Antibiotic use differentially affects the risk of anti-drug antibody formation during anti-TNFα therapy in inflammatory bowel disease patients: a report from the epi-IIRN.

OBJECTIVE: Anti-drug antibodies (ADA) to anti-tumour necrosis factor (anti-TNF) therapy drive treatment loss of response. An association between intestinal microbial composition and response to anti-TNF therapy was noted. We therefore aimed to assess the implications of antibiotic treatments on ADA formation in patients with inflammatory bowel disease (IBD). DESIGN: We analysed data from the epi-IIRN (epidemiology group of the Israeli IBD research nucleus), a nationwide registry of all patients with IBD in Israel. We included all patients treated with anti-TNF who had available ADA levels. Survival analysis with drug use as time varying covariates were used to assess the association between antibiotic use and ADA development. Next, specific pathogen and germ-free C57BL mice were treated with respective antibiotics and challenged with infliximab. ADA were assessed after 14 days. RESULTS: Among 1946 eligible patients, with a median follow-up of 651 days from initiation of therapy, 363 had positive ADA. Cox proportional hazard model demonstrated an increased risk of ADA development in patients who used cephalosporins (HR=1.97, 95% CI 1.58 to 2.44), or penicillins with ß-lactamase inhibitors (penicillin-BLI, HR=1.4, 95% CI 1.13 to 1.74), whereas a reduced risk was noted in patients treated with macrolides (HR=0.38, 95% CI 0.16 to 0.86) or fluoroquinolones (HR=0.20, 95% CI 0.12 to 0.35). In mice exposed to infliximab, significantly increased ADA production was observed in cephalosporin as compared with macrolide pretreated mice. Germ-free mice produced no ADA. CONCLUSION: ADA production is associated with the microbial composition. The risk of ADA development during anti-TNF therapy can possibly be reduced by avoidance of cephalosporins and penicillin-BLIs, or by treatment with fluoroquinolones or macrolides.

Murine Genetic Background Has a Stronger Impact on the Composition of the Gut Microbiota than Maternal Inoculation or Exposure to Unlike Exogenous Microbiota.

The gut microbiota is a complex ecosystem, affected by both environmental factors and host genetics. Here, we aim at uncovering the bacterial taxa whose gut persistence is controlled by host genetic variation. We used a murine model based on inbred lines BALB/c and C57BL/6J and their F1 reciprocal hybrids (♀C57BL/6J × â™‚BALB/c; ♀BALB/c × â™‚C57BL/6J). To guarantee genetic similarity of F1 offspring, including the sex chromosomes, we used only female mice. Based on 16S rRNA gene sequencing, we found that the genetically different inbred lines present different microbiota, whereas their genetically identical F1 reciprocal hybrids presented similar microbiota. Moreover, the F1 microbial composition differed from that of both parental lines. Twelve taxa were shown to have genetically controlled gut persistence, while none were found to show maternal effects. Nine of these taxa were dominantly inherited by the C57BL/6J line. Cohousing of the parental inbred lines resulted in a temporary and minor shift in microbiota composition, which returned back to the former microbial composition following separation, indicating that each line tends to maintain a unique bacterial signature reflecting the line. Taken together, our findings indicate that mouse genetics has an effect on the microbial composition in the gut, which is greater than maternal effect and continuous exposure to different microbiota of the alternative line. Uncovering the bacterial taxa associated with host genetics and understanding their role in the gut ecosystem could lead to the development of genetically oriented probiotic products, as part of the personalized medicine approach.IMPORTANCE The gut microbiota play important roles for their host. The link between host genetics and their microbial composition has received increasing interest. Using a unique reciprocal cross model, generating genetically similar F1 hybrids with different maternal inoculation, we demonstrate the inheritance of gut persistence of 12 bacterial taxa. No taxa identified as maternally transmitted. Moreover, cohabitation of two genetically different inbred lines did not dramatically affect the microbiota composition. Taken together, our results demonstrate the importance of the genetic effect over maternal inoculation or effect of exposure to unlike exogenous microbiota. These findings may lead to the development of personalized probiotic products, specifically designed according to the genetic makeup.

Next-generation prebiotics: Maillard-conjugates of 2'-fucosyllactose and lactoferrin hydrolysates beneficially modulate gut microbiome composition and health promoting activity in a murine model.

Current prebiotics are predominantly carbohydrates. However, great competition exists among gut microbes for the scarce protein in the colon, as most consumed protein is digested and absorbed in the small intestine. Herein we evaluated in-vivo novel next-generation prebiotics: protein-containing-prebiotics, for selectively-targeted delivery of protein to colonic probiotics, to boost their growth. This system is based on micellar-particles, composed of Maillard-glycoconjugates of 2'-Fucosyllactose (2'-FL, human-milk-oligosaccharide) shell, engulfing lactoferrin peptic-then-tryptic hydrolysate (LFH) core. This core-shell structure lowers protein-core digestibility, while the prebiotic glycans are hypothesized to serve as molecular-recognition ligands for selectively targeting probiotics. To study the efficacy of this novel prebiotic, we fed C57BL/6JRccHsd mice with either 2'-FL-LFH Maillard-glycoconjugates, unconjugated components (control), or saline (blank). Administration of 2'-FL-LFH significantly increased the levels of short-chain-fatty-acids (SCFAs)-producing bacterial families (Ruminococcaceae, Lachnospiraceae) and genus (Odoribacter) and the production of the health-related metabolites, SCFAs, compared to the unconjugated components and to saline. The SCFAs-producing genus Prevotella significantly increased upon 2'-FL-LFH consumption, compared to only moderate increase in the unconjugated components. Interestingly, the plasma-levels of inflammation-inducing lipopolysaccharides (LPS), which indicate increased gut-permeability, were significantly lower in the 2'-FL-LFH group compared to the unconjugated-components and the saline groups. We found that Maillard-glycoconjugates of 2'-FL-LFH can serve as novel protein-containing prebiotics, beneficially modulating gut microbial composition and its metabolic activity, thereby contributing to host health more effectively than the conventional carbohydrate-only prebiotics.

The rise of the sourdough: Genome-scale metabolic modeling-based approach to design sourdough starter communities with tailored-made properties.

Sourdough starters harbor microbial consortia that benefit the final product's aroma and volume. The complex nature of these spontaneously developed communities raises challenges in predicting the fermentation phenotypes. Herein, we demonstrated for the first time in this field the potential of genome-scale metabolic modeling (GEMs) in the study of sourdough microbial communities. Broad in-silico modeling of microbial growth was applied on communities composed of yeast (Saccharomyces cerevisiae) and different Lactic Acid Bacteria (LAB) species, which mainly predominate in sourdough starters. Simulations of model-represented communities associated specific bacterial compositions with sourdough phenotypes. Based on ranking the phenotypic performances of different combinations, Pediococcus spp. - Lb. sakei group members were predicted to have an optimal effect considering the increase in S. cerevisiae growth abilities and overall CO2 secretion rates. Flux Balance Analysis (FBA) revealed mutual relationships between the Pediococcus spp. - Lb. sakei group members and S. cerevisiae through bidirectional nutrient dependencies, and further underlined that these bacteria compete with the yeast over nutrients to a lesser extent than the rest LAB species. Volatile compounds (VOCs) production was further modeled, identifying species-specific and community-related VOCs production profiles. The in-silico models' predictions were validated by experimentally building synthetic sourdough communities and assessing the fermentation phenotypes. The Pediococcus spp. - Lb. sakei group was indeed associated with increased yeast cell counts and fermentation rates, demonstrating a 25 % increase in the average leavening rates during the first 10 fermentation hours compared to communities with a lower representation of these group members. Overall, these results provide a possible novel strategy towards the de-novo design of sourdough starter communities with tailored-made characterizations, including a shortened leavening period.

Soybean Oil Modulates the Gut Microbiota Associated with Atherogenic Biomarkers.

During the last few decades there has been a staggering rise in human consumption of soybean-oil (SO). The microbiome and specific taxa composing it are dramatically affected by diet; specifically, by high-fat diets. Increasing evidence indicates the association between dysbiosis and health or disease state, including cardiovascular diseases (CVD) and atherosclerosis pathogenesis in human and animal models. To investigate the effects of high SO intake, C57BL/6 mice were orally supplemented with SO-based emulsion (SOE) for one month, followed by analyses of atherosclerosis-related biomarkers and microbiota profiling by 16S rRNA gene sequencing of fecal DNA. SOE-supplementation caused compositional changes to 64 taxa, including enrichment in Bacteroidetes, Mucispirillum, Prevotella and Ruminococcus, and decreased Firmicutes. These changes were previously associated with atherosclerosis in numerous studies. Among the shifted taxa, 40 significantly correlated with at least one atherosclerosis-related biomarker (FDR < 0.05), while 13 taxa positively correlated with the average of all biomarkers. These microbial alterations also caused a microbial-derived metabolic-pathways shift, including enrichment in different amino-acid metabolic-pathways known to be implicated in CVD. In conclusion, our results demonstrate dysbiosis following SOE supplementation associated with atherosclerosis-related biomarkers. These findings point to the microbiome as a possible mediator to CVD, and it may be implemented into non-invasive diagnostic tools or as potential therapeutic strategies.