Bacteroides thetaiotaomicron Ameliorates Colon Inflammation in Preclinical Models of Crohn's Disease

SUPPLEMENTARY DATA: Supplementary data is available at Inflammatory Bowel Diseases onlinePeer reviewedPublisher PD

Bifidobacterium breve MRx0004 protects against airway inflammation in a severe asthma model by suppressing both neutrophil and eosinophil lung infiltration

All authors were employees of (or in the case of MID, seconded full-time to) 4D Pharma Research Ltd while engaged in the research project. This work was supported by funding provided by 4D Pharma PLC. 4D Pharma Research Ltd owns a family of patent applications which are pending internationally which are derived from International Patent Publication No. WO2016/203223 which protect the treatment of severe asthma using MRx0004. George Grant, Angela Patterson, Imke Mulder, Seanin McCluskey and Emma Raftis are named as inventors for this patent family. The authors declare no other competing interests.Peer reviewedPublisher PD

In vitro Characterization of Gut Microbiota-Derived Bacterial Strains With Neuroprotective Properties

Acknowledgments The authors are grateful to Dr. Nicole Reichardt and the 4D Pharma Isolation Team for their technical assistance with bacterial culture. Funding This work was privately funded by 4D Pharma PLC. The authors of the study, who are employees of (or in the case of MID, are funded by) 4D Pharma Research Ltd., a wholly owned subsidiary of the funder, were responsible for the design and execution of the study, as well as the analysis of the results obtained. Author Contributions In vitro experiments: AE, SA, and AB designed the experiments; SA, PF, NV, MG, SB, GB-A, and MD performed the majority of the in vitro experiments; SR, HD, and AB validated, performed, and analyzed the microbiological-related data output; AE coordinated and managed the research project; AE, SA, PF, and AB analyzed the data. IM oversaw the overall research plan. AE wrote the manuscript with the assistance of SA and AB. All authors have read and commented on the manuscript and have approved the final version of the manuscript. Data Availability: 16S gene sequences for MRx0005 and MRx0029 are disclosed in International Patent Publication Nos. WO2018/229189 and WO2018/229216, respectively, filed by 4D Pharma Research Ltd. The data supporting the findings in this paper are available within the article and its Supplementary Information Files.Peer reviewedPublisher PD

Restricting Microbial Exposure in Early Life Negates the Immune Benefits Associated with Gut Colonization in Environments of High Microbial Diversity

Background: Acquisition of the intestinal microbiota in early life corresponds with the development of the mucosal immune system. Recent work on caesarean-delivered infants revealed that early microbial composition is influenced by birthing method and environment. Furthermore, we have confirmed that early-life environment strongly influences both the adult gut microbiota and development of the gut immune system. Here, we address the impact of limiting microbial exposure after initial colonization on the development of adult gut immunity. Methodology/Principal Findings: Piglets were born in indoor or outdoor rearing units, allowing natural colonization in the immediate period after birth, prior to transfer to high-health status isolators. Strikingly, gut closure and morphological development were strongly affected by isolator-rearing, independent of indoor or outdoor origins of piglets. Isolator-reared animals showed extensive vacuolation and disorganization of the gut epithelium, inferring that normal gut closure requires maturation factors present in maternal milk. Although morphological maturation and gut closure were delayed in isolatorreared animals, these hard-wired events occurred later in development. Type I IFN, IL-22, IL-23 and Th17 pathways were increased in indoor-isolator compared to outdoor-isolator animals during early life, indicating greater immune activation in pigs originating from indoor environments reflecting differences in the early microbiota. This difference was less apparent later in development due to enhanced immune activation and convergence of the microbiota in all isolator-reared animals. This correlated with elevation of Type I IFN pathways in both groups, although T cell pathways were still more affected in indoor-reared animals. Conclusions/Significance: Environmental factors, in particular microbial exposure, influence expression of a large number of immune-related genes. However, the homeostatic effects of microbial colonization in outdoor environments require sustained microbial exposure throughout development. Gut development in high-hygiene environments negatively impacts on normal succession of the gut microbiota and promotes innate immune activation which may impair immune homeostasis