Introduction
Traditional approaches to supporting neonatal gut health
The rise of modern neonatal probiotics
Integrating genomic tools into probiotic design
Challenges and regulatory considerations
The future landscape
Conclusions
References
Further reading
From ancient garlic cures to precision-engineered microbes, discover how neonatal probiotics are being reshaped by genomics and synthetic biology to safeguard the most vulnerable patients.
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Introduction
The initial 28 days of a newborn’s life, which are otherwise known as the neonatal period, represent a critical window for physiological development. During this period, the newborn gastrointestinal tract transitions from an almost sterile environment to a complex and dynamic microbial ecosystem.1
This nascent gut microbiome is uniquely vulnerable, particularly to the effects of environmental factors like delivery mode, gestational age, feeding practices, and early-life antibiotic exposure.1 Preterm infants are particularly susceptible, as they often experience delayed and aberrant colonization patterns that increase the risk of life-threatening or chronic conditions.1
Establishing a healthy gut microbiome is essential to achieve maturation of the host immune system. Early microbial colonizers are considered the primary architects of immunity, as these microorganisms engage in a bidirectional interplay with host immune cells that co-evolve to establish competence, tolerance, and homeostasis.1
Disruptions to this colonization process, often caused by factors such as cesarean section delivery, formula feeding, or antibiotic exposure, have been linked to growth faltering, inflammation, and an increased long-term risk of metabolic and immune disorders.1
Aberrant disruptions to infant gut microbiota have been implicated in the pathophysiology of severe neonatal diseases like necrotizing enterocolitis (NEC), as well as a significantly increased risk of neonatal mortality.1
Your Baby’s Gut Microbiome | GutDr Mini-Explainer
Traditional approaches to supporting neonatal gut health
Garlic (Allium sativum) has been widely used throughout history for its perceived immune-enhancing ethnobotanical properties. Recent chemical analyses have validated the antimicrobial basis of these traditional uses.2
Most ethnobotanical practices involve crushing a garlic clove, a process that leads to the enzymatic conversion of allin into allicin through allinase.2 Allicin and its derivatives ajoenes and allyl sulfides exhibit broad-spectrum bactericidal, anti-biofilm, and anti-quorum-sensing activities, primarily through the formation of disulfide bonds with the sulfhydryl groups of essential microbial enzymes.2
Garlic also exhibits prebiotic properties, as this herb selectively inhibits pathogenic enterobacteria while having a mitigated effect on beneficial Lactobacillus species.2
Despite scientific evidence confirming its potential neonatal benefits, the lack of standardization in dosing, purity, and preparation limits its clinical use.1,3 These limitations create significant safety risks, particularly to infants’ immature organ systems that are susceptible to enhanced toxicity.3 For example, the topical application of raw crushed garlic has been shown to cause severe chemical burns on the delicate skin of infants, a side effect that is rarely observed in adults.4
The rise of modern neonatal probiotics
Numerous systematic reviews and meta-analyses support the judicious use of specific probiotic strains to reduce the incidence of severe NEC and all-cause mortality in preterm infants.1,4,5 One example includes a recent comprehensive meta-analysis of nine randomized controlled trials (RCTs) involving 7,180 preterm infants, which reported that supplementation with Bifidobacterium bifidum G001 (BBG001) significantly reduced NEC, all-cause mortality, and risks.5
However, not all probiotics demonstrate consistent efficacy, and strain-specific effects remain a central challenge in neonatal applications.6,7
Certain probiotic strains exhibit different genetic capacities to metabolize human milk oligosaccharides (HMOs), which are complex carbohydrates in breast milk that are indigestible to the infant and most other gut microbes.6 As a result, Bifidobacterium longum subspecies infantis, a key gut colonizer in healthy breastfed infants, experiences a competitive advantage that allows it to dominate the early gut ecosystem and exclude potential pathogens through resource exclusion.6
Certain metabolic byproducts of HMO fermentation, primarily short-chain fatty acids (SCFAs) such as acetate and butyrate, can enhance the expression of tight junction proteins, thereby supporting gut barrier integrity. These biomolecules may also modulate the neonatal immune system by promoting anti-inflammatory pathways.6
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High-throughput technologies, such as whole-genome sequencing (WGS), have enabled the identification of strains, which supports the development of precision probiotics in neonatal care.7 Bioinformatics analyses subsequently analyze genomic data to enable in silico risk screening for virulence factor genes, toxin-producing genes, and antibiotic resistance genes (ARGs) before the strain can be considered for use in infants.7
Annotation tools can also be used to identify genes involved in metabolic pathways and predict a strain’s ability to produce beneficial compounds, such as SCFAs, tolerate host defenses, and/or adhere to the intestinal mucosa.1,4,7 Synthetic biology, an interdisciplinary field that applies engineering principles to biology, is rapidly being explored to incorporate novel functionalities into safe probiotic chassis.8
Examples include engineered probiotics designed to detect gut pathogens, secrete antimicrobial peptides, or modulate host immune responses, thereby offering therapeutic strategies beyond those of natural strains.8
These probiotic strains can be further enhanced by precision genome editing tools, such as CRISPR-Cas systems, and synthetic gene circuits, which are engineered genetic pathways that function like molecular computers.8,9
Challenges and regulatory considerations
Administering live microorganisms to immunologically immature infants, especially those who were born preterm, is associated with numerous risks, including probiotic-associated sepsis. During this type of severe reaction, the probiotic microorganism may translocate across a compromised gut barrier, causing a systemic and potentially fatal infection.7
Global regulatory landscapes have historically treated probiotics as dietary supplements, resulting in poor standardization and a lack of mandated safety or efficacy testing.7 This regulatory gap has resulted in tragic consequences, as demonstrated in October 2023, when the United States Food and Drug Administration (FDA) issued a warning to healthcare providers after linking probiotic products to over two dozen adverse events since 2018, including one infant death.10
The FDA emphasized that no probiotic has yet been approved as a drug or biologic for infants of any age, underscoring the regulatory hurdles still to be overcome.10
The FDA has since updated its regulatory framework on probiotic supplements. To this end, any probiotic intended to treat, mitigate, or prevent a disease must now undergo the same rigorous Investigational New Drug (IND) application process as any other pharmaceutical product.10
The future landscape
The modern rate of rapid technological advancement, combined with the decreasing cost of sequencing and growing sophistication of synthetic biology tools, may enable the development of “N-of-1” therapeutics.
This involves sequencing an infant’s microbiome at birth using computational models to identify specific microbial or functional deficiencies. Thereafter, infants would be administered a personalized probiotic formulation that has been specifically engineered to restore optimal physiological functionality.8,9
Next-generation probiotics (NGPs), such as Akkermansia muciniphila and Faecalibacterium prausnitzii, are under investigation for tailored therapeutic use; however, their long-term safety in neonates remains to be established.7,8
Conclusions
The evolution of neonatal gut health interventions from garlic-based approaches to the design of genomically defined and synthetically programmed probiotics represents a profound advancement in medical science.
Significant safety, manufacturing, and regulatory challenges must be overcome before a ‘theranostics’ future is achieved. Precision probiotic therapies informed by genomics and enabled by synthetic biology have the transformative potential to shift neonatal care from a reactive to a proactive paradigm.
References
- Robertson, R. C., Manges, A. R., Finlay, B. B., & Prendergast, A. J. (2019). The Human Microbiome and Child Growth – First 1000 Days and Beyond. Trends in Microbiology 27(2); 131–147. DOI:10.1016/j.tim.2018.09.008, https://www.sciencedirect.com/science/article/pii/S0966842X1830204X
- El-Saber Batiha, G., Magdy Beshbishy, A., Wasef, L., et al. (2020). Chemical Constituents and Pharmacological Activities of Garlic (Allium sativum L.): A Review. Nutrients 12(3); 872. DOI:10.3390/nu12030872, https://www.mdpi.com/2072-6643/12/3/872
- Woolf, A. D. (2003). Herbal Remedies and Children: Do They Work? Are They Harmful? Pediatrics 112(Suppl. 1); 240-246. DOI:10.1542/peds.112.s1.240, https://publications.aap.org/pediatrics/article/112/Supplement_1/240/28747/Herbal-Remedies-and-Children-Do-They-Work-Are-They
- Rafaat, M., & Leung, A. K. C. (2000). Garlic Burns. Pediatric Dermatology 17(6); 475-476. DOI:10.1046/j.1525-1470.2000.01828.x, https://onlinelibrary.wiley.com/doi/10.1046/j.1525-1470.2000.01828.x
- Abdullahi, A. M., Zhao, S., & Xu, Y. (2025). Efficacy of probiotic supplementation in preventing necrotizing enterocolitis in preterm infants: a systematic review and meta-analysis. The Journal of Maternal-Fetal & Neonatal Medicine 38(1). DOI:10.1080/14767058.2025.2485215, https://www.tandfonline.com/doi/full/10.1080/14767058.2025.2485215
- Chichlowski, M., Shah, N., Wampler, J. L., et al. (2020). Bifidobacterium longum Subspecies infantis (B. infantis) in Pediatric Nutrition: Current State of Knowledge. Nutrients 12(6); 1581. DOI:10.3390/nu12061581, https://www.mdpi.com/2072-6643/12/6/1581
- Merenstein, D., Pot, B., Leyer, G., et al. (2023). Emerging issues in probiotic safety: 2023 perspectives. Gut Microbes 15(1). DOI:10.1080/19490976.2023.2185034, https://www.tandfonline.com/doi/full/10.1080/19490976.2023.2185034
- Tiwari, A., Ika Krisnawati, D., Susilowati, E., et al. (2024). Next-Generation Probiotics and Chronic Diseases: A Review of Current Research and Future Directions. Journal of Agricultural and Food Chemistry 72(50); 27679-27700. DOI:10.1021/acs.jafc.4c08702, https://pubs.acs.org/doi/10.1021/acs.jafc.4c08702
- Cruz, K. C. P., Enekegho, L. O., & Stuart, D. T. (2022). Bioengineered Probiotics: Synthetic Biology Can Provide Live Cell Therapeutics for the Treatment of Foodborne Diseases. Frontiers in Bioengineering and Biotechnology 10. DOI:10.3389/fbioe.2022.890479, https://www.frontiersin.org/articles/10.3389/fbioe.2022.890479
- U.S. Food and Drug Administration. (2023, October 26). FDA raises concerns about probiotic products sold for use in hospitalized preterm infants. [Press release]. https://www.fda.gov/news-events/press-announcements/fda-raises-concerns-about-probiotic-products-sold-use-hospitalized-preterm-infants. Accessed
Further Reading
Last Updated: Sep 17, 2025