A complex interplay of metabolic and immunological mechanisms underlies many diseases that represent a substantial unmet medical need. There is an increasing appreciation of the role microbes play in human health and disease, and evidence is accumulating that a new class of live biotherapeutics comprised of engineered microbes could address specific mechanisms of disease. Using the tools of synthetic biology, nonpathogenic bacteria can be designed to sense and respond to environmental signals in order to consume harmful compounds and deliver therapeutic effectors. In this perspective, we describe considerations for the design and development of engineered live biotherapeutics to achieve regulatory and patient acceptance.

Developing a new class of engineered live bacterial therapeutics to treat human diseases.

There is robust epidemiological evidence for the beneficial effects of broccoli consumption on health, many of them clearly mediated by the isothiocyanate sulforaphane. Present in the plant as its precursor, glucoraphanin, sulforaphane is formed through the actions of myrosinase, a β-thioglucosidase present in either the plant tissue or the mammalian microbiome. Since first isolated from broccoli and demonstrated to have cancer chemoprotective properties in rats in the early 1990s, over 3000 publications have described its efficacy in rodent disease models, underlying mechanisms of action or, to date, over 50 clinical trials examining pharmacokinetics, pharmacodynamics and disease mitigation. This review evaluates the current state of knowledge regarding the relationships between formulation (e.g., plants, sprouts, beverages, supplements), bioavailability and efficacy, and the doses of glucoraphanin and/or sulforaphane that have been used in pre-clinical and clinical studies. We pay special attention to the challenges for better integration of animal model and clinical studies, particularly with regard to selection of dose and route of administration. More effort is required to elucidate underlying mechanisms of action and to develop and validate biomarkers of pharmacodynamic action in humans. A sobering lesson is that changes in approach will be required to implement a public health paradigm for dispensing benefit across all spectrums of the global population.

/pdf/broccoli-or-sulforaphane-is-it-the-source-or-dose-that-tng7f1xf57.pdf

Broccoli or Sulforaphane: Is It the Source or Dose That Matters?

The gut microbiome has emerged as an important factor affecting human health and disease. The recent development of –omics approaches, including phylogenetic marker-based microbiome profiling, shotgun metagenomics, metatranscriptomics, metaproteomics, and metabolomics, has enabled efficient characterization of microbial communities. These techniques can provide strain-level taxonomic resolution of the taxa present in microbiomes, assess the potential functions encoded by the microbial community and quantify the metabolic activities occurring within a complex microbiome. The application of these meta-omics approaches to clinical samples has identified microbial species, metabolic pathways, and metabolites that are associated with the development and treatment of human diseases. These findings have further facilitated microbiome-targeted drug discovery and efforts to improve human health management. Recent in vitro and in vivo investigations have uncovered the presence of extensive drug-microbiome interactions. These interactions have also been shown to be important contributors to the disparate patient responses to treatment that are often observed during disease therapy. Therefore, developing techniques or frameworks that enable rapid screening, detailed evaluation, and accurate prediction of drug/host-microbiome interactions is critically important in the modern era of microbiome research and precision medicine. Here we review the current status of meta-omics techniques, including integrative multi-omics approaches, for characterizing the microbiome’s functionality in the context of health and disease. We also summarize and discuss new frameworks for applying meta-omics approaches and microbiome assays to study drug-microbiome interactions. Lastly, we discuss and exemplify strategies for implementing microbiome-based precision medicines using these meta-omics approaches and high throughput microbiome assays.

/pdf/advancing-functional-and-translational-microbiome-research-2jc82nq98j.pdf

Advancing functional and translational microbiome research using meta-omics approaches

Successful treatment of cancer remains a challenge, due to the unique pathophysiology of solid tumors, and the predictable emergence of resistance. Traditional methods for cancer therapy including radiotherapy, chemotherapy, and immunotherapy all have their own limitations. A novel approach is bacteriotherapy, either used alone, or in combination with conventional methods, has shown a positive effect on regression of tumors and inhibition of metastasis. Bacteria-assisted tumor-targeted therapy used as therapeutic/gene/drug delivery vehicles has great promise in the treatment of tumors. The use of bacteria only, or in combination with conventional methods was found to be effective in some experimental models of cancer (tumor regression and increased survival rate). In this article, we reviewed the major advantages, challenges, and prospective directions for combinations of bacteria with conventional methods for tumor therapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.2148

Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities.

Cell-based biosensors have great potential to detect various toxic and pathogenic contaminants in aqueous environments. However, frequently they cannot meet practical requirements due to insufficient sensing performance. To address this issue, we investigated a modular, cascaded signal amplifying methodology. We first tuned intracellular sensory receptor densities to increase sensitivity, and then engineered multi-layered transcriptional amplifiers to sequentially boost output expression level. We demonstrated these strategies by engineering ultrasensitive bacterial sensors for arsenic and mercury, and improved detection limit and output up to 5,000-fold and 750-fold, respectively. Coupled by leakage regulation approaches, we developed an encapsulated microbial sensor cell array for low-cost, portable and precise field monitoring, where the analyte can be readily quantified via displaying an easy-to-interpret volume bar-like pattern. The ultrasensitive signal amplifying methodology along with the background regulation and the sensing platform will be widely applicable to many other cell-based sensors, paving the way for their real-world applications.

Cascaded amplifying circuits enable ultrasensitive cellular sensors for toxic metals.

Chemoprevention—the use of medication to prevent cancer—can be augmented by the consumption of produce enriched with natural metabolites. However, chemopreventive metabolites are typically inactive and have low bioavailability and poor host absorption. Here, we show that engineered commensal microbes can prevent carcinogenesis and promote the regression of colorectal cancer through a cruciferous vegetable diet. The engineered commensal Escherichia coli bound specifically to the heparan sulphate proteoglycan on colorectal cancer cells and secreted the enzyme myrosinase to transform host-ingested glucosinolates—natural components of cruciferous vegetables—to sulphoraphane, an organic small molecule with known anticancer activity. The engineered microbes coupled with glucosinolates resulted in >95% proliferation inhibition of murine, human and colorectal adenocarcinoma cell lines in vitro. We also show that murine models of colorectal carcinoma fed with the engineered microbes and the cruciferous vegetable diet displayed significant tumour regression and reduced tumour occurrence.

Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention.

Antioxidant nanozyme microneedles with stem cell loading for in situ endometrial repair

PURPOSE: To investigate the effect of an acute (4-day) period of low energy availability (EA) on resting metabolic rate (RMR) and mood states in trained male endurance runners. METHODS: 12 male endurance runners (mean (standard deviation); age: 25.8 (3.7) yrs; body mass index: 20.9 (2.0) kg/m2; fat free mass (FFM): 52.8 (5.5) kg) completed three 4-day conditions of controlled EA (15, 30, and 45 kcal/kg/FFM), in a randomised and crossover manner. In each condition, participants ran on a treadmill at 65% of VO2max until they achieved a daily exercise energy expenditure of 15 kcal/kg/FFM. Energy intake was adjusted to achieve the desired level of EA in each condition. RMR and mood states were measured after a 10-12 hour fast on the morning of Day 1 (pre) and Day 5 (post) of each condition. RMR was measured by indirect calorimetry (ventilated hood) and mood states were measured by the Brunel Mood Scale (BRUMS), that consists of six dimensions - fatigue, depression, vigor, anger, tension, and confusion. A two-way repeated measures ANOVA (condition × time) was used to examine differences in RMR. A two-way repeated measures MANOVA (condition × time) was used to examine the differences in BRUMS dimensions. RESULTS: For RMR, no significant interaction was found between condition and time (p = 0.329). For mood states, a significant interaction was found in fatigue scores (p = 0.035). Participants felt greater fatigue (tiredness) in the post measure in the 15 kcal/kg/ FFM condition, as compared to the other conditions (30 and 45 kcal/kg/ FFM). A main effect was found in vigor scores over time (p = 0.036). Participants generally felt more vigor (energy) at the pre than post measure irrespective of EA conditions. CONCLUSIONS: These findings indicate that RMR in male runners was not influenced by short-term LEA induced by restricted energy intake and exercise energy expenditure, suggesting that metabolism may not be affected by acute periods of LEA. Hence, RMR may not be a sensitive enough tool to detect the early stages of LEA. Short-term LEA did affect mood states (fatigue and vigor) in male runners. This suggests that LEA should be adjusted as soon as it is detected to prevent further impact on psychological state. It also suggests that a state of increased fatigue, and/or decreased vigor, could be an indicator or symptom of LEA, in male runners. 

Short-term Induced Low Energy Availability On Metabolic Rate And Mood States In Male Runners

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

/pdf/author-correction-engineered-commensal-microbes-for-diet-2n4pscuh67.pdf

Author Correction: Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention.

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Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention.

Antioxidant nanozyme microneedles with stem cell loading for in situ endometrial repair

Short-term Induced Low Energy Availability On Metabolic Rate And Mood States In Male Runners

Author Correction: Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention.