Lactobacillus
1. Identity, Taxonomy, and Natural Sources
Nomenclature and Classification
Lactobacillus is a genus of Gram-positive, non-spore-forming, rod-shaped bacteria belonging to the family Lactobacillaceae and phylum Firmicutes. Initially proposed by Beijerinck in 1901 as Gram-positive, homofermentative, thermophilic and non-spore-forming rods, the genus Lactobacillus has experienced multiple taxonomical reassignments over its history.
Historically, the genus encompassed over 250 species that are integral to the production of fermented foods like yogurt, cheese, and sauerkraut, as well as contributing to human gut health. The genus Lactobacillus comprises 261 species (at March 2020) that are extremely diverse at phenotypic, ecological, and genotypic levels.
The 2020 Taxonomic Reclassification
In 2020, a major taxonomic revision based on phylogenomic analysis led to the reclassification of many species into 25 distinct genera, including Lactiplantibacillus, Lacticaseibacillus, Ligilactobacillus, and Fructilactobacillus. This reorganization was based on more precise genetic information and allowed for a deeper understanding of their evolutionary relationships, ecological adaptations, and probiotic functionalities. The reclassification produced the emended genus Lactobacillus (covering the L. delbrueckii group and Paralactobacillus) and 23 novel genera, including Acetilactobacillus, Agrilactobacillus, Amylolactobacillus, Apilactobacillus, Bombilactobacillus, Companilactobacillus, Dellaglioa, Fructilactobacillus, Furfurilactobacillus, Holzapfelia, Lacticaseibacillus, Lactiplantibacillus, Lapidilactobacillus, Latilactobacillus, Lentilactobacillus, Levilactobacillus, Ligilactobacillus, Limosilactobacillus, Liquorilactobacillus, Loigolactobacilus, Paucilactobacillus, Schleiferilactobacillus, and Secundilactobacillus.
Despite this formal reclassification, the name Lactobacillus remains in widespread use in the scientific, medical, and commercial literature, and many strains continue to be referenced by their pre-2020 names. For example, L. reuteri is now Limosilactobacillus reuteri, L. rhamnosus is now Lacticaseibacillus rhamnosus, L. salivarius is now Ligilactobacillus salivarius, L. casei is now Lacticaseibacillus casei, and L. plantarum subsp. plantarum is now Lactiplantibacillus plantarum subsp. plantarum. Throughout this article, the older genus name Lactobacillus is used for consistency with the bulk of the published clinical and scientific literature.
Natural Habitat and Occurrence
Lactobacilli are involved in the dietary supplementation of several species, including humans; their typical anatomical sites are the mouth cavity and the gastrointestinal (GI) tract. Lactobacilli found in the human intestinal tract include Lactobacillus acidophilus, Lactobacillus plantarum, and Lactobacillus cellobiosus. In addition to the GI tract, lactobacilli are a major component of the healthy human vaginal microbiome. The healthy cervicovaginal microbiota is dominated by various Lactobacillus species, which support a condition of eubiosis; among their many functions, vaginal lactobacilli contribute to the maintenance of an acidic pH, produce antimicrobial compounds, and modulate the host immune response to protect against vaginal bacterial and fungal infections.
Common Dietary Sources and Preparations
Lactic acid bacteria, particularly genus Lactobacillus, have been involved and employed in food microbiology especially in the fermentation of milk due to their high potential to produce important metabolites and improve the quality of the product. Yogurt is made using Lactobacillus bulgaricus and Streptococcus thermophilus; yogurt may also contain probiotic microorganisms from Bifidobacterium or Lactobacillaceae. Fermented foods that contain live cultures but do not typically contain proven probiotic microorganisms include many cheeses, kimchi (a Korean fermented cabbage dish), kombucha (a fermented tea), sauerkraut (fermented cabbage), miso (a fermented soybean-based paste), pickles, and raw unfiltered apple cider vinegar made from fermented apple sugars. Certain unfermented foods, such as milks, juices, smoothies, cereals, nutrition bars, and infant and toddler formulas, might be formulated with added probiotics.
As a dietary supplement, Lactobacillus strains are commercially available in capsules, tablets, powders, sachets, and liquid suspensions. Colony-forming units (CFU) per serving vary widely across products.
2. Traditional and Historical Use
Ancient and Pre-Industrial Fermentation Practices
The use of fermented foods reflects an intimate relationship between humans and microorganisms, and lactobacilli in particular, stretching back over 8,000 years. Fermented foods represent a distinct food culture in every community in the world, symbolizing the heritage and socio-cultural aspects of the people; the practice of consuming fermented foods has prevailed across civilizations and strata of societies over centuries because there is an obvious tangible benefit to the consumers of such products.
Ancient people in Asia were proficient in practicing or making fermented milk in a simple way, and nowadays these fermented milks are still produced under the name of traditional fermented milks. Fermentation was originally based on conversion of carbohydrate into organic acids, mostly lactic acid, intended to preserve nutrients in milk, but then developed in other capabilities associated with health benefit.
Koumiss, a traditional alcoholic fermented beverage of Kazakh nomads made from mares' milk, had been used by Russian doctors for the treatment of tuberculosis and diarrhea. In Africa, fermented foods constitute the main dietary components, as many foods are fermented spontaneously before consumption with the predominance of lactic acid bacteria (LAB). Europeans consume lacto-fermented dairy, sauerkraut, grape leaves, herbs, and root vegetables; the Alaskan Inuit ferment fish and sea mammals; the Orient is known for pickled vegetables, sauces, and kimchi; farming societies in central Africa are known for porridges made from soured grains.
The Metchnikoff Era and the Scientific Origins of Probiotic Theory
In 1905, the Bulgarian researcher Stamen Grigorov discovered "Bacillus bulgaricus," the lactic acid bacterium responsible for transforming milk into yogurt. In 1907, Élie Metchnikoff, the Nobel Prize winner and director of the Pasteur Institute, postulated in his book The Prolongation of Life that eating yogurt would extend the life span due to the health-improving influence of lactic acid bacteria (LAB) involved in yogurt fermentation on the gut flora. Metchnikoff made the ground-breaking observation that the regular consumption of lactic acid bacteria in fermented dairy products such as yogurt was associated with enhanced health and longevity in the Bulgarian peasant populations.
Metchnikoff had the idea that aging is caused by putrefactive activity by microbes that produce toxic substances in the intestine; proteolytic bacteria such as clostridia, which are part of the normal intestinal flora, produce toxic substances including phenols, ammonia, and indols by digestion of proteins — compounds he called "intestinal auto-intoxication," which he believed was the cause of the physical changes associated with old age. He knew the bacteria responsible for the fermentation of milk produced lactic acid, which created an acidic environment in the GI tract, and theorized that the lactic acid suppressed the growth of toxin-producing bacteria.
The specific regimen recommended by Metchnikoff for suppressing putrefactive colonic bacteria consisted of daily doses of probiotics in the form of "soured milk prepared by a group of lactic bacteria, or of pure cultures of the Bulgarian bacillus (Lactobacillus bulgaricus), but in each case accompanied by a certain quantity of milk, sugar, or sucrose." The craze for Bulgarian yoghurt finally died down in the 1920s — and even then only because of the discovery of another lactic acid bacterium, Lactobacillus acidophilus, which marked the start of a new wave of promoting bacteriotherapy, the precursor to modern probiotics.
Rettger continued to investigate different strains of Lactobacillus, concluding in 1935 that certain strains of Lactobacillus acidophilus not only could survive the environment of the human gut — they were very active. In 1930, Minoru Shirota discovered a new strain of L. casei and named it Lactobacillus casei Shirota after being inspired by Metchnikoff's work, and then developed a yogurt drink containing his probiotic strain.
3. Key Constituents and Active Compounds
Lactic Acid and Organic Acids
The primary metabolic product of lactobacilli is lactic acid, produced through the fermentation of carbohydrates. Lowering intestinal pH is potentially implicated in the antibacterial activity of organic acids. Lactobacillus is commonly employed in food manufacturing due to its ability to produce lactic acid and its well-recognized safety.
Bacteriocins
Lactic acid bacteria produce antimicrobial peptides known as bacteriocins, which inhibit or kill generally closely related bacterial strains and other pathogenic bacteria such as Listeria, Clostridium, and Salmonella. Bacteriocins are cationic peptides that kill the target cells by pore formation and the dissipation of cytosolic contents, leading to cell death. Bacteriocins are also known to modulate native microbiota and host immunity, affecting several health-promoting functions of the host.
Hydrogen Peroxide
In addition to lactic acid and bacteriocin production, hydrogen peroxide (H₂O₂) production by commensal or probiotic LAB may be an important antimicrobial mechanism against pathogens; hydrogen peroxide may cause reduced pathogen virulence, reduced pathogen invasion of epithelial cells, or death of intestinal pathogens after epithelial intracellular diffusion, which alters gene transcription and signal transduction. It has been demonstrated that L. plantarum produces hydrogen peroxide and therefore has remarkable antimicrobial activity.
Bioactive Peptides and Vitamins
It is expected that during the manufacture of fermented dairy products, some bioactive peptides from milk protein are released through proteolysis. Lactobacilli are also understood to be involved in the synthesis of vitamins; specifically, depending on the conditions of the bacterial culture, fermentation of lactobacilli has been reported to synthesize folic acid, niacin, vitamin B₁₂, and vitamin B₆.
Beta-Galactosidase (Lactase)
Lactobacillus acidophilus fermentation can help lactose-intolerant individuals since this bacterial species produces β-galactosidase, which metabolizes a significant portion of the lactose from the ingested dairy product, thereby preventing gastric complications resulting from its ingestion.
4. Mechanisms of Action
Antimicrobial and Competitive Exclusion Activity
On the one hand, Lactobacillus can antagonize pathogenic bacteria infection in the intestine primarily through bacteriocin, organic acids, and hydrogen dioxide; on the other hand, commensal organisms contribute to the colonization and function of lactobacilli via cross-feeding. Experimental studies have shown that lactobacilli, which can adhere to enterocytes, are effective in preventing the enteropathogen-mediated infection by competing for adhesion sites.
Intestinal Barrier Enhancement
Lactobacillus has been demonstrated to induce mucin expression, enhance the intestinal epithelial tight junction (TJ), protect intestinal epithelial cells (IECs), and mitigate inflammation through its surface components and metabolites, thereby enhancing the intestinal epithelial barrier function.
Immunomodulation
Interactions between the ligands from lactobacilli and immunomodulatory receptors are implicated in immunomodulation. Probiotics have a beneficial effect on inflammatory responses and immune regulation via the JAK/STAT and NF-κB signaling pathways. Key mechanisms reviewed in published literature include: colonization and normalization of perturbed intestinal microbial communities; competitive exclusion of pathogens and bacteriocin production; enzymatic activity and production of volatile fatty acids; cell adhesion, cell antagonism, and mucin production; modulation of the immune system; and interaction with the brain-gut axis.
Gut Microbiome Modulation
In vitro and in vivo investigations have shown that prolonged lactobacilli administration induces qualitative and quantitative modifications in the human gastrointestinal microbial ecosystem. In vitro and in vivo investigations have shown that prolonged probiotic administration induces qualitative and quantitative modifications in complex, well-settled microbial ecosystems through bacteriocin substrate competition and possibly other mechanisms that still need to be acknowledged.
Lactose Digestion
Some probiotics promote lactose digestion in lactose intolerance through increasing the overall hydrolytic capacity in the small intestine and increasing the colonic fermentation; they can decrease lactose concentration in fermented products and also increase active lactase enzyme entering the small intestine with the fermented products.
5. Scientific Evidence by Area of Use
5.1 Acute Infectious Diarrhea (Children)
The most thoroughly studied strain for acute diarrhea in children is Lactobacillus rhamnosus GG (LGG). A systematic review and meta-analysis of nineteen RCTs showed that, compared with the control group, LGG administration notably reduced the diarrhea duration (mean difference –24.02 hours, 95% CI: –36.58 to –11.45), with more effective results detected at a high dose of ≥10¹⁰ CFU per day.
LGG was effective when used at a daily dose of ≥10¹⁰ CFU or <10¹⁰ CFU; however, the latter produced results of borderline significance. LGG was more effective when used in European countries compared with non-European countries; LGG use was associated with a reduced duration of hospitalisation, though one RCT found that LGG had no effect on the total clinical severity score at 14 days after enrolment. Despite a recent large RCT demonstrating no effect of LGG, current evidence shows that, overall, LGG reduced both the duration of diarrhoea and hospitalisation in inpatients. Evidence strength: Moderate overall, with heterogeneity across geographic regions.
5.2 Antibiotic-Associated Diarrhea (AAD)
LGG with a minimal daily dose of 2 × 10⁹ CFU has been assigned a strong recommendation for reduction in the incidence of AAD, as it is associated with a significant reduction in the incidence of AAD in multiple independent clinical studies. Several meta-analyses of efficacy and safety of LGG in the treatment of antibiotic-associated diarrhea have indicated a significant effect; children and infants were more likely to have significant effects, but positive effects were also observed in adults.
LGG acts through several mechanisms to potentially prevent dysbiosis or restore normal bacterial flora resulting from antibiotic administration, such as competitive exclusion of pathogens, modulation of the immune system, and outcompeting less acid-tolerant bacteria as LGG produces lactic acid. In one pediatric ICU trial, patients were randomly assigned to receive LGG 30 × 10⁹ CFU every 12 hours, with the study drug administered twice daily for the duration of antibiotic therapy. Evidence strength: Moderate to strong for LGG in children; moderate in adults.
5.3 Irritable Bowel Syndrome (IBS)
In a systematic review and meta-analysis published in Gastroenterology, there was low certainty in the evidence for a benefit of Lactobacillus strains, used in 16 trials involving 1,498 patients, compared with placebo (RR, 0.84; 95% CI, 0.72–0.98), with significant heterogeneity between studies (I² = 69%; P < .001).
For global symptoms, there was moderate certainty in the evidence for a benefit of Escherichia strains, and only low certainty for Lactobacillus strains and Lactobacillus plantarum 299V. Diarrhea-predominant IBS (IBS-D) showed the most consistent improvements, particularly with strains like Saccharomyces boulardii and Lactobacillus rhamnosus. Dosages in IBS studies ranged from 10⁷ to 10¹¹ CFU, with treatment durations spanning two weeks to six months. Evidence strength: Low to moderate; significant heterogeneity across trials, results are strain-specific.
5.4 Inflammatory Bowel Disease (IBD)
A number of fermented dairy products contain lactic acid bacteria and bifidobacteria, some of which have been characterized as probiotics that can modify the gut microbiota and may be beneficial for the treatment and prevention of IBD. As a dietary supplement, Lactobacillus spp. can both prevent and reduce inflammation-related diseases such as inflammatory bowel disease in preclinical models.
Owing to the conflicting evidence regarding the effectiveness of probiotics for IBD and the usage of several different kinds of probiotics, the existing literature includes a review of 55 articles to summarize the results and conclusions of clinical trials of probiotics in IBD. Certain probiotic formulations, including single-strain Lactobacillus or mixed-strain combinations of Lactobacillus and Bifidobacterium, have proven effective in improving the clinical, immunological, and symptomatic aspects of the disease course. While promising, these findings remain inconclusive due to inconsistent study designs, small sample sizes, and varying patient responses; larger, well-controlled trials are needed. Evidence strength: Preliminary to moderate; results are mixed across IBD subtypes (ulcerative colitis vs. Crohn's disease) and probiotic strains.
5.5 Vaginal Health and Bacterial Vaginosis (BV)
A body of evidence has shown that the vaginal microbiota can likely be clustered into five community state types (CSTs); CST I corresponds to a microbiota dominated by Lactobacillus crispatus, CST II by Lactobacillus gasseri, CST III by Lactobacillus iners, CST V by Lactobacillus jensenii, and CST IV corresponds to a microbiota characterized by very low lactobacilli content. Evidence suggests a correlation between CST I and a lower risk for women of recurrent vaginosis and vulvovaginitis, papilloma virus persistence, and preterm delivery.
A disruption of the vaginal ecosystem is characterized by the depletion of Lactobacillus species and the overgrowth of non-Lactobacillus microbes; typically, the overgrowth of anaerobic bacteria can result in bacterial vaginosis (BV) and sexually transmitted infections (STIs), as well as pregnancy-related complications.
A systematic review of 16 RCTs on probiotic treatment for bacterial vaginosis (2014–2024) found that Lactobacillus rhamnosus TOM 22.8 at 10 × 10⁹ CFU/day for 10 days was the most effective strain and dose, significantly improving Nugent scores, vaginal pH, and microbiota composition. Probiotics help alleviate symptoms, reduce recurrence, and support vaginal health through antimicrobial production, pH modulation, and immune regulation; despite certain limitations, current evidence supports their use as adjunctive or alternative therapy, though further research is needed to refine strain selection and optimize dosing. Evidence strength: Moderate for adjunctive use in BV; strain-specific effects, with L. crispatus, L. rhamnosus, L. acidophilus, and L. plantarum showing therapeutic potential.
5.6 Lactose Intolerance
The effect of L. acidophilus strain LBKV-3 on fecal residual lactase activity was tested in undernourished children; lactase activity increased over the course of the treatment. Many humans are lactose intolerant — unable to metabolize lactose (milk sugar) — due to the lack of the β-galactosidase enzyme that metabolizes milk sugars; persons lacking this enzyme may suffer from severe gastrointestinal problems if lactose-containing products are consumed. This nutritional problem may be overcome by L. acidophilus fermentation since this bacterial species produces β-galactosidase, which metabolizes a significant portion of the lactose from the ingested dairy product. Evidence strength: Moderate; the mechanism is well understood, though clinical effect size varies by strain and preparation.
5.7 Immune Modulation and Other Conditions
Applications of lactobacilli under investigation include kidney support for renal insufficiency, pancreatic health, management of metabolic imbalance, and cancer treatment and prevention. Modulating the gut microbiota, regulating the immune system, showing anti-inflammatory effects, and having activities against pathogens by regulating mucus secretion are some of the important functions of probiotics. Probiotics play an important role in maintaining the stability of the vaginal microenvironment, improving immune defense, and blocking the progression of cervical cancer. Evidence strength for most of these areas: Preliminary or exploratory; the bulk of supporting data comes from in vitro or animal studies, with limited high-quality human RCTs.
6. Dosage Forms and Dosages Reported in Studies
Lactobacillus supplements are marketed in several physical forms, including hard-shell capsules, enteric-coated tablets, chewable tablets, sachets, and powders for reconstitution in water or milk. Products may be refrigerated (live cultures maintained at low temperature) or shelf-stable (with lyophilized/freeze-dried strains). Potency is expressed in colony-forming units (CFU).
- Acute diarrhea in children (LGG): Nineteen RCTs showed LGG administration reduced diarrhea duration; more effective results were detected at a high dose of ≥10¹⁰ CFU per day (mean difference –22.56 hours, 95% CI –36.41, –8.72) vs. lower doses.
- Antibiotic-associated diarrhea (LGG): A minimal daily dose of 2 × 10⁹ CFU of Lactobacillus rhamnosus GG was identified in a meta-analysis as associated with significant reduction in the incidence of AAD. In a pediatric ICU trial, LGG was administered at 30 × 10⁹ CFU twice daily for the duration of antibiotic therapy.
- Bacterial vaginosis: Lactobacillus rhamnosus TOM 22.8 at 10 × 10⁹ CFU/day for 10 days was found to be the most effective strain and dose.
- IBS trials: Dosages in IBS randomized controlled trials ranged from 10⁷ to 10¹¹ CFU, with treatment durations spanning two weeks to six months.
No universally standardized dose has been established across all conditions. Dose, strain, and duration are highly condition-specific, and the evidence base for dose–response relationships remains limited and heterogeneous.
7. Safety Considerations and Interactions
General Safety Profile
Lactobacilli have been documented to have a long history of safe use, supported by recognition as Generally Recognized as Safe (GRAS). For many decades, lactobacilli have been used as an effective therapy for treatment of several pathological conditions displaying an overall positive safety profile. Lactobacillus species, being a normal body flora, have generally not posed much concern about causing disease in immunocompetent individuals; they are considered contaminants or opportunistic pathogens when isolated from specimens belonging to immunocompetent individuals.
Risks in Immunocompromised Populations
There have been recorded cases of persons experiencing illnesses caused by Lactobacillus species; the patients encompass individuals with AIDS, neutropenia, and individuals who have undergone organ transplants. The most prevalent diseases caused by lactobacilli are localized infections such as abscesses, bacteremia, and endocarditis; reported risk factors include diabetes mellitus, preexisting structural heart disease, cancer (particularly leukemia), the utilization of total parenteral nutrition, broad-spectrum antibiotics, chronic kidney disease, inflammatory bowel disease, pancreatitis, chemotherapy, neutropenia, organ transplantation, and the use of steroids.
A few recent cases of bacteremia and/or sepsis associated with lactobacilli have been reported in patients with different underlying diseases such as ulcerative colitis in pediatric or adult patients, suggesting that an extensive damage of the colonic mucous membrane increases the risk of bacteremia. Increasing reports on Lactobacillus bacteremia-associated morbidity and mortality in immunocompromised patients have raised safety concerns about its use in this group.
The PROPATRIA Study — Severe Pancreatitis
One clinical trial caused significant concern about probiotic safety: the PROPATRIA study was a double-blind placebo-controlled RCT that examined the ability of a multistrain probiotic to prevent infectious complications in 296 patients with severe pancreatitis; subjects assigned to the probiotic arm of the study experienced higher mortality, which was attributed to bowel ischemia.
Population-Level Bacteremia Risk
Lactobacillus bacteremia in Sweden was examined over a 6-year period during which time there was increasing use of three commercial probiotic Lactobacillus strains; there was no change in the rate of lactobacillemia, and no case of Lactobacillus isolated from the bloodstream was identified as one being related to the probiotic strains. In an epidemiological study of Lactobacillus bacteremia in Finland, the researchers did not find any correlation between the increased probiotic use of L. rhamnosus GG (ATCC 53103) and the incidence of Lactobacillus bacteremia during 1990–2000.
FDA-Identified Risk Groups
The FDA suggested immunosuppression, structural heart disease, inpatient status, pregnancy, and potential for translocation of probiotic across the bowel wall as factors potentially at risk for adverse events in probiotic clinical trials.
Adequacy of Safety Reporting
Gathered data from several published trials examining how harms-related information is reported in publications of 384 RCTs of probiotics, prebiotics, and synbiotics concluded that harms reporting in published reports of RCTs assessing these interventions is often lacking or inadequate, and it cannot be broadly concluded that these interventions are safe without reporting safety data.
Strain-Specific Safety Assessments
Some Lactobacillus strains have been documented to cause bacteremia and sepsis in immunocompromised or critically ill hospitalized patients, challenging the universally presumed safety of lactobacilli; therefore, strain-specific risk assessments are required for the use of Lactobacillus as a probiotic.
References
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