Lactobacillus rhamnosus
Overview
Lactobacillus rhamnosus (recently reclassified as Lacticaseibacillus rhamnosus) is a Gram-positive, non-spore-forming, facultatively anaerobic rod-shaped bacterium that has become the most extensively studied probiotic species worldwide. The strain L. rhamnosus GG (LGG, ATCC 53103), isolated from healthy human feces by Sherwood Gorbach and Barry Goldwin, has been the subject of hundreds of clinical trials spanning gastrointestinal health, immune modulation, allergy prevention, and beyond.
Key Characteristics
L. rhamnosus is known for its remarkable environmental resilience, surviving the harsh conditions of the gastrointestinal tract including low pH and bile salts. This resilience is partly due to its ability to form biofilms and produce galactose-rich exopolysaccharides that protect from environmental stressors.
Several strains show tissue-specific tropism:
- LGG: Intestinal specialist with SpaCBA pili for strong mucosal adhesion
- GR-1: Vaginal niche adaptation with superior oxidative stress resistance
- HN001: Superior eczema prevention with long-lasting effects
SpaCBA Pili: The Key to Intestinal Adhesion
LGG's unique intestinal colonization ability stems from its SpaCBA pili—heterotrimeric surface appendages that mediate adhesion to intestinal mucosa.
Pilus Structure and Function
- SpaB: Primary mucus-binding subunit with 7-fold greater binding than other pilus proteins; uses electrostatic contacts (pI 8.0)
- SpaC: Contains von Willebrand factor-like domain for lectin-type binding; directly binds immature human intestinal epithelial cells
- Antiserum effect: SpaA antiserum reduces whole-cell mucus binding 5-fold
Immunomodulatory Role
Pilus knockout mutants show drastically reduced adhesion and abolish biofilm formation. Importantly, pilus-deficient strains induce ~2-fold higher IL-8 production, demonstrating that pili dampen inflammatory responses while maintaining adhesion.
Immune System Modulation
IgA Production via p40-EGFR-APRIL Pathway
LGG secretes a protein called p40 that activates a sophisticated immune signaling cascade:
- p40 binding: Activates EGFR (epidermal growth factor receptor) on intestinal epithelial cells
- Akt phosphorylation: Leads to NF-κB p65 nuclear translocation
- APRIL release: Epithelial cells secrete APRIL (a proliferation-inducing ligand)
- IgA class switching: APRIL promotes IgA+ B cell differentiation in lamina propria
Administration of 10 μg p40 daily for 3 weeks significantly elevated fecal IgA at 2 and 3 weeks (p<0.05). Effects were abolished in intestinal epithelium-specific EGFR-knockout mice.
Dendritic Cell Activation and T Cell Regulation
LGG-derived soluble mediators modulate dendritic cell functionality:
- Significantly higher CD86 expression after TNF-α stimulation (p<0.05)
- Enhanced Foxp3+ CD25+ regulatory T cells
- Increased IFN-γ and IL-2 production in CD4+ CD25+ T cells
Th1/Th2 Balance
LGG promotes Th1 responses while modulating inflammation:
- Significantly increases IL-12 and TNF-α in macrophages (p<0.05)
- Increases anti-inflammatory IL-10
- Decreases Th2-associated cytokines (IL-4, IL-5)
- Down-regulates TLR2 on DCs, macrophages, and monocytes
Gut Barrier Function
Tight Junction Enhancement
L. rhamnosus strains significantly enhance intestinal barrier integrity:
| Study | Model | Key Findings |
|---|---|---|
| OLL2838 strain | DSS colitis mice | ZO-1 increased 4.8-fold; FITC-dextran permeability significantly decreased |
| CY12 strain | LPS-challenged Caco-2 | Upregulated occludin, ZO-1, claudin (p<0.05); inhibited TLR4/NF-κB pathway |
Mucus Production
LGG's p40 protein activates EGFR → Akt → Muc2 gene expression pathway:
- MUC2 mRNA increased 2.5-3.5 fold at 50 ng/mL p40
- Thickened colonic mucus layer in wild-type mice
- Increased MUC2-positive goblet cells per crypt (p<0.05)
- Effects abolished with EGFR or Akt inhibition
Competitive Exclusion of Pathogens
LGG produces lectin-like molecules (Llp1, Llp2) that specifically disrupt pathogen biofilms:
- Salmonella typhimurium: 90% biofilm reduction at 200 μg/mL Llp2
- E. coli UTI89: 88-90% reduction at 50 μg/mL
- Beneficial effect: ~2-fold increased biofilm of other Lactobacillus strains
Clinical Evidence: Antibiotic-Associated Diarrhea
LGG demonstrates strong evidence for AAD prevention. A systematic review of 12 RCTs (n=1499) showed:
| Outcome | LGG | Placebo | Relative Risk | 95% CI |
|---|---|---|---|---|
| Overall AAD | 12.3% | 22.4% | 0.49 | 0.29-0.83 |
| Children | - | - | 0.48 | 0.26-0.89 |
| H. pylori eradication AAD | - | - | 0.26 | 0.11-0.59 |
Number needed to treat: 7 to prevent one case of AAD.
Clinical Evidence: Acute Gastroenteritis
Contrasting Results
A landmark NEJM trial (n=971 children) showed no benefit of LGG for acute gastroenteritis in North American emergency departments:
- Moderate-to-severe gastroenteritis: LGG 11.8% vs placebo 12.6% (RR 0.96, p=0.83)
- Median diarrhea duration: 49.7 vs 50.9 hours (p=0.26)
However, meta-analysis of 18 trials (n=4,208) found:
- Diarrhea duration reduction: -0.85 days (CI -1.15 to -0.56)
- More effective at doses ≥10¹⁰ CFU daily
- Greater efficacy in European vs non-European settings
Rotavirus Mechanism
LGG inhibits rotavirus-induced chloride secretion and oxidative stress. Both live bacteria and conditioned medium (postbiotic):
- Significantly reduced short-circuit current
- Maintained TEER (transepithelial electrical resistance)
- Reduced ROS and maintained GSH/GSSG ratio
- Inhibited caspase-3-mediated apoptosis and NF-κB p65 translocation
Clinical Evidence: Allergy and Eczema Prevention
Landmark Finnish Study
A double-blind RCT (n=132) provided breakthrough evidence for prenatal/postnatal LGG in allergy prevention:
| Outcome | LGG Group | Placebo Group | p-value |
|---|---|---|---|
| Atopic eczema | 23% (15/64) | 46% (31/68) | 0.008 |
| Relative risk | 0.51 | - | - |
| NNT | 4.5 | - | - |
Intervention: LGG administered 2-4 weeks before delivery + 6 months postnatally.
Strain Comparison: HN001 vs LGG
A comparative trial (n=474) showed L. rhamnosus HN001 achieved superior outcomes:
- Eczema prevention: HR 0.51 (95% CI 0.30-0.85, p=0.01)
- Skin prick test sensitization: HR 0.69 (95% CI 0.48-0.99)
- Effects persisted to age 6 years
- Mechanism: Increased cord blood IFN-γ, breast milk TGF-β and IgA
Clinical Evidence: Respiratory Infections
LGG significantly reduces respiratory infections in children attending daycare:
| Outcome | Relative Risk | 95% CI | NNT |
|---|---|---|---|
| URTI | 0.66 | 0.52-0.82 | 5 |
| Respiratory infections ≥3 days | 0.57 | 0.41-0.78 | 5 |
| Symptom duration | Significantly lower | - | - |
Study: 281 children, 10⁹ CFU LGG daily for 3 months (p<0.001 for duration).
Gut-Brain Axis Effects
Anxiety and Mood
Early-life LGG colonization in mice reduces anxiety-like behavior in adulthood through:
- EGFR activation → increased SERT expression
- Increased BDNF and GABA receptors in hippocampus/amygdala
- Enhanced gut barrier (ZO-1, villus length, crypt depth)
- Modulated intestinal serotonergic system
Cognitive Function
In a human trial (n=145), LGG supplementation improved cognition in impaired adults:
- Total Cognition Score: 38.7→47.6 (RCI=2.07) vs placebo 37.7→42.4 (p=0.03)
- Effect size: ηp²=0.03
- Mechanisms: Reduced IL-8, enhanced CREB/BDNF, improved glucose/insulin sensitivity
Colonization and Persistence
LGG colonization studies (n=21) reveal important kinetics:
| Time Point | Biopsy Recovery | Fecal Recovery |
|---|---|---|
| Immediately post-dosing | 100% | 100% |
| 1 week post | 88% | 25% |
| 2 weeks post | 29% | 0% |
Biopsy counts ranged from 6×10¹ to 4×10⁴ CFU/biopsy (mean 6×10³). Notably, LGG persists on colonic mucosa even after becoming undetectable in feces, indicating that fecal analysis underestimates true colonization.
Strain Comparison: LGG vs GR-1
Comparative genomic analysis reveals niche-specific adaptations:
| Feature | LGG | GR-1 |
|---|---|---|
| Primary niche | Intestinal | Vaginal |
| SpaCBA pili | Present | Absent |
| Gastric acid survival | Superior | Moderate |
| Oxidative stress resistance | Moderate | Superior (0.1% H₂O₂) |
| Lactose metabolism | No | Yes |
| Fucose metabolism | Yes | No |
| Inflammatory induction | TNF, IL-8, IL-6 in vaginal cells | No TNF/IL-8 induction |
| Unique orthogroups | 270 | 48 |
GR-1 is specifically adapted for urogenital health applications, typically used with RC-14 for vaginal health.
Safety Profile
General Safety
LGG has Generally Recognized as Safe (GRAS) status and is well-tolerated in healthy populations. Dropout rates are comparable between probiotic (6%) and placebo (13%) groups across trials.
Bacteremia Risk
A comprehensive review of 75 bacteremia cases reveals important safety considerations:
| Risk Factor | Prevalence/Incidence |
|---|---|
| Hospitalized patients | 0.1-0.2% of blood isolates |
| Immunocompromised | 0.5% of blood isolates |
| Pediatric ICU receiving LGG | 1.1% vs 0.009% not receiving |
| Overall mortality | 30% |
| 1-year mortality | 48% |
High-risk populations (caution/contraindicated):
- Critically ill ICU patients
- Severely immunocompromised individuals
- Patients with central venous catheters
- Post-surgical patients with intestinal barrier disruption
- Hematopoietic cell transplant recipients
Antibiotic Susceptibility
| Antibiotic | Susceptibility |
|---|---|
| Erythromycin | 94.3% susceptible |
| Clindamycin | 90.0% susceptible |
| Penicillin | 63.6% susceptible |
| Vancomycin | 22.5% susceptible (intrinsic resistance) |
Recommended Dosing
| Indication | Dose | Duration |
|---|---|---|
| AAD prevention | ≥10¹⁰ CFU daily | During antibiotic course |
| Acute gastroenteritis | 10¹⁰ CFU twice daily | 5 days |
| Respiratory infection prevention | 10⁹ CFU daily | 3 months |
| Eczema prevention | 6×10⁹ CFU daily | Prenatal + 2 years postnatal |
| Mucosal colonization | ~6×10¹⁰ CFU/day | 12 days minimum |
Summary of Clinical Efficacy
Strong Evidence
- Antibiotic-associated diarrhea prevention (63% risk reduction, NNT=7)
- Eczema prevention with prenatal/early-life supplementation (49-51% risk reduction)
- Upper respiratory tract infection reduction in children (34% risk reduction, NNT=5)
- Healthcare-associated diarrhea prevention in hospitalized children
Moderate Evidence
- Traveler's diarrhea prevention (up to 39.5% protection at specific locations)
- Cognitive improvement in cognitively impaired older adults
- Metabolic health improvements in obesity
- Gut-brain axis effects on anxiety and mood
Negative or Inconsistent Evidence
- Acute gastroenteritis treatment in North American children (NEJM 2018)
- General atopy prevention (inconsistent across studies)
- URTI frequency reduction (may affect severity, not frequency)