Lactobacillus bulgaricus

Lactobacillus bulgaricus (Lactobacillus delbrueckii subsp. bulgaricus)

1. Identity, Nomenclature, and Natural Sources

Scientific Names and Taxonomic History

The full current scientific name of this organism is Lactobacillus delbrueckii subsp. bulgaricus, though it remains widely known by its older and more popular name, Lactobacillus bulgaricus. In bacterial taxonomy, the basionym was Thermobacterium bulgaricum Orla-Jensen, 1919. The entity became Lactobacillus bulgaricus in 1973 with the work of Rugosa and Hansen, and was reclassified as a subspecies under Lactobacillus delbrueckii in 1984. In 2020, the entire Lactobacillus genus underwent a major reclassification based on genomic data. Remarkably, L. delbrueckii and its bulgaricus subspecies retained their original placement within the genus.

Per the NCBI Taxonomy Browser, the organism is classified within: cellular organisms → Bacteria → Bacillati → Bacillota → Bacilli → Lactobacillales → Lactobacillaceae → Lactobacillus → Lactobacillus delbrueckii.

Physical and Microbiological Characteristics

Lactobacillus delbrueckii subsp. bulgaricus is a Gram-positive, facultatively anaerobic, non-motile, non-spore-forming, rod-shaped bacterium measuring 0.5–0.8 μm in width and 2.0–9.0 μm in length. It is a Gram-positive rod, nonmotile, and does not form spores. It is regarded as aciduric or acidophilic, since it requires a low pH environment. As a homofermentative lactic acid bacterium, it metabolizes carbohydrates with lactic acid as the major end product. It grows best at temperatures between 40–44°C, which is why traditional yogurt is made in warm conditions.

Natural Sources and Habitat

First identified in 1905 by the Bulgarian doctor Stamen Grigorov, the bacteria can be found naturally in the gastrointestinal tract of mammals living in the Sofia region and along the Balkan Mountain (Stara Planina) mesoregion of the Balkan Peninsula. The subspecies is primarily found in plant-derived materials and associated environments, such as grains, vegetables, and decaying vegetation, rather than being a dominant component of soil or aquatic ecosystems. Strains have been isolated from various wild plants including watercress (Nasturtium officinale), sheep's sorrel (Rumex acetosella), wheat (Triticum spp.), barley (Hordeum vulgare), ryegrass (Lolium spp.), field mustard (Sinapis arvensis), and trees like cypress (Cupressocyparis spp.).

One strain, Lactobacillus bulgaricus GLB44, is extracted from the leaves of Galanthus nivalis (the snowdrop flower) in Bulgaria. GLB44 is derived from the leaves of the snowdrop plant; it is the only known strain of this subspecies that has a vegan origin (not from yogurt) and it is considered a probiotic.

Common Preparations and Dosage Forms

Lactobacillus delbrueckii subsp. bulgaricus is commonly used alongside Streptococcus thermophilus as a starter for making yogurt. It is well known as a food additive and dietary supplement, and is one of the components required by the FDA to be included in any product identified as "yogurt." Beyond fermented dairy, it is available in:

• Fermented dairy products: yogurt (all commercial yogurts in the US must contain L. bulgaricus plus S. thermophilus), Greek yogurt, kefir.
• Dietary supplement capsules and powders: L. delbrueckii is available over the counter as a supplement and in some fermented foods, and is used to improve gut and brain health, though its benefits are not fully defined.
• Multi-strain probiotic formulations: The commercially available probiotic VSL#3 contains a combination of eight lactic acid bacteria, including L. delbrueckii subsp. bulgaricus, L. casei, L. acidophilus, Bifidobacterium breve, B. longum, B. infantis, and Streptococcus salivarius subsp. thermophilus.

---

2. Traditional and Historical Use

Ancient and Pre-Scientific Use in the Balkans

Bulgarian yogurt, known as kiselo mlyako, holds a revered place in Bulgarian culture. Its origins date back centuries, when shepherds in the Balkan region discovered that milk stored in animal skins naturally fermented into a thick, tangy, and nutritious product. The key to this process was the presence of Lactobacillus bulgaricus, a strain native to Bulgaria's natural environment. Bulgaria's affectionate relationship with yogurt dates back to the Thracians, ancient inhabitants of the Bulgarian lands, when stock-breeders placed sheep's milk in lambskin bags around their waists and fermented yogurt using their own body heat. The word "yogurt" is derived from the words for "thick" and "milk" in ancient Thracian.

Bulgarian yogurt became more than a dietary staple. It was celebrated for its health-promoting properties, including aiding digestion and boosting vitality. For Bulgarians, Lactobacillus bulgaricus is a source of national pride, deeply ingrained in the country's traditions. Families have passed down yogurt-making techniques for generations, preserving the authentic methods that ensure the probiotic's vitality.

Scientific Discovery in the Early 20th Century

In 1905, Bulgarian physician Stamen Grigorov discovered the lactic acid bacterium responsible for fermenting kiselo mlyako — Bulgaria's traditional yogurt. His identification of the rod-shaped Lactobacillus bulgaricus marked a milestone in microbiology. Dr. Grigorov, at the time a fourth-year medical student at Geneva University, undertook research on Bulgarian yogurt and found that the cause of fermentation was due to one rod-shaped and one spherical bacterium. Notice of his discovery was published in Revue Médicale de la Suisse Romande, issue 10, dated 20 October 1905.

Professor Ilya Metchnikoff confirmed the discovery of Dr. Grigorov three years later. His assistants Koendi and Mikelson (1907) named the microorganism discovered by Grigorov Bacillus bulgaricus (Grigorov), currently known under Bergey's Classification of Bacteria as Lactobacillus delbrueckii subsp. bulgaricus.

Grigorov's discovery caught the attention of Nobel Prize-winning scientist Ilya Mechnikov, who associated the longevity of Bulgarian villagers with their daily yogurt consumption. Mechnikov suggested that L. bulgaricus might help combat ageing by suppressing harmful bacteria in the colon, a theory that boosted yogurt's reputation as a health food worldwide. Proteolytic bacteria such as clostridia, which are part of the normal intestinal flora, produce toxic substances including phenols, ammonia and indoles by digestion of proteins. These compounds are responsible for what Metchnikoff called "intestinal auto-intoxication," which, according to him, was the cause of the physical changes associated with old age. It was already known at that time that fermentation with lactic acid bacteria inhibits the deterioration of milk because of its low pH. Metchnikoff's research also noted that rural populations in Southeastern Europe and the Russian steppes who daily consumed milk fermented with lactic acid bacteria lived relatively longer than other populations.

Interested in Grigorov's discoveries, Ilya Metchnikoff — a Nobel Prize laureate in Physiology and Medicine — went on to find that more people lived to the age of 100 in Bulgaria than in any of the 36 other countries he studied. He directly linked this to the country's most traditional food: yogurt. Promotion of Bulgarian yogurt in other European countries had begun even earlier, after the reported recovery of the French King Francis I (1515–1547), who had suffered a stomach disease.

---

3. Key Constituents and Active Compounds

Lactic Acid

Lactobacillus bulgaricus plays a key role in fermenting milk into yogurt. It converts lactose into lactic acid, giving yogurt its characteristic sour taste, thick texture, and natural preservation properties. Certain physiological properties of lactic bacteria are of particular importance in the mechanism of their probiotic functioning: metabolism leading to accumulation of organic acids and other fermentation products in the media; resistance to those metabolites; and competitive assimilation of the major nutrients of the media. The production of lactic acid lowers the pH of the intestinal environment, which provides significant antimicrobial effect of probiotics towards pathogens and potentially pathogenic microorganisms.

Exopolysaccharides (EPS)

In dairy fermentations, S. thermophilus and L. delbrueckii subsp. bulgaricus play a pivotal role in acidification, proteolysis, and the synthesis of exopolysaccharides (EPS), which can affect the products' texture, viscosity, and flavor profile. Exopolysaccharides produced by lactic acid bacteria play a role in the rheology and texture of fermented milks and could also provide a new source of safe additives for use in various food products. The physical properties of EPS depend on several factors, including sugar composition, type of sugar linkages, the presence of organic or inorganic substituents, the degree of polymerization, and the length of the side chains.

EPS from specific strains — particularly the immunologically active strain OLL1073R-1 — have attracted considerable scientific attention. OLL1073R-1 was selected for its ability to produce large amounts of immunomodulatory exopolysaccharide (EPS). OLL1073R-1 and its derived EPS (R-1 EPS) can augment NK cell activity, and R-1 EPS shows anti-influenza virus effects both in vitro and in vivo. The ability of R-1 EPS to promote IFN-γ production followed by activation of NK cell cytotoxicity has been well studied in vitro, in vivo, and in clinical studies.

Bacteriocins

Peptides, exopolysaccharides, bacteriocins, some amylase, protease, lipase enzymes, and lactic acid are the major bioactive molecules produced by lactic acid bacterial activity during fermentation. Some strains of L. d. bulgaricus, such as L. bulgaricus GLB44, produce bacteriocins, which have been shown to kill undesired bacteria in vitro. Research aimed at isolating bacteriocin-producing lactic acid bacteria with high wide-spectrum antibacterial activity found that seven LAB strains, including Lactobacillus delbrueckii ssp. bulgaricus (BB18), isolated from authentic Bulgarian dairy products were capable of producing bacteriocins inhibiting the widest range of pathogenic bacteria. The bacteriocins were resistant to heating at 121°C for 15 minutes, stable at pH 2–10, sensitive to protease, and insensitive to alpha-amylase and lipase. Two of the bacteriocins produced by L. bulgaricus BB18 (bulgaricin BB18) were purified and their molecular masses determined. Furthermore, bulgaricin BB18 strongly inhibits Helicobacter pylori.

Bioactive Peptides and Proteolytic Activity

Lactobacillus delbrueckii subsp. bulgaricus, commonly used in yogurt production, is associated with lactose metabolism, and its metabolic characteristics are shaped by its genetic composition and growth conditions. Many beneficial effects are elicited by components of the bacteria cell membrane or secreted molecules, such as cell surface proteins, exopolysaccharides, bioactive metabolites, and peptides. Proteolysis during fermentation releases bioactive peptides from milk proteins, which may contribute to downstream health effects.

β-Galactosidase (Lactase)

Despite poor gut colonization, L. bulgaricus produces β-galactosidase (lactase) in the gut during transit, improving lactose digestion — making yogurt better tolerated than plain milk for lactose-intolerant individuals. This enzymatic activity is central to the well-established benefit of yogurt consumption in lactose maldigestion (see Section 5 below).

---

4. Mechanisms of Action

Acidification and Competitive Exclusion

According to Metchnikoff's research, the aging process results from the activity of putrefactive (proteolytic) microbes producing toxic substances in the large bowel. He knew that milk fermented with lactic acid bacteria inhibits the growth of proteolytic bacteria because of the low pH produced by the fermentation of lactose. This competitive exclusion mechanism, mediated primarily through lactic acid production and the resulting acidic milieu, remains one of the most well-understood functions of L. bulgaricus.

Immunomodulation via Exopolysaccharides

The mechanisms by which orally administered R-1 EPS modulates immune function in vivo remain not fully elucidated, but studies using mice have shown that oral administration of R-1 EPS enhances NK cell activity in the spleen and increases antibody production in the bronchi. Clinical studies have demonstrated that consuming yogurt fermented with OLL1073R-1 leads to an increase in peripheral blood NK activity and dendritic cell activity. Based on these studies, researchers hypothesize that R-1 EPS exerts its immunomodulatory effect by initially interacting with immune cells in the intestinal mucosa or circulating blood and subsequently stimulating the immune response in peripheral tissues via cytokine production and immune cell migration.

Intestinal Barrier and Mucosal Immunity

L. delbrueckii maintains and improves the intestinal barrier function by stimulating immune cells, and has also improved intestinal integrity and immune responses in animal models. Lactic acid bacteria regulate pro-inflammatory cytokines, stimulate immunoglobulin secretion, and reduce oxidative stress, improving gut and systemic health.

Short-Chain Fatty Acid (SCFA) Production

After yogurt intake containing L. bulgaricus strains, studies have found an increase of lactic acid bacteria and a decrease of Bacteroides-Prevotella-Porphyromonas, with detectable increases in acetic, butyric, and 2-hydroxy-butyric acids in feces. The LB42 strain, in a clinical study, enhanced IgA/IgG responses and reshaped gut microbiota by enriching short-chain fatty acid producers and reducing inflammation.

Antigenotoxic Effects

L. delbrueckii subsp. bulgaricus was determined to be antigenotoxic in laboratory research (Wollowski et al., J. Nutr., 1999), with bacteria used for yogurt production shown to inactivate carcinogens and prevent DNA damage in the colon of rats.

---

5. Scientific Evidence by Area of Use

5.1 Lactose Digestion and Lactose Intolerance

Evidence strength: Moderate to strong (for yogurt consumption; weaker for isolated supplementation).

Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus improve lactose digestion and reduce symptoms related to lactose intolerance. This was confirmed in a number of controlled studies with individuals consuming yogurt with live cultures. This position is endorsed by the World Gastroenterology Organisation (WGO) in its 2023 Global Guidelines on Probiotics and Prebiotics.

Scientific studies have shown that consuming yogurt containing live cultures, including L. delbrueckii bulgaricus, improves lactose digestion and reduces symptoms such as bloating, gas, and diarrhea in lactose-intolerant individuals. However, the evidence is not as strong for the use of isolated L. delbrueckii bulgaricus supplements; most studies focus on the consumption of fermented dairy products containing this bacterium in combination with Streptococcus thermophilus. Meta-analyses and clinical trials support the beneficial role of yogurt with live cultures in lactose intolerance, but the effect is attributed to the overall product rather than L. delbrueckii bulgaricus alone. Therefore, while there is moderate scientific evidence supporting its use (especially in yogurt), the evidence for isolated supplementation is less robust.

In 2010, the European Food Safety Authority (EFSA) evaluated health claims related to live yogurt cultures. The EFSA published a "Scientific Opinion on the substantiation of health claims related to live yoghurt cultures and improved lactose digestion" (EFSA Journal, 2010;8(10):1763), which underpins the regulatory recognition in the EU of the lactose digestion benefit for yogurt bacteria including L. bulgaricus.

5.2 Immune Function and Reduction of Infections

Evidence strength: Moderate (for specific strains, particularly OLL1073R-1, in elderly populations).

Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1, a polysaccharide-producing lactic acid bacterial strain, has been confirmed by studies using mice to exhibit more marked effects on the immune system than other lactic acid bacteria. Several clinical studies have demonstrated the immunomodulatory effects of yogurt fermented with OLL1073R-1 and OLS3059. These effects include enhanced NK cell activity, increased antibody production in serum and saliva, and improvement in subjective symptoms.

Earlier research highlighted that the intake of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 probiotic markedly reduces the occurrence of the common cold in elderly individuals. A study published in the British Journal of Nutrition (Makino et al., 2010) reported this finding in elderly subjects consuming OLL1073R-1 yogurt. Strain OLL1073R-1 has been shown beneficial to older people by preventing infection with influenza A virus subtype H3N2 via increasing the production of H3N2-bound salivary IgA and improving mucosal immune function.

Several clinical studies suggest a potential inhibitory effect of yogurt fermented with OLL1073R-1 against infections. The effects include reducing the risk of catching the common cold, enhancing dendritic cell and natural killer cell activities, and augmenting antibody production in serum and saliva. Taken together with the results of previous clinical studies, it may be concluded that consumption of yogurt fermented with OLL1073R-1 augmented the serum antibody titer against the seasonal influenza vaccine, suggesting the potential of R-1 EPS as a vaccine adjuvant.

An important limitation is that most immune studies have been conducted using a specific strain (OLL1073R-1) rather than generic L. bulgaricus, and effects are understood to be strain-specific. Research in elderly populations is the most developed, with effects in younger, healthy adults less well characterized.

5.3 Anti-Fatigue Effects

Evidence strength: Preliminary (single randomized controlled trial).

A previous study showed that Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 produces high amounts of exopolysaccharide (EPS), which can induce interferon (IFN)-gamma production and augment natural killer (NK) cell activity in mice. In the elderly, ingestion of yogurt fermented using this strain was also shown to augment NK cell activity and reduce the risk of catching colds. A 12-week randomized, double-blind, placebo-controlled trial (published in Nutrients, PMC6073584) examined OLL1073R-1 yogurt in healthy people experiencing summer heat fatigue. Primary outcome measures included between-group differences in the scores of questionnaires associated with potent symptoms of summer fatigue (VAS, Profile of Mood States, Face Scale) and NK cell activities. This trial represented early human evidence for anti-fatigue properties but requires replication before conclusions can be drawn.

5.4 Metabolic Effects: Body Weight and Blood Lipids

Evidence strength: Preliminary (small pilot trial; mixed results).

A randomized pilot trial aimed to evaluate the efficacy of Lactobacillus delbrueckii ssp. bulgaricus in improving body weight, obesity-related outcomes, and lipid profiles of overweight people. Thirty-six overweight participants were randomly assigned to either a probiotic or a placebo group. A placebo powder or L. bulgaricus powder containing 1 × 10⁸ CFU of the probiotic was administered daily for 12 weeks. L. bulgaricus supplementation under the conditions of this trial did not affect body weight, fat percentage, or body mass index (BMI) of the participants, while it resulted in a notable decrease in blood triglyceride (TG) levels, which corresponded to a lowering of the TG proportion in the composition of large VLDL (L–XXL sized fractions) and HDL (M and L fractions) in the probiotic-treated group. The small sample size (n=36) and single-center nature of the pilot study represent significant limitations; the findings require confirmation in larger trials.

5.5 Gestational Diabetes Mellitus

Evidence strength: Limited (a small number of clinical trials; results are preliminary).

Clinical trials have revealed that L. bulgaricus can improve various inflammation and oxidative stress biomarkers in women with gestational diabetes mellitus. In a study of 64 pregnant women with gestational diabetes, L. delbrueckii reduced weight gain and fasting blood sugar compared to the placebo. Research on anti-inflammatory and immunomodulatory benefits includes the finding that Lactobacillus delbrueckii subsp. bulgaricus LBY-2 has shown to improve several inflammatory and oxidative stress biomarkers in women with gestational diabetes mellitus. These findings are promising but rest on a limited evidence base.

5.6 Atopic Dermatitis (Inflammatory Skin Disease)

Evidence strength: Preliminary (one cell culture study; animal models; no large human RCTs confirmed).

L. delbrueckii subsp. bulgaricus may be involved in regulation of immune factor secretion in patients with atopic dermatitis. In animal research, oral administration with L. delbrueckii subspecies bulgaricus OLL1073R-1 attenuated dermatitis by inhibiting the IL-6 response and restoring the elevation of serum amyloid levels in the NC/Nga mouse model of atopic dermatitis. A cell culture study in which immune cells were treated with L. bulgaricus cells showed that after 48- and 72-hour treatments, L. bulgaricus may control the secretion of various cytokines in atopic dermatitis patients, suggesting it may be a potential treatment upon further study. Robust human clinical trial data are lacking for this indication.

5.7 Gastrointestinal Function and Gut Microbiota Modulation

Evidence strength: Moderate for gut microbiota modification; limited for specific GI disease endpoints.

L. delbrueckii can tolerate industrial and gastrointestinal stressors, and this property can be enhanced by incorporating these microorganisms into dairy matrices. The biotherapeutic activity of L. delbrueckii has been demonstrated in intestinal inflammation, enteric infections, and metabolic and psychological disorders.

A 2025 randomized placebo-controlled clinical trial evaluated strain LB42. The clinical trial revealed improved gastrointestinal function, sleep quality, and reduced fecal calprotectin. Genomic screening confirmed the absence of pathogenic, resistance, or virulence genes. LB42 exhibited no cytotoxicity or hemolysis, showed broad antibiotic sensitivity, and adhered strongly to Caco-2 cells. Acute oral toxicity testing revealed no adverse effects in mice. In humans, LB42 was well tolerated without biochemical or hematological abnormalities, and no adverse events or allergic reactions were reported.

A study exploring the genetic diversity of L. delbrueckii subsp. bulgaricus isolated a probiotic-resistant strain (K98) with resistance to bile and high acidity. Qualitative and quantitative changes in intestinal microbiota were found after ingestion of a homemade yogurt containing this strain, with a concomitant increase in fecal short-chain fatty acids.

5.8 Gastrointestinal Survival and Colonization Potential

A subject of long-standing scientific debate has been whether L. bulgaricus can survive the acidic and bile-rich conditions of the upper gastrointestinal tract. There is significant controversy as to the survival of yogurt bacteria after passage through the human gastrointestinal tract. Survival of both species in human feces was investigated by culture on selective media. Out of 39 samples recovered from 13 healthy subjects over a 12-day period of fresh yogurt intake, 32 and 37 samples contained viable S. thermophilus (median value of 6.3 × 10⁴ CFU g^-1 of feces) and L. delbrueckii (median value of 7.2 × 10⁴ CFU g^-1 of feces), respectively. The results indicate that substantial numbers of yogurt bacteria can survive human gastrointestinal transit.

Animal model studies using fistulated minipigs confirmed that S. thermophilus and L. delbrueckii subsp. bulgaricus are usually not part of the indigenous flora of mammals, though they can survive transit. Despite survival in transit, the organism is generally characterized as a transient rather than permanently colonizing species. Specific strains such as KLDS 1.0207 exhibit desirable probiotic properties including high acid and bile tolerance, enabling survival in the gastrointestinal tract, and adhesion to gut mucosa, which facilitates colonization and interaction with host cells. These attributes contribute to its potential as a probiotic candidate, though efficacy is strain-specific.

---

6. Body Systems Associated with Lactobacillus bulgaricus

• Gastrointestinal system: While it may not permanently colonize the gut, L. bulgaricus can support digestive health and help maintain a balanced gut microbiome during consumption.
• Immune system: It has demonstrated immunoregulatory capabilities and has suppressed lung inflammation in mice with asthma, with its exopolysaccharides shown to inhibit influenza virus infection in lung cells.
• Metabolic/cardiovascular system: Preliminary evidence suggests a role in blood triglyceride reduction, as shown in the 2024 pilot trial described above.
• Integumentary (skin) system: Preliminary in vitro and animal data suggest modulation of the immune cytokine balance relevant to atopic dermatitis.
• Reproductive/endocrine system: Limited evidence from small trials in gestational diabetes shows effects on inflammatory and oxidative stress markers.
• Microbiome (broadly): Probiotics of this type confer health advantages by modifying the gut microbiota, limiting pathogen colonisation, regulating the host immunological response, reducing serum cholesterol, and exhibiting antidiabetic, antihypertensive and antioxidant actions, and creating bacteriocins.

---

7. Dosage Forms and Dosages Reported in Studies

No universally accepted standard clinical dose for isolated L. bulgaricus supplementation has been established. The following dosages appear in published research and regulatory contexts:

• Yogurt (most studied delivery vehicle): The WGO confirms benefit from yogurt with live cultures in lactose intolerance based on a number of controlled studies. A typical commercial yogurt serving provides approximately ≥10⁸ CFU/g at manufacture.
• Pilot trial for overweight/lipid management: A placebo powder or L. bulgaricus powder containing 1 × 10⁸ colony-forming units (CFU) of the probiotic was administered daily for 12 weeks.
• Registered trial for intestinal/immune function: A registered clinical trial used Lactobacillus delbrueckii subsp. bulgaricus LB42 at 30 billion CFU per day (3 g), administered daily for 8 weeks.
• General supplement range: A typical dosage of L. d. bulgaricus in supplements ranges from one billion to about a hundred billion live bacteria per dose. There is no established optimal amount.

---

8. Safety Profile, Regulatory Status, and Interactions

Regulatory Status

Lactobacillus delbrueckii subsp. bulgaricus is recognized as a probiotic microorganism by the World Health Organization (WHO) and Food and Agriculture Organization (FAO), with strains demonstrating safety for human consumption. It holds Generally Recognized as Safe (GRAS) status from the U.S. Food and Drug Administration (FDA) and Qualified Presumption of Safety (QPS) from the European Food Safety Authority (EFSA), supporting its use in food and supplements without safety concerns for healthy individuals.

General Safety

Few plasmids were identified in L. delbrueckii, reducing the spread of antibiotic-resistance genes. Additionally, this species has a lower capacity to act as a pathogen. Genomic analysis of representative strains has confirmed the absence of antibiotic resistance genes, genes encoding toxins, and virulence factor genes in risk-associated sequences. Safety has also been confirmed by indole assay, nitroreductase assay, and antibiotic resistance tests.

Genomic screening confirmed the absence of pathogenic, resistance, or virulence genes in the LB42 strain. It exhibited no cytotoxicity or hemolysis, showed broad antibiotic sensitivity, and adhered strongly to Caco-2 cells. Acute oral toxicity testing revealed no adverse effects in mice. In humans, it was well tolerated without biochemical or hematological abnormalities, and no adverse events or allergic reactions were reported.

Common Adverse Effects

Common side effects include gas and an upset stomach. Serious side effects are rare but include infections in some people who are at high risk for infections. These mild GI effects are consistent with the general profile of lactic acid bacteria probiotics.

Antibiotic Interactions

A clinically relevant consideration is the interaction between probiotic viability and antibiotic use. Human subjects in gastrointestinal survival studies had not received any antibiotic treatment during the 3 months preceding the study, recognizing that concurrent antibiotic therapy substantially reduces viable probiotic cell counts. Concurrent administration with broad-spectrum antibiotics is generally expected to reduce or eliminate the viability and therefore the functional activity of L. bulgaricus in the gut.

Immunocompromised Individuals

Serious side effects are rare but include infections in some people who are at high risk for infections. This is consistent with the broader scientific literature on live probiotic bacteria, which indicates that immunocompromised individuals, patients with severe illness, or those with indwelling catheters may be at elevated (though still very low) risk of bacteremia from LAB organisms. However, the specific pathogenic risk for L. bulgaricus in such populations is considered very low given its limited pathogenic capacity.

Strain Specificity of Effects

A central safety and efficacy principle that applies to L. bulgaricus is that effects are strain-specific. The benefits of probiotics are reported to be strain-specific and depend on the host's baseline immune competence. Commercial and research strains are not interchangeable, and safety or efficacy data from one strain (e.g., OLL1073R-1, IDCC 3601, LB42) cannot automatically be generalized to others.

Exclusion Criteria Observed in Clinical Trials

Published clinical trials have used the following exclusion criteria, reflecting real contraindications and conditions relevant to safe use: Exclusion criteria in trials of OLL1073R-1 yogurt have included presence of immunodeficiency, malignancy, drug treatment, allergies to food or medicines, lactose intolerance, regular alcohol intake of more than 60 g/day, frequent pre-existing use of fermented milk or beverages containing lactic acid bacteria, and intake of antibiotics, laxatives, or functional foods in the preceding months.

---

References

• Wikipedia — Lactobacillus delbrueckii subsp. bulgaricus
• Chu et al. (2024). "The Efficacy of Lactobacillus delbrueckii ssp. bulgaricus Supplementation in Managing Body Weight and Blood Lipids of People with Overweight: A Randomized Pilot Trial." Metabolites. PMC10890272
• PMC10417365 — "A Comprehensive Review of Bioactive Compounds from Lactic Acid Bacteria: Potential Functions as Functional Food in Dietetics and the Food Industry." PMC
• "The Bacteriocins Produced by Lactic Acid Bacteria and the Promising Applications in Promoting Gastrointestinal Health." PMC11640443
• Beshkova et al. (2009). "Characterization and antimicrobial spectrum of bacteriocins produced by lactic acid bacteria isolated from traditional Bulgarian dairy products." PubMed PMID 19200334
• World Gastroenterology Organisation (WGO) Global Guidelines: Probiotics and Prebiotics (2023)
• EFSA NDA Panel (2012). Scientific Opinion on health claims related to L. acidophilus, L. delbrueckii, and S. thermophilus. EFSA Journal
• "Lactobacillus spp. for Gastrointestinal Health: Current and Future Perspectives." PMC9019120
• PMC6073584 — "Anti-Fatigue Effects of Yogurt Fermented with Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 in Healthy People Suffering from Summer Heat Fatigue: A Randomized, Double-Blind, Placebo-Controlled Trial."
• Elli et al. (2006). "Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus survive gastrointestinal transit of healthy volunteers consuming yogurt." LWT — Food Science and Technology
• PMC93140 — "Survival of Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus in the Terminal Ileum of Fistulated Göttingen Minipigs." PMC
• PubMed PMID 23889646 — "Screening in a Lactobacillus delbrueckii subsp. bulgaricus collection to select a strain able to survive to the human intestinal tract."
• ScienceDirect — "Health-promoting effects and safety aspects of Lactobacillus delbrueckii: A food industry species." (2024)
• ScienceDirect — "Yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 and Streptococcus thermophilus OLS3059 enhances dendritic cell activity and reduces cold-like symptoms in healthy adults: A randomized controlled trial." (2026)
• Makino et al. (2010). "Reducing the risk of infection in the elderly by dietary intake of yoghurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1." British Journal of Nutrition
• PMC12391341 — "Immune factors produced by PBMCs upon stimulation with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1-derived exopolysaccharides inhibit HCoV-229E and SARS-CoV-2 replication."
• Frontiers in Cellular and Infection Microbiology (2023) — "Lactobacillus for the treatment and prevention of atopic dermatitis: Clinical and experimental evidence."
• ScienceDirect (2025) — "Gut microbiota and immune regulation by Lactobacillus delbrueckii subsp. bulgaricus LB42: From preclinical safety assessment to clinical evidence."
• PMC11510087 — "Safety Assessment and Evaluation of Probiotic Potential of Lactobacillus bulgaricus IDCC 3601 for Human Use."
• Scientific Reports (2025) — "Whole genome sequencing of promising Lactobacillus delbrueckii subsp. bulgaricus strains isolated from Egyptian dairy products for probiotic characteristics."
• ScienceDirect (2023) — "Assessment of the safety and probiotic properties of Lactobacillus delbrueckii DMLD-H1 based on comprehensive genomic and phenotypic analysis."
• Taylor & Francis (2025) — "Exploring lactic acid bacteria in food, human health, and agriculture." Critical Reviews in Food Science and Nutrition
• ISAPP (International Scientific Association for Probiotics and Prebiotics) — "Bulgarian yogurt: An old tradition, alive and well."
• PMC9311557 — "Effects of the Probiotic, Lactobacillus delbrueckii subsp. bulgaricus, as a Substitute for Antibiotics on the Gastrointestinal Tract Microbiota and Metabolomics Profile of Female Growing-Finishing Pigs."
• ClinicalTrials.gov NCT06873438 — "The Effect of Probiotics on the Improvement of Intestinal and Immune Function" (LB42, 30 billion CFU/day).
• NCBI Taxonomy Browser — Lactobacillus delbrueckii subsp. bulgaricus
• PubMed PMID 15954646 — "Biosynthesis of exopolysaccharides by two strains of Lactobacillus bulgaricus in whey-based media."
• Wikipedia — Lactobacillus bulgaricus GLB44