communal protection. As a proof of principle, we molecularly dissected a prominent case: species expressing specific nitroreductases degraded niclosamide, thereby protecting both themselves and sensitive community members., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Exposure to environmental pollutants and human microbiome composition are important predisposition factors for tumour development 1,2 . Similar to drug molecules, pollutants are typically metabolized in the body, which can change their carcinogenic potential and affect tissue distribution through altered toxicokinetics 3 . Although recent studies demonstrated that human-associated microorganisms can chemically convert a wide range of xenobiotics and influence the profile and tissue exposure of resulting metabolites 4,5 , the effect of microbial biotransformation on chemical-induced tumour development remains unclear. Here we show that the depletion of the gut microbiota affects the toxicokinetics of nitrosamines, which markedly reduces the development and severity of nitrosamine-induced urinary bladder cancer in mice 6,7 . We causally linked this carcinogen biotransformation to specific gut bacterial isolates in vitro and in vivo using individualized bacterial culture collections and gnotobiotic mouse models, respectively. We tested gut communities from different human donors to demonstrate that microbial carcinogen metabolism varies between individuals and we showed that this metabolic activity applies to structurally related nitrosamine carcinogens. Altogether, these results indicate that gut microbiota carcinogen metabolism may be a contributing factor for chemical-induced carcinogenesis, which could open avenues to target the microbiome for improved predisposition risk assessment and prevention of cancer., (© 2024. The Author(s).)

The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks 1-4 . Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues 5-9 . However, the systemic impact of the gut microbiome on the germline-and consequently on the F 1 offspring it gives rise to-is unexplored 10 . Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function., (© 2024. The Author(s).)

Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently 1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Surveillance of illegal use of growth promoters such as β 2 -agonists in food producing animals rely on the detection of drug residues by LC-MS/MS. Screening strategies focusing on indirect physiological responses following administration of active compounds are promising approaches to strengthen existing targeted methods and ensure food safety. A metabolomics analysis based on LC-HRMS was carried out on liver extracts from bulls experimentally treated with clenbuterol combined with dexamethasone (n = 8) to mimic a potential anabolic practice, and control animals (n = 8). Nicotinic acid and 5'-deoxy-5'-methylthioadenosine were identified as biomarkers of treatment. Ratio values of such markers to others of the same metabolic pathways (nicotinamide or methionine) were used to develop a classification model to assign animals as treated with clenbuterol or non-treated. The classification model was tested on an external validation set comprising 74 animals either treated with different anabolic compounds (β 2 -agonists, sexual steroids, corticosteroid), or non-treated, showing 100% sensitivity and specificity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The aim of this study was to profile plasma proteome responses in bulls experimentally treated with dexamethasone at anabolic dosage. Illicit use of active substances in animal husbandry remains a matter of concern in Europe. Corticosteroids are probably one of the most widespread growth promoter family illegally used in beef cattle and veal calves. Testing for corticosteroids relies on detection of drug residues or their metabolites in biological fluids or tissues. Their indirect detection by mapping altered physiological parameters may overcome limits linked to route of administration, dosage, biotransformation and elimination kinetics that can lower residual drug concentration, hampering official controls. A set of 11 proteins proposed in literature as potential markers of anabolic treatments with dexamethasone, was quantified in bovine plasma by targeted proteomics based on liquid chromatography-high resolution tandem mass spectrometry. Among investigated proteins, sex hormone-binding globulin (SHBG), histidine-rich glycoprotein (HRG) and paraoxonase-1 (PON1) were found to be biomarkers of treatment. To investigate further such biomarkers, an additional group of veal calves was experimentally treated with dexamethasone at anabolic. These animals also demonstrated a significant alteration in SHBG, HRG and PON1 concentration, suggesting that quantification of plasma markers have the potential to detect animals illegally exposed to dexamethasone., (© 2021 Wiley-VCH GmbH.)

Salmonella enterica subsp. enterica serovar Napoli (S. Napoli) ranks among the top serovars causing human infections in Italy, although not common in other European countries. Isolates are generally pan-susceptible or resistant to aminoglycosides only, however data on antimicrobial resistance genes in strains of S. Napoli are limited. Recently an isolate encoding resistance to third generation cephalosporins was reported. This study aimed to characterize plasmid-encoded cephalosporin resistance due to the bla CTX-M-15 gene in a human S. Napoli isolate in Italy, and to investigate plasmid stability over time. S. Napoli 16/174478 was confirmed to be ESBL-producing. The bla CTX-M-15 gene was shown to be located on an IncI1α plasmid of 90,272 bp (50.03 GC%) encoding for 107 coding sequences (CDS). The plasmid was successfully transferred by conjugation to an E. coli 1816 recipient strain (conjugation frequency 3.9 × 10 -2 transconjugants per donor). Transconjugants were confirmed to carry the IncI1α plasmid, and to be ESBL-producing strains as well. Moreover, transconjugant colonies maintained the plasmid for up to 10 passages. The identification of S. Napoli isolates able to produce ESBLs is of great concern, as this pathogen is frequently associated with invasive infections and a higher risk of bacteraemia, and its reservoir has not yet been clearly identified., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Campylobacter is the most frequent foodborne zoonotic bacteria worldwide, with chicken meat being overwhelmingly the most important reservoir for human infections. Control measures implemented at the farm level (i.e., biosecurity or vaccination), which have been successfully applied to limit other pathogens, such as Salmonella , have not been effective in reducing Campylobacter occurrence. Thus, new approaches are needed to fully understand the ecological interactions of Campylobacter with host animals to effectively comprehend its epidemiology. The objective of this study was to analyse longitudinally the gut microbiota composition of Campylobacter -infected and non-infected farms to identify any difference that could potentially be indicative of gut colonization by Campylobacter spp. Differences in the colonization rate and timing were observed at the farms that became positive for Campylobacter jejuni over the investigated time points, even though in positive tests, the occurrence of Campylobacter jejuni gut colonization was not observed before the second week of the life of the birds. Significant differences were observed in the abundances of specific bacterial taxa between the microbiota of individuals belonging to farms that became Campylobacter positive during the study and those who remained negative with particular reference to Bacteroidales and Clostridiales , respectively. Moreover, Campylobacter colonization dramatically influenced the microbiota richness, although to a different extent depending on the infection timing. Finally, a key role of Faecalibacterium and Lactobacillus genera on the Campylobacter microbial network was observed. Understanding the ecology of the Campylobacter interaction with host microbiota during infection could support novel approaches for broiler microbial barrier restoration. Therefore, evidence obtained through this study can be used to identify options to reduce the incidence of infection at a primary production level based on the targeted influence of the intestinal microbiota, thus helping develop new control strategies in order to mitigate the risk of human exposure to Campylobacter by chicken meat consumption.

Background: Surgical sterilization is the most effective method of contraception for dogs. It also prevents pyometra and reduces the risk of mammary tumour development. However, this procedure also has negative effects, such as urinary incontinence. Steroid hormone deprivation following gonadectomy could also affect canine vaginal mucosa conditions and the microbial community colonizing the vaginal tract. This hypothesis was tested by comparing the vaginal cytology and microbial community of two groups of bitches, including 11 in anoestrus and 10 sterilized bitches (post-pubertal sterilization in the last 4 years). Bacteria were identified through metataxonomic analysis, amplifying the V3-V4 regions of 16S rRNA gene, and culturing methods., Results: Vaginal mucosa cytology was suggestive of dystrophic conditions in sterilized bitches, whereas a typical anoestrus pattern with parabasal and intermediate cells was appreciable in anoestrous animals. Metataxonomic analysis revealed large inter-individual variability. Salmonella, Mycoplasma and Staphylococcus were present in moderate quantities in almost all the samples in both groups. Mollicutes (class level) and Tenericutes (phylum level) were commonly present in moderate quantities in anoestrus samples, whereas these microbes were present at high levels in a single sample from the sterilized group. Based on culturing, a higher number of different species were isolated from the anoestrous bitches, and Mycoplasma canis was exclusively identified in an anoestrous bitch. Staphylococcus spp. was the most frequently isolated genus in both groups, followed by Streptococcus spp., and, among gram-negative bacteria, Escherichia spp. and Haemophilus spp. A comparison of the numbers of the most frequently isolated genera of bacteria from vaginal cultures of bitches revealed that Pasteurella and Proteus were the most frequently identified in sterilized animals based on metataxonomic analysis (p-value = 0.0497 and 0.0382, respectively), whereas Streptococcus was significantly and most frequently isolated from anoestrous bitches using culture methods (p value = 0.0436)., Conclusions: In this preliminary investigation, no global patterns of the vaginal bacteria community were noted that characterized the condition of the bitches; however, cytology suggested local modifications. Sterilization after puberty caused minimal alterations in the vaginal microbial community of bitches within 4 years after surgery.

Background: Salmonella enterica subsp. enterica serovar Napoli (S. Napoli) is among the top serovars causing human infections in Italy, although it is relatively uncommon in other European countries; it is mainly isolated from humans and the environment, but neither the reservoir nor its route of infection are clearly defined. This serovar is characterized by high genomic diversity, and molecular evidences revealed important similarities with typhoidal serovars., Results: 179 S. Napoli genomes as well as 239 genomes of typhoidal and non-typhoidal serovars were analyzed in a comparative genomic study. Phylogenetic analysis and draft genome characterization in terms of Multi Locus Sequence Typing (MLST), plasmid replicons, Salmonella Pathogenicity Islands (SPIs), antimicrobial resistance genes (ARGs), phages, biocide and metal-tolerance genes confirm the high genetic variability of S. Napoli, also revealing a within-serovar phylogenetic structure more complex than previously known. Our work also confirms genomic similarity of S. Napoli to typhoidal serovars (S. Typhi and S. Paratyphi A), with S. Napoli samples clustering primarily according to ST, each being characterized by specific genomic traits. Moreover, two major subclades of S. Napoli can be clearly identified, with ST-474 being biphyletic. All STs span among isolation sources and years of isolation, highlighting the challenge this serovar poses to define its epidemiology and evolution. Altogether, S. Napoli strains carry less SPIs and less ARGs than other non-typhoidal serovars and seldom acquire plasmids. However, we here report the second case of an extended-spectrum β-lactamases (ESBLs) producing S. Napoli strain and the first cases of multidrug resistant (MDR) S. Napoli strains, all isolated from humans., Conclusions: Our results provide evidence of genomic plasticity of S. Napoli, highlighting genomic similarity with typhoidal serovars and genomic features typical of non-typhoidal serovars, supporting the possibility of survival in different niches, both enteric and non-enteric. Presence of horizontally acquired ARGs and MDR profiles rises concerns regarding possible selective pressure exerted by human environment on this pathogen.