Colorectal cancer (CRC) is increasingly affecting young individuals under 40 years of age, with its global incidence continuously rising. Existing treatments are often invasive and frequently accompanied by severe side effects. To address this, we have developed a precision-targeted therapeutic strategy based on genetically engineered Escherichia coli Nissle 1917 (EcN).

Neoeriocitrin, a natural flavonoid compound widely found in citrus plants such as dried tangerine peel (chenpi), exhibits significant antioxidant, anti-inflammatory, and immunomodulatory activities. Studies have shown that it holds great potential in the prevention and adjuvant therapy of colorectal cancer. However, current production of neoeriocitrin relies primarily on traditional herbal extraction methods, which face critical bottlenecks including low yield, high cost, and significant batch-to-batch variability, severely limiting its clinical translation.

To overcome these limitations, we have reconstructed the complete biosynthetic pathway of neoeriocitrin in the engineered E. coli Nissle 1917 strain, heterologously expressing three key enzymes: VvRHM, UGT73B2, and Cm1,2RhaT, enabling efficient and controllable intracellular synthesis.

Furthermore, we have introduced an acid-inducible system that allows neoeriocitrin to be specifically expressed only within the tumor microenvironment (low pH), achieving spatially precise delivery and minimizing interference with normal tissues.

For safety, we have constructed a dual suicide switch system:

• The arabinose-inducible pBAD system: allows oral administration of arabinose to trigger engineered bacterial lysis in vivo;
• The cold-inducible pCspA system: activates suicide gene expression ex vivo (e.g., during environmental discharge or waste disposal). Together with the MazF ribonuclease, these systems form a "double insurance" mechanism, ensuring that the engineered bacteria are safe and controllable in vivo, and completely inactivated in the environment, eliminating risks of gene leakage.

This study integrates efficient biosynthesis, tumor microenvironment responsiveness, and dual biosecurity control, establishing for the first time an engineered probiotic strain capable of in situ production of neoeriocitrin—offering a precise, safe, and scalable novel adjuvant treatment paradigm for colorectal cancer.

Figure1. Schematic of Neoeriocitrin-Producing Engineered Probiotic

A chance moment of caregiving changed the direction of our research. While accompanying an elderly grandfather undergoing colorectal cancer treatment, a team member observed his wife preparing daily tangerine peel soup. "The elders say dried tangerine peel regulates qi, strengthens the spleen—when you can eat, you have strength to fight illness," she said softly. At that moment, we couldn't help but wonder: Could this small piece of citrus peel truly harbor untapped therapeutic potential overlooked by modern medicine?

Motivated by this simple question, we delved into scientific literature and unexpectedly discovered neoeriocitrin as its core active component. Modern pharmacology confirms that this natural flavonoid not only possesses potent antioxidant, anti-inflammatory, and immunomodulatory properties but also plays multiple roles in early intervention of colorectal cancer: suppressing inflammation-driven tumorigenesis, blocking the cancer cell cycle, and even synergistically enhancing the efficacy of chemotherapeutic agents like 5-FU. Yet, the reality is disappointing: current production of neoeriocitrin still depends on traditional plant extraction—a process taking months, with yields below 0.1%, and high variability in composition, failing to meet clinical demands. The scientific outlook is promising, but the technological gap is profound.

Thus, we decided to use synthetic biology to give this piece of tangerine peel a "rebirth." We are not satisfied with merely "extracting"—we aim to "create"; not just "oral intake," but targeted release; not only "effective," but absolutely safe. What we have built is not merely a strain of engineered bacteria, but an intelligent therapeutic system capable of sensing tumors, autonomously producing drugs, and self-destructing after completing its mission.

We envision a future where a patient no longer needs to endure the suffering of chemotherapy—simply swallowing a capsule containing the wisdom of tangerine peel, the warmth of technology, and life’s response to life.

Figure 2. Schematic of Dried Tangerine Peel (Chenpi)

Current Status of Colorectal Cancer

Colorectal cancer (CRC) is a malignant tumor originating from epithelial cells of the colon or rectum, primarily classified into colon cancer and rectal cancer. As the third most common cancer and the second leading cause of cancer-related deaths worldwide, CRC has become a severe public health challenge. According to 2020 global cancer statistics, approximately 9.4% of cancer-related deaths are attributed to CRC [1]. With increasing population aging, the global incidence of CRC is projected to more than double by 2035, with the most significant increases expected in low- and middle-income countries.

Figure 3. Colorectal Cancer Incidence in 2022 (Age-Standardized Rate, per 100,000 population) [4]

Traditionally, CRC primarily affected individuals over 50 years of age. However, in recent years, the incidence of early-onset CRC (<50 years) has been continuously rising globally, drawing widespread attention. In the United States, the proportion of new CRC cases among individuals under 55 has increased from approximately 10% in 1995 to 20% in 2020, doubling over 25 years; between 2012 and 2021, the annual incidence in this group rose at a rate of 2.4%. In Australia, the CRC incidence among 39-year-olds rose from 6.3 per 100,000 in 2000 to 17.2 per 100,000 in 2024; among 40–49-year-olds, it increased from 24.9 to 29.9 per 100,000. Similar trends have been confirmed in several high-income countries including Canada, the UK, South Korea, and Western Europe [2].

Figure 4. Colorectal Cancer Deaths in 2020 [1]

For colorectal cancer, the "adenoma–carcinoma sequence"—from normal mucosa → adenoma → carcinoma—typically takes 10–15 years, providing a valuable window for clinical intervention. During this process, a chronic inflammatory intestinal microenvironment significantly promotes tumor initiation and progression. Increasing evidence reveals that the gut microbiota and its metabolites (e.g., short-chain fatty acids, secondary bile acids, hydrogen sulfide) play a central regulatory role in CRC development by modulating immune surveillance, epithelial barrier function, and inflammatory signaling pathways (e.g., NF-κB, Wnt/β-catenin). Therefore, the gut microbiome is emerging as a novel preventive and therapeutic target, becoming a cutting-edge frontier in CRC research.

Figure 5. Stages of Colorectal Cancer [1]

Bottlenecks in Current CRC Therapies

Current mainstay therapies for colorectal cancer face multiple limitations:

• Surgery is difficult in late-stage cases, with long recovery periods and high risk of complications;
• Chemotherapy and radiotherapy can control tumors but are associated with severe side effects such as bone marrow suppression and radiation-induced injury;
• Targeted therapy and immunotherapy are more precise but suffer from drug resistance, high costs, and applicability limited to a small subset of patients, severely restricting their widespread use and clinical efficacy.

Treatment Method	Main Content	Advantages	Disadvantages
Surgery	Removal of primary tumor and lymph nodes; curative for early-stage CRC	High cure rate for early-stage patients	High surgical difficulty in late stages; long recovery; postoperative complications
Chemotherapy	Common regimens include FOLFOX, FOLFIRI	Controls tumor spread; prolongs survival	Severe side effects: bone marrow suppression, nausea, neuropathy
Radiotherapy	Used preoperatively to shrink rectal tumors or as adjuvant therapy	Reduces local recurrence; improves curability	May cause radiation proctitis, skin damage, urinary frequency
Targeted Therapy	Anti-EGFR (Cetuximab), anti-VEGF (Bevacizumab)	More precise; lower side effects than chemo	Drug resistance, high cost, side effects like hypertension and rash
Immunotherapy	For MSI-H/dMMR patients; PD-1 inhibitors like Pembrolizumab	High efficacy in specific patients; relatively low side effects	Only applicable to a minority; immune-related adverse events; expensive

Therapeutic Potential of Neohesperidin in CRC

Neohesperidin, a natural flavonoid compound, has recently shown significant promise in antitumor drug development, particularly in targeted therapy for colorectal cancer. Studies indicate that neohesperidin and its structural analog—such as isorhamnetin-3-O-neohesperidoside—can effectively inhibit tumor cell proliferation by modulating key cell death pathways, such as ferroptosis. Thus, using neohesperidin as a natural, targeted intervention agent for early-stage CRC treatment is not only supported by molecular mechanisms but also aligns with the current clinical trend of developing low-toxicity, multi-target natural drugs, holding strong translational potential.

Physiological Functions of Neohesperidin

Neohesperidin and its derivative neohesperidin dihydrochalcone (NHDC) are flavonoid compounds extracted from citrus plants (e.g., Citrus reticulata Blanco, i.e., chenpi), exhibiting various biological activities including antioxidant, anti-inflammatory, antiviral, and antitumor effects [5]. They are widely used in food, health supplements, and drug development.

Figure 6. Physiological Functions of Neohesperidin

Production Methods for Neohesperidin

Neohesperidin is a flavonoid compound widely present in the peels of Citrus spp., especially abundant in traditional Chinese medicinal herbs such as Citrus aurantium (bitter orange) and chenpi. Its extraction primarily relies on solvent extraction combined with chromatographic purification—a mature and commonly used method for natural product isolation. The process typically involves grinding dried bitter orange peel or chenpi, extracting with 70% ethanol under reflux or ultrasound, concentrating the extract to obtain crude flavonoids, preliminary separation using macroporous adsorption resin, followed by purification via silica gel column chromatography or C18 preparative HPLC, and finally crystallization to obtain high-purity neohesperidin, which is then freeze-dried or spray-dried into powder.

Limitations of Neohesperidin Extraction

Neohesperidin extraction faces multiple challenges: extremely low natural abundance and difficult separation lead to low extraction efficiency; high temperatures and strong acids/bases during processing may degrade active ingredients and pose risks of solvent residue; product purity struggles to meet high standards, and bioavailability is low; industrially, equipment costs are high and raw material supply is unstable, making it difficult to meet large-scale production needs.

(1) Low extraction efficiency and poor raw material utilization: Neohesperidin content is extremely low—only 0.29% in bitter orange buds and just 0.0057% in Nandina domestica Thunb.—and often coexists with structurally similar compounds like hesperidin and naringin, making separation difficult. The dense cellulose and pectin structure of plant cell walls hinders solvent penetration; traditional aqueous or alcoholic extraction requires prolonged processing and typically achieves yields below 15%.

(2) Processing damages active ingredients: High temperatures cause degradation—improper temperature control during heat reflux or microwave extraction may trigger hydrolysis or oxidation; strong acids/bases damage glycosidic bonds—alkaline extraction using high-concentration NaOH/KOH may disrupt flavonoid glycoside structures during acid precipitation; chemical synthesis routes may involve pyrrolidine or Pd/C catalysts, posing risks of heavy metal and organic solvent residues, severely limiting pharmaceutical applications.

(3) Purity and bioavailability bottlenecks: Traditional purification methods (e.g., macroporous adsorption resins) show poor selectivity for structurally similar flavonoids, requiring multiple recrystallizations (≥3 times), with purity rarely exceeding 95%; neohesperidin has poor oral absorption and low water solubility, severely limiting its pharmacological activity.

(4) Industrialization barriers: High equipment requirements—extraction requires corrosion-resistant specialized equipment (e.g., titanium alloy reactors), increasing investment costs by 50%; unstable raw material supply—plant materials are seasonal, and high-purity purification processes (e.g., column chromatography) are complex, making it difficult to meet ton-scale production demands.

Figure 7. Limitations of Neohesperidin Extraction

To achieve precise, efficient, and safe prevention and treatment of colorectal cancer (CRC), avoiding the trauma and side effects associated with traditional surgery and chemoradiotherapy, our team proposes an innovative solution: constructing an engineered probiotic system capable of stably releasing the anti-CRC active compound—neohesperidin (NH)—within the intestine.

This probiotic is based on Escherichia coli Nissle 1917 (EcN) and features three core functional systems:

1. Neohesperidin synthesis system
2. Hesperetin synthesis system
3. Biosecurity system

Figure 8. Engineered Probiotic System for Neohesperidin Production

Chassis Strain

Escherichia coli Nissle 1917 (EcN) is a well-studied and widely used Gram-negative probiotic. Its advantages include:

• Ability to colonize the gastrointestinal tract long-term, with competitive growth advantage over other gut bacteria, effectively inhibiting pathogen colonization [13];
• Long-term use as a probiotic formulation (e.g., Mutaflor®) in adults and infants for treating intestinal infections and inflammatory diseases, with an excellent safety record;
• Amenable to genetic engineering, serving as a "live biotherapeutic product (LBP)" for metabolite production or targeted delivery;
• Possession of mature genetic tools (e.g., λ-Red recombination system), enabling efficient and precise genetic modifications.

Thus, EcN is an ideal microbial chassis for constructing an intelligent delivery system for colorectal cancer (CRC) intervention.

System I: Neohesperidin Synthesis System

Building upon externally supplied hesperetin, we constructed a three-step glycosylation pathway to enable de novo synthesis of neohesperidin (NH).

Traditionally, UDP-rhamnose synthesis requires three independent enzymes—RHM, RHM2, RHM3—catalyzing sequential reactions. This not only significantly increases the genetic expression burden but also leads to side reactions and metabolic imbalance due to the instability of the intermediate UDP-4-keto-6-deoxyglucose. To overcome this, we introduced the bifunctional enzyme VvRHM-NRS from Vitis vinifera (grape). This enzyme completes the two-step conversion of UDP-glucose to UDP-rhamnose at a single catalytic site: first dehydrating to form UDP-4-keto-6-deoxyglucose, then reducing it to UDP-rhamnose. This strategy greatly simplifies the genetic circuit, significantly enhancing system stability and metabolic flux efficiency.

Hesperetin contains multiple potential glycosylation sites (7-OH, 3'-OH, 4'-OH). Most glycosyltransferases (GTs) lack regioselectivity, easily generating multiple structural isomers that compromise product purity and downstream applications. We selected and employed UGT73B2 from Arabidopsis thaliana, a glycosyltransferase exhibiting exceptional regioselectivity—efficiently and specifically recognizing the 7-OH site of hesperetin and strictly relying on UDP-glucose as the sugar donor—making it an ideal core catalytic component for constructing a high-selectivity glycosylation pathway.

The hallmark structure of neohesperidin is its rhamnose linked to the glucose unit via an α-(1→2)-glycosidic bond. To achieve this critical stereospecific linkage, we introduced Cm1,2RhaT, a rhamnosyltransferase from Citrus maxima (pomelo), which exhibits strict substrate recognition, catalyzing only the formation of the α-(1→2) glycosidic bond from UDP-rhamnose to hesperetin-7-O-glucoside, ensuring structural uniqueness and biological activity integrity.

We co-expressed VvRHM-NRS, UGT73B2, and Cm1,2RhaT in E. coli Nissle 1917 (EcN), constructing a complete integrated glycosylation pathway, enabling de novo biosynthesis of neohesperidin in E. coli.

This pathway breaks through the traditional yield bottleneck reliant on citrus peel extraction, offering a low-cost, sustainable solution for the large-scale production of neohesperidin.

Figure 9. Neohesperidin Biosynthesis Pathway

System II: Hesperetin Synthesis System

Figure 10. Hesperetin Biosynthesis Pathway

Hesperetin is an O-methylated flavonoid naturally produced by citrus plants of the Rutaceae family. Growing evidence indicates that hesperetin is a bioactive compound with antiviral, anti-inflammatory, antioxidant, and antitumor activities, showing significant potential in the treatment of diabetes and its complications [14].

However, using hesperetin directly as a precursor for neohesperidin synthesis remains costly. We considered that if a cheaper precursor—naringenin—could be used, production costs could be reduced by tens of times, making neohesperidin synthesis far more advantageous. Therefore, we chose naringenin as the starting substrate and constructed a two-step enzymatic conversion pathway for efficient hesperetin synthesis.

This synthetic pathway comprises two key catalytic steps:

1. 3′-Hydroxylation reaction: Catalyzed by the flavonoid 3′-hydroxylase (ThF3′H) from Tricyrtis hirta (Japanese lily) in conjunction with cytochrome P450 reductase (CPR) from Arabidopsis thaliana, forming a P450 monooxygenase system. ThF3′H is a typical plant cytochrome P450 enzyme (CYP), localized in the endoplasmic reticulum membrane, dependent on NADPH for reducing equivalents, and transfers electrons via CPR. It selectively hydroxylates the 3′-carbon adjacent to the 4′-hydroxyl group on the B-ring of naringenin, producing eriodictyol.
2. 4′-O-Methylation reaction: Eriodictyol is then methylated at the 4′-hydroxyl group on the B-ring by flavonoid 4′-O-methyltransferase mutant MpOMT S142V from Mentha × piperita (peppermint), yielding the target product, hesperetin.

The MpOMT S142V mutant, through key amino acid site engineering, significantly enhances substrate preference for eriodictyol while suppressing non-specific catalysis of naringenin, reducing byproduct accumulation by >90%, enabling highly selective biosynthesis of hesperetin [15].

Acid-Inducible System

Acidic environment is a key feature of the tumor microenvironment (TME), significantly influencing tumor growth, metastasis, and treatment resistance.

In rapidly proliferating tumor tissues, abnormal metabolism—especially reliance on glycolysis—leads to massive lactate production even under aerobic conditions ("Warburg effect"), resulting in a local acidic environment (decreased pH). This acidity not only promotes tumor invasion and metastasis (e.g., by activating matrix metalloproteinases) but also suppresses the activity of immune effector cells like T cells, thereby reducing the efficacy of immunotherapy.

In recent years, leveraging the hypoxic and acidic characteristics of cancer tissues for therapeutic purposes has become an important direction in anticancer research.

The pcadBA promoter, derived from E. coli, is an acid-inducible promoter highly sensitive to external acidic conditions (pH < 5.8), commonly used to construct environment-responsive gene expression systems. Its activation depends on the regulatory protein CadC, which, under low pH conditions, becomes activated and binds to the upstream regulatory region of the pcadBA promoter, initiating downstream gene expression [19]. This mechanism makes pcadBA an ideal tool for specific gene activation in acidic microenvironments such as the gut or tumors [20].

Based on the acidic microenvironment of CRC, our team designed an acid-sensitive neohesperidin synthesis system. The enzymes involved in neohesperidin synthesis were inserted into the expression cassette under the control of the pcadBA promoter. Due to the length of the synthetic pathway, only the rhamnosyltransferase (Cm1,2RhaT) was placed under pcadBA control to regulate its transcription. Neohesperidin synthesis occurs only under low pH conditions, precisely responding to the lactic acid-rich microenvironment generated by the "Warburg effect" in colorectal cancer tissue, achieving tumor targeting.

This system effectively distinguishes between tumor and normal tissues, initiating neohesperidin synthesis only at the lesion site, significantly enhancing spatial precision and local drug concentration, enabling "on-demand synthesis", greatly reducing systemic side effects, and improving therapeutic specificity and safety.

Figure 11. Acid-Inducible Circuit for Neohesperidin Synthesis

Biosecurity System

To comprehensively ensure biosafety, we constructed a dual-mechanism targeted suicide system addressing both in vivo clinical risks and ex vivo environmental risks:

• The in vivo safety system allows oral administration of arabinose to specifically induce lethal gene expression if adverse reactions occur, enabling controlled, rapid strain clearance and ensuring the therapy is safe and reversible.
• The ex vivo safety system employs the cold-inducible pCspA promoter to drive suicide gene expression. Once the engineered bacteria are excreted into the external cold environment (e.g., <20 °C), the lysis program is automatically activated, achieving "environment-triggered self-destruction", effectively preventing survival and gene spread in the natural environment and fundamentally mitigating potential ecological risks.

This two-layer safety design—"patient-controllable" and "environmentally self-destructing"—achieves dual closed-loop protection for clinical application and ecological safety, providing high reliability for the clinical translation of engineered bacteria.

MazF

MazF is the toxin component of the E. coli MazE/MazF toxin-antitoxin system, capable of specifically cleaving mRNA and blocking protein synthesis, thereby inhibiting cell growth or inducing programmed cell death. MazF activity is inhibited by its antitoxin MazE, maintaining cell viability under normal conditions. When MazE is degraded or MazF is induced to overexpress, MazF rapidly degrades intracellular mRNA, leading to growth arrest or lysis. While regulating MazF expression alone can achieve controlled suicide, combining it with regulatory systems enables more precise triggering of cell death under specific conditions, enhancing biosafety.

Figure 12. Mechanism of MazF Action [25]

In Vivo Safety System – Arabinose-Inducible Suicide System

The arabinose promoter (pBAD) originates from the araBAD operon in E. coli and is a classic inducible promoter. Its transcriptional activity is determined by the regulatory protein AraC and exogenous arabinose. In the absence of arabinose, AraC prevents RNA polymerase binding, keeping the gene off. When arabinose is present, AraC undergoes a conformational change, allowing RNA polymerase to initiate downstream gene transcription. Due to its rapid induction, low background expression, and fine-tunability via arabinose concentration, pBAD is widely used for strict control of foreign molecule expression.

By using the arabinose-inducible pBAD system to drive the expression of the toxic protein MazF, we constructed a highly controllable "molecular switch"-type suicide mechanism: upon addition of arabinose, pBAD strongly activates MazF transcription, leading to specific degradation of cellular mRNA and rapid, complete death of E. coli; in the absence of inducer, background expression is minimal, ensuring strain stability during storage and transport. This design not only enables precise spatiotemporal control of E. coli but also significantly enhances biosafety in environmental release or biotherapy applications.

Ex Vivo Safety System – Cold-Inducible Suicide System

Using the cold-inducible pCspA promoter to drive the toxin gene MazF constructs an environment-responsive suicide switch: when the engineered bacteria are exposed to low temperatures (e.g., 16 °C), pCspA activates and efficiently expresses MazF, inducing programmed cell lysis; at normal temperatures (37 °C), gene expression is strictly suppressed, ensuring stable bacterial growth. This mechanism requires no exogenous inducer, relying solely on environmental temperature changes for precise control, significantly enhancing biosafety and controllability of engineered bacteria in open or non-contained environments, providing a more reliable "self-destruct" safeguard for synthetic biology applications.

Figure 13. Circuit Diagram of the Engineered Bacterial Suicide System

Proposed Implementation

Target Population

Our engineered probiotic therapy is designed for adult patients diagnosed with or highly suspected of having colorectal cancer (CRC), with a particular focus on the early-onset CRC population (<50 years). Conventional treatments like surgery, chemotherapy, and targeted therapy, while extending survival, are associated with bone marrow suppression, radiation-induced enteritis, drug resistance, and treatment-related adverse events affecting up to 60% of patients, severely compromising quality of life.

Factory Production

Our production process centers on industrial-scale microbial fermentation, completely replacing traditional plant extraction.

First, in GMP-standard clean rooms, large bioreactors are used to culture the genetically modified EcN strain at scale using a medium of glucose, yeast extract, and inorganic salts.

Next, bacterial cells are collected via deep freezing and centrifugation to produce high-activity, high-stability lyophilized bacterial powder. To enhance storage stability and oral bioavailability, the lyophilized powder is compressed into enteric-coated capsules. The entire production process implements full-process sterile control and genetic stability monitoring to ensure no gene leakage or unintended mutations.

Figure 14. Schematic of Factory Production

How Consumers Use It

Patients take one enteric-coated capsule daily on an empty stomach in the morning, swallowing it with warm water. The capsule remains intact in the acidic gastric environment and releases the strain upon reaching the colon, where it colonizes the intestinal mucosa and actively migrates toward tumor sites via natural chemotaxis.

When the engineered bacteria enter the tumor microenvironment (pH < 5.8), the built-in pCadBA acid-sensitive promoter is activated, triggering the neohesperidin synthesis pathway—the three enzymes VvRHM-NRS, UGT73B2, and Cm1,2RhaT work in concert to produce neohesperidin locally near tumor cells, maximizing local concentration while sparing healthy tissues.

If the patient experiences suspected adverse reactions such as abdominal pain or fever during treatment, they can immediately take 5g of food-grade arabinose (about one teaspoon). Within 2–4 hours, the pBAD promoter will drive MazF toxin expression, rapidly degrading bacterial mRNA and causing programmed lysis—achieving a safe, controllable, and reversible "one-button stop".

To eliminate residual bacteria after treatment or prevent environmental release during disposal, no action is required—once the engineered bacteria are excreted and exposed to ambient temperatures below 20°C, the pCspA cold-sensitive promoter will spontaneously activate MazF, achieving "environmental self-destruction" and completely blocking gene diffusion risks.

Figure 15. Schematic of Probiotic Usage

Project Advantages

This technology leverages the hypoxia-tropic engineered bacterium EcN to target and accumulate in the hypoxic, acidic microenvironment of colorectal cancer (CRC), enabling precise, localized drug release through a pH-sensitive neohesperidin synthesis system. The engineered bacteria synthesize neohesperidin directly in the gut, avoiding first-pass metabolism and gastrointestinal degradation, achieving high local enrichment. The dual suicide switches—induced by arabinose and low temperature—ensure in vivo controllability and environmental safety. Microbial fermentation significantly reduces raw material costs. The produced neohesperidin possesses multiple functions including anti-inflammatory, antitumor, and immunomodulatory effects, showing synergistic potential when combined with chemotherapy or immunotherapy, demonstrating excellent druggability and clinical prospects.

Figure 16. Advantages of the Neohesperidin-Producing Probiotic

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