Obesity, defined by a body mass index (BMI) exceeding 30, has emerged as one of the most pressing public health challenges of the 21st century. Characterized by excessive adipose tissue accumulation, it significantly contributes to the global burden of chronic diseases, including type 2 diabetes, cardiovascular disorders, non-alcoholic fatty liver disease, osteoarthritis, and certain types of cancer. Beyond its physiological impacts, obesity imposes profound socioeconomic costs—increasing healthcare expenditures, reducing productivity, and exacerbating health inequities across populations.

The complexity of obesity lies in its multifactorial etiology, which involves genetic, environmental, behavioral, and metabolic determinants. This intricacy makes sustained intervention particularly challenging. As obesity rates continue to rise worldwide, there is an urgent need to develop effective, accessible, and affordable therapeutic strategies.

Globally, countries such as the United States, Mexico, and members of the Gulf Cooperation Council report some of the highest prevalence rates of obesity. In contrast, China has experienced a rapid increase in overweight and obesity rates over the past two decades, driven by dietary transitions, urbanization, and changing lifestyles. Although China’s average BMI remains lower than that of many Western nations, its sheer population size renders it home to the largest number of obese individuals worldwide. The situation is further compounded by regional disparities, with significant differences between urban and rural areas in terms of nutrition awareness and resource allocation.

Current domestic and international efforts to combat obesity include public health campaigns, regulatory measures such as sugar taxes, and advancements in pharmacological and surgical treatments. However, a persistent implementation gap remains, especially in low- and middle-income countries where healthcare systems are often underprepared for the long-term management of obesity-related conditions. Moving forward, a more integrated approach-combining policy intervention, community education, and individualized care-is essential to curb this escalating epidemic.

Why This Problem Matters

The significance of addressing obesity extends far beyond individual health, representing a structural challenge with implications for social welfare, economic stability, and medical systems worldwide. Obesity contributes to declining life expectancy, diminished quality of life, and places a growing-and increasingly unsustainable-burden on healthcare infrastructures. Furthermore, the social stigma associated with obesity often leads to psychological distress and social isolation, further complicating prevention and treatment efforts.

From a metabolic perspective, obesity is increasingly recognized as a state of chronic low-grade inflammation and endocrine dysfunction. Emerging research has highlighted the role of the gut microbiota and microbial metabolites, such as hydrogen sulfide (H₂S), in regulating host appetite, energy metabolism, and systemic inflammation—unveiling new potential avenues for therapeutic intervention.

Inspiration: The H ₂ S-GLP-1 Relationship

Inspired by a growing body of scientific evidence, we turned our attention to the relationship between hydrogen sulfide (H₂S) and impaired glucagon-like peptide-1 (GLP-1) signaling in individuals with obesity. A pivotal study by Qi et al. (2024), published in Nature Metabolism, demonstrated that elevated H₂S production by gut microbiota negatively affects GLP-1 secretion in mice, leading to suppressed insulin release and disrupted glucose homeostasis. This finding is highly significant, as GLP-1-an incretin hormone-stimulates insulin secretion, suppresses appetite, and slows gastric emptying, playing a fundamental role in metabolic regulation.

Figure 1. Schematic diagram of H₂S produced by Desulfobacter inhibiting GLP-1

Although existing pharmacotherapies such as GLP-1 receptor agonists (e.g., semaglutide) have proven effective, they are associated with gastrointestinal adverse effects, potential pancreatitis risk, and high costs, which limit their accessibility and long-term usability. This prompted us to ask: Could we develop a targeted enzymatic strategy to modulate gut H₂S levels, thereby restoring natural GLP-1 function and offering a safer, more affordable, and sustainable therapeutic alternative?

To address this, we Fatbuster UCS-A designed Slimspore—a synthetic biology-based therapeutic system using engineered E.coli to metabolize excess hydrogen sulfide.

Two principal enzymes are known to mediate sulfide oxidation: flavocytochrome c sulfide dehydrogenase (FCSD), a sulfide: cytochrome c oxidoreductase; and sulfide: quinone oxidoreductase (SQR). These correspond to soluble and membrane-bound protein complexes, respectively (Figure 2).

Figure 2. SQR and FCSD roles in H₂S oxidation(Filipe M. Sousa et al., 2018)

Sulfide:quinone oxidoreductase (SQR)

SQR is a membrane-bound enzyme widely distributed across bacteria, archaea, and eukaryotes (with the exception of plants), belonging to the two dinucleotide-binding domains flavoprotein (tDBDF) superfamily. Its core function is to catalyze the oxidation of hydrogen sulfide (H₂S) to elemental sulfur, while transferring electrons to the quinone pool to generate quinol, thereby coupling sulfur metabolism with respiratory energy transduction. SQR is involved not only in H₂S detoxification but also plays a central role in energy metabolism and global sulfur cycling across diverse organisms. Its enzymatic activity and substrate affinity exhibit remarkable diversity, as reflected in varying Kₘ values-from low (e.g., ~23 µM in Arenicola marina) to high (e.g., ~2 mM in Schizosaccharomyces pombe)-indicating its dual role in efficient sulfur oxidation and detoxification in different ecological contexts. Phylogenetically, SQR can be classified into six subtypes (Type I-VI), and its broad and ancient evolutionary origins suggest its fundamental role in early life sulfur metabolism.

Flavocytochrome c sulfide dehydrogenase (FCSD)

FCSD is a soluble sulfide-oxidizing enzyme exclusively found in bacteria, particularly abundant in typical sulfur-metabolizing phyla such as Chlorobi, Proteobacteria, and Aquificae. This enzyme uses cytochrome c as an electron acceptor, catalyzing the oxidation of H₂S to elemental sulfur and directly transferring electrons to the cytochrome c oxidase pathway, bypassing the quinone pool. Due to the higher redox potential of cytochrome c, this pathway yields less energy compared to SQR, indicating that FCSD represents an adaptive metabolic strategy primarily employed by obligate sulfur-oxidizing bacteria in sulfide-rich environments. Structurally, FCSD forms a heterodimer, with its flavin subunit belonging to the tDBDF superfamily but featuring two “capping loops” that occlude the NAD(P)H-binding site, reflecting molecular adaptation to its specific substrate profile. Although phylogenetically restricted, FCSD plays a significant role in sulfur biogeochemical cycling and metabolic networks of certain photosynthetic sulfur bacteria.

Figure 3. Cartoon representing the main players in Sulfur metabolism of Eukarya - (A), and Prokarya (B).(Filipe M. Sousa et al., 2018)

The SQR and FCSD Modules

Recognizing that elevated H₂S levels in obesity significantly impair the GLP-1 pathway-a key regulator of insulin secretion and glucose homeostasis-we designed a microbial intervention strategy leveraging two sulfide-oxidizing enzymes: sulfide:quinone oxidoreductase (SQR) and flavocytochrome c sulfide dehydrogenase (FCSD). These enzymes were selected based on their high catalytic efficiency, well-characterized mechanisms in sulfur metabolism, and compatibility with prokaryotic expression systems. To enable recombinant production, the coding sequences of SQR and FCSD were codon-optimized for E. coli, amplified via PCR, and cloned into pET expression vectors using homologous recombination, yielding plasmids pET-SQR and pET-FCSD under the control of inducible T7 promoters.

Following sequence verification in E.coli DH5α, the constructs were transformed into E.coli BL21(DE3) for protein production. Expression was induced with IPTG, resulting in high-yield synthesis of soluble SQR and FCSD. Functional validation was performed in E. coli MG1655 pre-treated with L-cysteine to stimulate endogenous H₂S production. Upon introduction of the recombinant enzymes, sulfide oxidation activity was quantitatively assessed. Ultimately, the functional impact on the GLP-1 signaling pathway was evaluated through downstream glucose-responsive assays, confirming the recovery of pathway activity in treated cells. (See Experiments and Protocols and Results sections for full methodological details)

Hardware Integration

To enable precise and reliable monitoring of hydrogen sulfide (H₂S) levels, we developed a dedicated hardware system tailored for two distinct usage environments: a clinical version designed for hospital settings and a compact variant intended for daily home-based monitoring. Both systems incorporate advanced electrochemical sensors capable of delivering real-time, quantitative H₂S concentration measurements, significantly improving upon conventional qualitative or semi-quantitative detection methods. Furthermore, the devices are engineered with integrated safety mechanisms-including sealed sensor chambers and gas flow controls-to prevent accidental leakage of toxic H₂S gas, ensuring user safety throughout operation. (Detailed descriptions of the hardware design, sensor specifications, and safety validation are provided in the Hardware section)

To address the disruption of GLP-1 signaling caused by elevated hydrogen sulfide (H₂S) in obesity, we propose a targeted enzymatic strategy designed to restore metabolic function and support long-term weight management. Our solution centers on the development of Slimspore-an orally delivered live biotherapeutic product (LBP) consisting of non-pathogenic, engineered E. coli that stably express highly efficient sulfide-oxidizing enzymes (SQR and FCSD). These enzymes actively degrade excess H₂S in the gut, mitigating its inhibitory effect on endogenous GLP-1 secretion and sensitivity.

Complementing the biotherapeutic, we are also developing a dual-format H₂S monitoring device-with versions tailored for clinical accuracy and home-based usability-to provide quantitative, real-time feedback on H₂S levels. This integrated system allows for personalized dosing and treatment monitoring, enhancing both safety and efficacy.

We envision Slimspore as a safe, affordable, and accessible therapeutic alternative to existing obesity pharmacotherapies. By acting locally within the gastrointestinal tract, Slimspore aims to minimize systemic side effects while offering a sustainable mechanism for metabolic restoration.

Deeply concerned with the global challenge of obesity and motivated by insights gathered from numerous interviews highlighting the limitations of current treatments, Fatbuster UCS-A has developed Slimspore-a novel therapeutic strategy that leverages the potential of two key hydrogen sulfide-metabolizing enzymes, SQR and FCSD. By targeting elevated H₂S levels that impair GLP-1 signaling in obese patients, this approach aims to restore metabolic balance through efficient enzymatic degradation of H₂S in the gut.

Slimspore is designed as an orally administered live biotherapeutic product (LBP) using engineered probiotics capable of delivering SQR and FCSD activity directly to the gastrointestinal tract. The functional efficacy of these recombinant enzymes has been rigorously validated through wet lab experiments and biological models, confirming their ability to mitigate H₂S-mediated suppression of GLP-1.

To support personalized treatment and real-time monitoring, we have also developed a dual-format H₂S detection device suitable for both clinical and home use. This system provides quantitative, user-friendly H₂S measurement, and its feasibility has been further reinforced through computational modeling and simulation.

Together, these innovations position Slimspore as a safe, accessible, and scientifically grounded contribution to the global effort against obesity-opening new pathways for effective and sustainable metabolic health management.

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