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Background: The welfare of farmed fish is influenced by numerous environmental and management factors. Fish skin is an important site for immunity and a major route by which infections are acquired. The objective of this study was to characterize bacterial composition variability on skin of healthy, diseased and recovered Gilthead Seabream (Sparus aurata) and Barramundi (Lates calcarifer). S. aurata, which are highly sensitive to gram-negative bacteria, were challenged with Vibrio harveyi. In addition, and to provide a wider range of infections, both fish species (S. aurata and L. calcarifer ) were infected with gram-positive Streptococcus iniae, to compare the response of the highly sensitive L. calcarifer to that of the more resistant S. aurata. All experiments also compared microbial communities found on skin of fish reared in UV (a general practice used in aquaculture) and non-UV treated water tanks. Results: Skin swab samples were taken from different areas of the fish (lateral lines, abdomen and gills) prior to controlled infection, and 24, 48 and 72 hours, 5 days, one week and 1 month post-infection. Fish skin microbial communities were determined using Illumina iSeq100 16S rDNA for bacterial sequencing. The results showed that naturally present bacterial composition is similar on all sampled fish skin sites prior to infection, but the controlled infections (T1 24 h post infection) altered the bacterial communities found on fish skin. Moreover, when the naturally occurring skin microbiome did not quickly recover, fish mortality was common following T1 (24 h post infection). We further confirmed the differences in bacterial communities found on skin and in the water of fish reared in non-UV and UV treated water under healthy and diseased conditions. Conclusions: Our experimental findings shed light on the fish skin microbiome in relation to fish survival (in diseased and healthy conditions). The results can be harnessed to provide management tools for commercial fish farmers; predicting and preventing fish diseases can increase fish health and welfare, and enhance commercial fish yields.

The bacterial community that colonizes the human face imparts physiochemical and physiological effects on the facial skin. These skin-microbe interactions impact dermatological, cosmetic and skincare applications due to the centrality of the human face in daily interactions. However, fine-scale characterization of the human face skin microbiome is lacking. Using 16S rRNA sequencing and 3D cartography, this study plotted and characterized the facial skin microbiome in high- definition, based on 1,649 samples from 12 individuals. Analysis yielded a number of novel insights, including that of the relative uniformity of skin microbiome composition within skin sites, site localization of certain microbes, and the interpersonal variability of the skin microbiome. The results show that high-resolution topographical mapping of the skin microbiome is a powerful tool for studying the human skin microbiome. Despite a decade of skin microbiome research, there is still much to be discovered.

TPS2685 Background: Immune-Checkpoint inhibitors (ICI) have transformed the treatment of solid tumors, specifically in cutaneous melanoma, clear cell renal cell carcinoma (ccRCC) and non-small cell lung cancer (NSCLC). Despite these advances, a significant proportion of patients do not respond to ICI and only a fraction of responding patients will experience durable responses. Recent reports have found that patients showing poor response to ICI are characterized by a reduced gut microbiome diversity, suggesting that the gut microbiome might affect immune activation by ICI. BMC128 is a live bacterial consortium of 4 bacterial strains predicted to induce anti-tumor immune function when given in conjunction with ICI. These strains were identified by analyzing data obtained from NSCLC and ccRCC patients presenting varied responses to ICI, using a proprietary computational discovery platform enabling high-resolution functional microbiome analysis. In pre-clinical studies, treatment with BMC128 potentiated the efficacy of ICI in breast cancer and melanoma mouse models, reducing tumor volume, increasing the number of responders, and demonstrating an increase in infiltrating immunocytes: CD4, CD8 and NK cells. Methods: In this phase I, first-in-human trial, patients with ccRCC, cutaneous melanoma and NSCLC-adenocarcinoma (EGFR/ALK wild-type), who previously progressed on PD1/PDL-1 inhibitors will be treated with BMC128 8*108 CFU BID in combination with Nivolumab at a fixed-dose of 480mg q4weeks in a 3+3 design, followed by a 9 patient expansion phase. No dose escalation is planned. The primary objective is to investigate the safety and tolerability of BMC128 in combination with Nivolumab. Enrollment is intended to start in Feb, 2022. Clinical trial information: 202122207. [Table: see text]

Dead Sea climatotherapy (DSC) is a therapeutic modality for a variety of chronic skin conditions, yet there has been scarce research on the relationship between the cutaneous microbiota and disease states in response to DSC. We characterized the skin bacterial and fungal microbiome of healthy volunteers who underwent DSC. Bacterial community diversity remained similar before and after treatment, while fungal diversity was significantly reduced as a result of the treatment. Individuals showed greater inter-individual than temporal bacterial community variance, yet the opposite was true for fungal community composition. We further identified Malassezia as the genus driving temporal mycobiome variations. The results indicate that the microbiome remains stable throughout DSC, while the mycobiome undergoes dramatic community changes. The results of this study will serve as an important baseline for future investigations of microbiome and mycobiome temporal phenomena in diseased states.

The mechanisms by which the intestinal microbiome affects intestinal inflammation and disease activity in IBD is not clear. Most of the current data on the association between the intestinal microbiome and IBD is focusing on the intestinal microbial taxa and very little is known about the functionality of the microbiome in this condition. Aim: To construct a live bacterial consortium for reduction of intestinal inflammation in IBD based on a high-resolution functional microbial analysis, and its association with anti-inflammatory processes. Methods: Fecal metagenomics samples (n=581) and corresponding fecal calprotectin (FCP) levels from patients with Crohn’s disease and Ulcerative Colitis were downloaded from the NCBI (SRA SRP057027, http://hmpdacc.org, SRA SRP002163 and SRP056641 (BioProject PRJNA275349)). Computational analysis was performed using PRISM (Biomica Ltd, Rehovot Israel), a proprietary metagenomics analysis platform integrating assembly-based and reference-based analyses for functional genomics profiling and utilizing BioCOGS, Biomica’s internal comprehensive catalogue of microbial gene-orthology groups. We compared microbial functions between subjects based on severity of inflammation (FCP250 and FCP >250 vs FCP Validation of the anti-inflammatory activity of BMC322 was performed using a DSS-induced colitis mouse model. Results: Out of the dozens of identified functions, 32 were related to host anti-inflammatory processes, intestinal barrier integrity and colonocyte function. Our functional microbiome investigation has pointed to novel metabolic mechanisms by which specific strains may attenuate mucosal inflammation. Using functional annotations, we infer the biological processes governing microbe-host interactions contributing to reduced inflammation, and identify 16 bacteria of which 4 strains comprise the full array of the identified microbial functions associated with lower disease severity. These strains comprise BMC322- a novel live-bacterial consortium for inflammation reduction in IBD. The anti-inflammatory activity of these strains was validated in in-vitro studies and demonstrated efficacy in preliminary a mouse model of DSS-induced colitis; including shortening period of recovery, disease activity index and fecal lipocalin 2. Conclusion: High-resolution functional genomics profiling of the gut microbiome enables identification of microbial-derived functions relevant to inflammatory disease activity, and microbial strains bearing specific inflammation-reduction activity. These strains have provided the basis for the construction of a 4-strain consortium for intervention in IBD. Preliminary work has validated the anti-inflammatory activity of these strains and their potential as novel therapeutic modality for IBD.

The human skin microbiome plays an important role in both health and disease. Microbial biofilms are a well-characterized mode of surface-associated growth, which present community-like behaviors. Additionally, biofilms are a critical element in certain skin diseases. We review how the perception of the resident skin microbiota has evolved from the early linkages of certain microbes to disease states, to a more comprehensive and intricate understanding brought on by biofilm and microbiome revelations. Rapidly expanding arsenals of experimental methods are opening new horizons in the study of human–microbe and microbe–microbe interactions. Microbial community profiling has largely remained a separate discipline from that of biofilm research, yet the introduction of metatranscriptomics, metabolomics, and the ability to distinguish between dormant and active members of a community have all paved the road toward a convergent cognizance of the encounter between these two microbial disciplines.

Commiphora gileadensis is an aromatic plant traditionally used in the Middle East as a common remedy for pain and inflammation. Recently, several studies have reported on its anti-proliferative effect in cancer cell lines. Yet, scientific evidence regarding the other properties of C. gileadensis is limited. The aim of the current study was to investigate the cytotoxic action of C. gileadensis sap extracts (CgSE) on human epidermal cells and skin tissues and to ascertain its mode of action. The effects of the extract on cell viability and apoptosis were evaluated on immortalized keratinocytes, human dermal fibroblasts, human dermoid carcinoma cells and on human ex vivo skin cultures. CgSE significantly reduced the viability of both immortalized and transformed epidermal cells by 64% and 68%, respectively. However, normal fibroblasts and human skin organ cultures were protected from this effect. The cytotoxicity was coupled with the induction of capsase-3 and the morphological characteristics of apoptosis. In addition, CgSE-induced apoptosis did not occur in cells in the pre-replicative, G1 phase, but only at later phases involved in DNA replication and cell division. HPLC analysis of CgSE showed only negligible traces of β-caryophyllene, a secondary metabolite previously isolated from C. gileadensis and reported to be cytotoxic. Therefore, additional active compound(s) may be involved in the anti-proliferative phenomenon of the extract. The authors concluded that CgSE contains cytotoxic products which specifically target proliferating cells in a cell cycle-dependent manner, and hence may be relevant for the treatment of skin disorders characterized by hyperproliferation, such as skin cancer and psoriasis.

Dead Sea climatotherapy (DSC) is a well-established therapeutic modality for the treatment of several diseases, including atopic dermatitis. Skin microbiome studies have shown that skin microbiome diversity is anticorrelated with both atopic dermatitis severity and concurrent Staphylococcus aureus overgrowth. This study aimed to determine whether DSC induces skin microbiome changes concurrent with clinical improvements in atopic dermatitis. We sampled 35 atopic dermatitis patients and ten healthy controls on both the antecubital and popliteal fossa. High-resolution microbial community profiling was attained by sequencing multiple regions of the 16S rRNA gene. Dysbiosis was observed in both lesional and nonlesional sites, which was partially attenuated following treatment. Severe AD skin underwent the most significant community shifts, and Staphylococcus epidermidis, Streptococcus mitis and Micrococcus luteus relative abundance were significantly affected by Dead Sea climatotherapy. Our study highlights the temporal shifts of the AD skin microbiome induced by Dead Sea climatotherapy and offers potential explanations for the success of climatotherapy on a variety of skin diseases, including AD.

Cell-to-cell variations in protein abundance, called noise, give rise to phenotypic variability between isogenic cells. Studies of noise have focused on stochasticity introduced at transcription, yet the effects of post-transcriptional regulatory processes on noise remain unknown. We study the effects of RyhB, a small-RNA of Escherichia coli produced on iron stress, on the phenotypic variability of two of its downregulated target proteins, using dual chromosomal fusions to fluorescent reporters and measurements in live individual cells. The total noise of each of the target proteins is remarkably constant over a wide range of RyhB production rates despite cells being in stress. In fact, coordinate downregulation of the two target proteins by RyhB reduces the correlation between their levels. Hence, an increase in phenotypic variability under stress is achieved by decoupling the expression of different target proteins in the same cell, rather than by an increase in the total noise of each. Extrinsic noise provides the dominant contribution to the total protein noise over the total range of RyhB production rates. Stochastic simulations reproduce qualitatively key features of our observations and show that a feed-forward loop formed by transcriptional extrinsic noise, an sRNA and its target genes exhibits strong noise filtration capabilities.