The global rise in chronic colitis, especially ulcerative colitis, demands innovative therapies rooted in mechanistic insights. Dietary fiber profoundly shapes the gut microbiota and mucosal immunity. Fiber deficiency drives dysbiosis, erodes barrier integrity, and fuels inflammation. This chapter explores this axis and the therapeutic promise of GLP-1-engineered probiotics.

The Role of Dietary Fiber in Gut Health

Dietary fiber sustains gut homeostasis by fueling microbial fermentation into short-chain fatty acids (SCFAs) like butyrate, which energize colonic epithelial cells, curb inflammation, and bolster the mucus barrier. Low-fiber diets rapidly shift the microbiota toward mucus-degraders, thinning the mucus layer within days. This exposes epithelia to antigens, sparking immune activation and colitis risk.

Pathogenesis: The Fiber Deficiency–Microbiota–Colitis Axis

Fiber scarcity slashes SCFA production, impairing epithelial repair and anti-inflammatory signals. Mucus erosion enables chemokine release (e.g., CXCL2), neutrophil influx, and a proinflammatory feed-forward loop. Animal models show fiber-depleted guts exhibit dysbiosis and primed immunity, worsening dextran sulfate sodium (DSS)-induced colitis versus fiber-rich states. Clinically, low fiber correlates with severe flares and relapses, underscoring its protective role.

GLP-1 Signaling Beyond Glucose Homeostasis

Beyond incretin effects, GLP-1 from nutrient/SCFA-stimulated L-cells fortifies barriers via tight junctions (ZO-1, occludin) and dampens cytokines (TNF-α, IL-1β, IL-6). It blocks NF-κB and MAPK pathways, curbing neutrophil recruitment. SCFAs via GPR43 drive GLP-1 secretion, linking fiber to mucosal healing. Fiber deficiency disrupts this axis, heightening colitis vulnerability—making GLP-1 restoration a prime target.

Synthetic Biology: Engineered Probiotics

Synthetic biology engineers safe chassis like Lactobacillus or E. coli Nissle 1917 to produce GLP-1 in the gut, bypassing dietary needs. These probiotics colonize the colon, deliver localized therapy, minimize systemic effects, and promote anti-inflammatory taxa. Multiplexed strains could release IL-10 or antioxidants for precision modulation.

Preclinical Evidence and Mechanisms

In colitis models, GLP-1-engineered strains restore colon length, crypts, and barrier function while cutting neutrophil infiltration and myeloperoxidase. They suppress AKT/NF-κB and MAPK, replenish beneficial microbes, and alleviate weight loss, diarrhea, and bleeding. IL-10-delivering variants show similar promise, highlighting platform versatility with low systemic risks.

Expanding Therapeutic Horizons

Multiplexed probiotics now target multiple pathways: trefoil factors for healing, IL-10/IL-35 for immunity, and antioxidants for oxidative stress. This synergy tackles colitis heterogeneity.

Translating to Clinical Practice

Translation demands GMP production, safety checks (no toxigenicity, stable inserts, no gene transfer), and phased trials: phase 1 for safety, phase 2/3 versus 5-ASA/steroids/biologics. Evolving regulations address live biotherapeutics' challenges.

Patient Selection and Monitoring

Target relapsing/refractory cases with fiber insufficiency. Pair with diet, drugs, and monitoring via CRP, fecal calprotectin, endoscopy, and microbiome profiling.

Long-Term Integration and Ethics

Registries, biobanks, education, and consent ensure safety, stability, and acceptance of GMOs.

Future Directions

Personalized "sense-and-respond" strains with inflammation biosensors enable on-demand therapy. Preventive use in at-risk groups could intercept dysbiosis.

Collaborative Innovation

Societies, academia, and biotech must collaborate for scalable, regulated implementation.

Conclusion

GLP-1-engineered probiotics revolutionize fiber-deficient colitis management by merging diet, microbiota, and immunity for targeted mucosal repair. Preclinical data affirm GLP-1's anti-inflammatory, barrier-enhancing roles, disrupted by dysbiosis. Multiplexing broadens impact, shifting paradigms to microbiome-centric precision medicine.

Challenges like safety and regulation persist, but synthetic biology advances pave the way. Coupled with biosensors, these living drugs promise flare control and prevention, transforming IBD care worldwide.

References (Harvard style, selected key sources):

1. PubMed (2025) 'Engineered probiotic restores GLP-1 signaling to ameliorate fiber-deficiency exacerbated colitis'. Available at: [Accessed 9 Nov. 2025].

2. Science (2025) 'Engineered probiotic restores GLP-1 signaling to ameliorate fiber-deficiency exacerbated colitis'. Available at: [Accessed 9 Nov. 2025].

3. Zhang, L. et al. (2025) ‘Recent advances of engineered probiotics for therapeutic purposes’, ScienceDirect.

4. Jain, S. et al. (2024) ‘Revolutionizing disease treatment through bioengineered probiotics and GLP-1’, Wiley Online Library.

5. Mishra, J. et al. (2022) ‘Inflammatory Bowel Disease Therapeutics: A Focus on Engineered Probiotics’, PMC.
   (Full DOIs/details per Harvard style in final manuscript.)