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Bacillus Clausii

Scientific Name(s): Bacillus clausii
Common Name(s): Enterogermina, Erceflora, Probiotic

Medically reviewed by Drugs.com. Last updated on Nov 1, 2018.

Clinical Overview

Use

B. clausii is a commonly used Bacillus spp. probiotic. Clinical data support its use for the treatment and prevention of gut barrier impairment. Small trials have investigated use in preterm neonates to prevent infection, treatment of nasal allergies and upper respiratory infections in children, and treatment of acute or chronic diarrhea, small-intestine bacterial overgrowth (SIBO), and adverse effects of Helicobacter pylori therapy in adults.

Dosing

Generally in clinical studies, 2 x 109 spores have been administered orally as a capsule or suspension 2 or 3 times daily, for 10 days up to 3 months. Manufacturer's product information: Adults: 4 to 6 x 109 spores/day (2 to 3 vials/day or 2 to 3 capsules/day). Children and breast-feeding infants: 2 to 4 x 109 spores/day. Use is recommended for short periods of time. Preterm neonates (less than 34 weeks' gestational age): 2.4 x 109 spores/day (2 mL every 8 hours mixed with enteral feeds through orogastric tube or orally) given until postnatal age of 6 weeks. Nasal allergies (children): 3 vials/day (2 x 109 spores/vial) administered orally for 3 weeks to reduce nasal symptoms.

Contraindications

Hypersensitivity to B. clausii or to any of the product excipients.

Pregnancy/Lactation

According to the product information, B. clausii can be used during pregnancy and lactation, and in breast-feeding infants.

Interactions

None well documented.

Adverse Reactions

No adverse effects were noted in clinical trials of B. clausii or in the product information.

Toxicology

No data.

History

Spore-forming Bacillus spp. have been used for decades in the form of fermentation products or spore-based probiotic supplements; however, only a few Bacillus strains are recognized as safe and are available for commercial use.Ghelardi 2015, Upadrasta 2016 Clinically, B. clausii is one of the most commonly used microorganisms of the Bacillus spp.Lopetuso 2016 Historically considered to be soil microorganisms, Bacillus spp. bacteria may need to be reconsidered as gut commensals because their prevalence in the feces of animals is now recognized to be higher than previously thought.Ghelardi 2015

Probiotic preparations have been used throughout history. In a Persian version of the Old Testament, Abraham's longevity was purported to be the result of drinking sour milk. In 76 BC, the Roman historian Plinius described fermented milk as a remedy for gastroenteritis. In 1916, experiments were conducted to implant Escherichia coli as a means of fighting pathogenic intestinal flora.Schrezenmeir 2001

In 1965, the term "probiotic" was first used to describe "substances secreted by one microorganism that stimulate the growth of another"—in other words, the opposite of an antibiotic.Schrezenmeir 2001 Revised definitions have appeared in the literature to accommodate mechanisms of action and stimulation of systems other than bacteria. An all-encompassing definition has been proposed by one group: "A preparation of or a product containing viable, defined microorganisms in sufficient numbers, which alter the microflora (by implantation or colonization) in a compartment of the host and by that exert beneficial health effects in this host."Schrezenmeir 2001 Related concepts of prebiotics and synbiotics have also been elaborated.Elmer 2001, Schrezenmeir 2001 The study of microbes inhabiting the human GI tract and their effect on disease is an important part of the ongoing Human Microbiome Project of the US National Institutes of Health.NIH 2014

Uses and Pharmacology

Probiotics are intended to assist the body's natural gut microbiota.Gastroenterology 2016 The potential mechanisms by which probiotics exert their action include production of pathogen-inhibitory substances, inhibition of pathogen attachment, inhibition of the action of microbial toxins, stimulation of immunoglobulin A, and trophic effects on intestinal mucosa. Each agent or preparation may have unique actions, with some bacterial strains being more or less effective than others. Trials included in meta-analyses are generally heterogeneous, especially with respect to the strain of probiotic used.Di Caro 2005, Hill 2013, Oelschlaeger 2010, Ohland 2010 See also the Probiotics monograph.

Studies of preparations containing B. clausii spores support its use for the treatment and prevention of gut barrier impairment.Lopetuso 2016 In contrast to lactic acid probiotics such as lactobacilli and bifidobacteria, the spore-forming Bacillus spp. probiotics are extremely resistant to acid and heat. B. clausii is characterized by some unique properties, including its resistance to bile and gastric acids and its ability to grow in high-salt concentrations, adhere to the intestinal wall, promote epithelial proliferation, and survive transit through the GI tract. As a commercial product, these unique characteristics allow B. clausii to be stored without refrigeration or in a desiccated form without negatively affecting its viability.Ghelardi 2015, Upadrasta 2016 Other attributes of Bacillus spp. include colonization, immunostimulation, and antimicrobial properties. B. clausii is resistant to commonly used antibiotics and demonstrates intrinsic resistance to penicillins, cephalosporins, aminoglycosides, and macrolides. It exhibits acquired resistance to tetracycline and chloramphenicol, and resistance to rifampin due to a chromosomal mutation. Resistance to lincomycin, isoniazid, cycloserine, and nalidixic acid has also been reported. B. clausii strains have been observed to release antimicrobial substances that are active against Staphylococcus aureus, Enterococcus faecium, and Clostridium difficile. B. clausii is capable of producing various vitamins, in particular the group B vitamins.Di Caro 2005, Erceflora 2016, Lopetuso 2016

Experimental studies reveal that B. clausii affects intestinal mucosa homeostasis via regulation of gene expression. In the small bowel mucosa, up- and down-regulation of genes involved in immune response and inflammation (eg, interleukin 1 [IL-1], IL-6, tumor necrosis factor, plasminogen activator), apoptosis, cell growth, and cell cycle (eg, RAS oncogenes, insulin-like growth factor, somatostatin), as well as cell adhesion, transcription, cell communication, and defense response functions were observed.Di Caro 2005

Animal data

Widespread use of probiotics in humans, together with a largely safe adverse event profile, makes data from animal experiments mostly irrelevant to human health. A sufficient number of clinical trials exist to enable meta-analyses for certain clinical conditions.Hooijmans 2012

Nasal allergies

Clinical data

A 3-week pilot study was conducted during the pollen season in 20 allergic children (average age, 13.4 years). All 20 children were allowed levocetirizine 5 mg for symptomatic relief. Ten children were randomly assigned to receive 3 vials of oral B. clausii per day (2 x 109 spores/vial) in addition to levocetirizine. Compared with baseline, a significant improvement in total nasal symptoms and nasal eosinophils was observed in the B. clausii group (P = 0.049 and P = 0.048, respectively); this improvement was not observed in the control group, which received only on-demand antihistamine (levocetirizine). Children receiving B. clausii also required fewer days of levocetirizine use than children in the control group (8.1 vs 11.1 days; P = 0.034).Ciprandi 2005

Cancer

Experimental data

Antigenotoxicity, specifically microbial inhibition of DNA-reacting compounds, is a functional property characterizing probiotic bacteria that is of clinical interest. Mutagens may induce change directly or indirectly, the latter being represented by many food-related compounds such as the mycotoxin aflatoxin B1 (AFB1) and the highly mutagenic heterocyclic amine 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) that results from the pyrolysis of protein foods (meat and fish). Relevant cell-mutagen interactions that contribute to genotoxicity include binding to bacterial cell components, reaction with bacterial metabolites, genotoxin-bacterial metabolite conjugation, and bioconversion to nonreactive moieties by bacterial enzymes. Antigenotoxicity is often considered strain dependent.Cenci 2008

Of the 21 strains of Bacillus spp. (eg, B. clausii, Bacillus subtilis, Bacillus lentus, Bacillus pumilus, Bacillus firmus, Bacillus megaterium, Bacillus spp.) tested for inhibition of genotoxicity against 4 genotoxins (4-nitroquinoline-1-oxide [4-NQO], the nitrosamine N-methyl-N′-nitro-nitrosoguanidine [MNNG], AFB1, and MeIQ), all strains reduced genotoxicity without the species-strain specificities that have been reported for the probiotics lactobacilli and bifidobacteria. The bacilli exhibited higher antigenotoxicity against the direct genotoxin 4-NQO (greater than 92%) than the probiotic Lactobacillus rhamnosus GG (85.7%) and the dairy lactobacilli; however, L. rhamnosus was more active against MeIQ (62.8%) and AFB1 (80.8%) than the bacilli (range, 25% to 45% and 25% to 64.3%, respectively). L. rhamnosus was ineffective against MNNG, whereas the bacilli strains exhibited 78% to 99% genotoxin inhibitory activity.Cenci 2008

Clinical data

Research reveals no clinical data regarding use of B. clausii in the treatment of cancer.

Diarrhea

Experimental data

In an in vitro experimental study, the cytotoxic effects of C. difficile and Bacillus cereus were prevented by proteolytic compounds secreted by the probiotic B. clausii strain O/C; the hemolytic effect of B. cereus was also inhibited. The proteolytic enzyme activity was 4-fold higher during sporulation than during vegetative cell growth; after purification, the enzymatic-specific activity of the purified protease was 13-fold higher than the spore supernatant activity. The increased cell detachment and loss of mitochondrial dehydrogenase induced by C. difficile toxins was completely prevented in Vero cells by coincubation with B. clausii in a time-dependent manner; similar results were observed in Caco-2 cells. Likewise, high cell viability was retained when B. cereus was coincubated with B. clausii; time of coincubation was crucial to counteract the toxic effects.Ripert 2016

Clinical data

A prospective phase 2 clinical study conducted in India investigated the antidiarrheal activity of B. clausii (strain UBBC 07) in 27 adult patients with acute diarrhea (3 or more loose stools in 24 hours for longer than 7 days). Administration of one B. clausii capsule orally twice daily (2 x 109 colony-forming units [CFU]/capsule) for 10 days significantly improved mean duration of diarrhea from 34.8 to 9.3 minutes/day, frequency of diarrhea from 6.96 to 1.78 times/day, abdominal pain score from 3.22 (severe) to 0.74 (absent), and stool consistency score from 3.93 (watery) to 1.22 (soft) (P < 0.0001 for all). Additionally, stool analysis revealed the absence of previously documented fat, resolution of mild mucus and occult blood, and absence of red and white blood cells. Entamoeba histolytica cysts were documented in the stools of 3 participants on day 1 but were completely eliminated by the end of the 10-day treatment. No serious adverse events were observed.Sudha 2013

In Italy, a randomized, single-blind controlled study of 571 children 3 to 36 months of age with acute diarrhea compared 5-day treatment efficacy of 5 probiotic preparations: L. rhamnosus; Saccharomyces boulardii; B. clausii; E. faecium; or a mixture of Lactobacillus delbrueckii var bulgaricus, Streptococcus thermophilus, Lactobacillus acidophilus, and Bifidobacterium bifidum. L. rhamnosus and the probiotic mix reduced total duration of diarrhea, daily stool output, and stool consistency (P < 0.001); no effect was found with the other 3 formulations, including B. clausii. No adverse events were observed.Canani 2007

Dysbiosis (antibiotic-associated diarrhea)

Clinical data

A systematic review of published trials of probiotic use for the prevention or treatment of various diseases assessed the effectiveness of probiotics to correct dysbiosis (ie, antibiotic-associated diarrhea) resulting from disease or disruptive events. No trials assessing the ability of B. clausii to restore or improve normal microbiota were identified, and trial results regarding the eradication of H. pylori and the treatment of pediatric diarrhea were not significant.McFarland 2014

H. pylori treatment–induced adverse effects

A double-blind, randomized, placebo-controlled trial involving 120 symptom-free H. pylori–positive adults investigated the effect of oral bacteriotherapy with B. clausii on GI adverse effects occurring during H. pylori triple therapy (clarithromycin, amoxicillin, and rabeprazole). B. clausii probiotic therapy (1 vial of Enterogermina 3 times daily [each vial containing 2 x 109 spores of B. clausii]) was given adjunctively during the 7-day H. pylori treatment and for 7 days afterwards. H. pylori eradication rates were not different between groups; however, the occurrence of nausea was reduced by half and the risk of diarrhea was reduced in the B. clausii group compared with placebo. Tolerability was also better with B. clausii after 2 weeks of treatment (P < 0.05).Nista 2004 According to the World Gastroenterology Organization guidelines, data suggest that probiotics as adjuvant therapy may be helpful in H. pylori eradication (level 1b evidence), but data are insufficient to support probiotic monotherapy as an effective eradication strategy.Gastroenterology 2016

Infection

Clinical data

Prophylactic administration of B. clausii to reduce the risk of late-onset sepsis in preterm infants was assessed in a double-blind, randomized, placebo-controlled trial in 244 preterm neonates (less than 34 weeks' gestational age) in India. Neonates were grouped as extreme preterm (27 to 30 weeks, 6 days' gestational age) and very preterm (31 to 33 weeks, 6 days' gestational age). B. clausii (Enterogermina) 2.4 x109 spores/day was administered until postnatal age of 6 weeks, discharge, death, or the occurrence of late-onset sepsis, whichever occurred first. No difference was observed in the incidence of definite and probable sepsis; however, full feeds were achieved at a faster rate with probiotic supplementation.Tewari 2015

Small-intestine bacterial overgrowth

Clinical data

The use of B. clausii for SIBO decontamination was assessed in 40 patients with chronic bloating, flatulence, abdominal discomfort or pain, and diarrhea plus an abnormal hydrogen glucose breath test, which is indicative of the presence of SIBO. Results of a glucose breath test 1 month after B. clausii therapy (1 vial of Enterogermina 3 times daily for 1 month [each preparation containing 2 x 109 spores of B. clausii]) revealed a 47% decontamination rate comparable to the 20% to 75% rate observed with many antibiotics. One patient reported constipation as an adverse effect.Gabrielli 2009

Upper respiratory tract infection

Clinical data

A single-blind, randomized, multicenter pilot study of 80 children 3 to 6 years of age who attended daycare centers (ie, a nursery or primary school) and who experienced recurrent respiratory infections investigated the safety and efficacy of B. clausii treatment on the incidence of recurring infections. All children were allowed desloratadine for symptomatic use. Half of the children were randomized to receive 1 vial of B. clausii (Enterogermina 2 x 109 spores per 5 mL) orally twice daily for 90 days. During the treatment period, the duration of respiratory infections was significantly reduced in children receiving B. clausii compared with children in the control group (mean, 11.7 days vs 14.4 days, respectively; P = 0.037); however, the number of respiratory infections was less in the probiotic group, but the difference was not significant (3.2 vs 3.9). During the 3-month follow-up period, significant improvements were observed in the duration of respiratory infections overall for the probiotic group (6.6 days vs 10.9 days; P = 0.049) as well as for the control group (7.7 days vs 13.1 days; P = 0.039). No treatment-related adverse events were observed.Marseglia 2007

Dosing

B. clausii should be administered at regular intervals for a short time period. When used during treatment with antibiotics, B. clausii should be administered during the interval between antibiotic administrations.Erceflora 2015, Enterogermina 2008

Manufacturer's product information (Erceflora and Enterogermina)

Adults

4 to 6 x 109 spores/day (2 to 3 vials/day or 2 to 3 capsules/day).Erceflora 2015, Enterogermina 2008

Children and breast-feeding infants

2 to 4 x 109 spores/day. Use is recommended for short periods of time.Erceflora 2015, Enterogermina 2008

Acute diarrhea (adults)

One B. clausii capsule (2 x 109 CFU/capsule) administered orally twice daily for 10 days.Sudha 2013

Nasal allergies (children)

B. clausii 3 vials/day (2 x 109 spores/vial) administered orally for 3 weeks to allergic children (average age, 13.4 years).Ciprandi 2005

H. pylori treatment–induced adverse effects

B. clausii (Enterogermina 2 x 109 spores/vial) 3 times daily given adjunctively to symptom-free H. pylori–positive adults during the 7-day H. pylori treatment (clarithromycin, amoxicillin, and rabeprazole) and for 7 days afterwards.Nista 2004

Preterm neonates (less than 34 weeks' gestational age)

B. clausii (Enterogermina 2 x 109 spores per 5 mL oral suspension) administered at 2 mL every 8 hours mixed with enteral feeds (delivering 2.4 x 109 spores per day) until postnatal age of 6 weeks, discharge, death, or occurrence of late-onset sepsis, whichever occurs first.Tewari 2015

Small-intestine bacterial overgrowth

B. clausii (Enterogermina) 1 vial (2 x 109 spores) given orally 3 times daily for 1 month.Gabrielli 2009

Upper respiratory tract infection (children)

B. clausii (Enterogermina) 1 vial (2 x 109 spores per 5 mL oral suspension) orally twice daily for 90 days in children 3 to 6 years of age.Marseglia 2007

Pregnancy / Lactation

B. clausii can be used during pregnancy and lactation, and in breast-feeding infants.Erceflora 2016, Enterogermina 2008

B. clausii has been used safely for up to 6 weeks in preterm infants (less than 34 weeks' gestational age) in a clinical study that enrolled 244 neonates.Tewari 2015

Interactions

The only known interaction is with antibiotics; B. clausii supplements should be administered during the interval between antibiotic administrations.Erceflora 2016, Enterogermina 2008

Adverse Reactions

Probiotics are considered to be relatively safe, even in low-birth-weight infants and neonates. No adverse effects were noted in clinical trials of B. clausii or in the manufacturer's product information.

The FDA has issued a warning that advises practitioners of the potential risks of using dietary supplements containing live bacteria or yeast in immunocompromised patients (eg, premature infants).FDA 2014

Toxicology

No data.

References

Canani RB, Cirillo P, Terrin G, et al. Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations. BMJ. 2007;335(7615):340.17690340
Cenci G, Caldini G, Trotta F, Bosi P. In vitro inhibitory activity of probiotic spore-forming bacilli against genotoxins. Lett Appl Microbiol. 2008;46(3):331-337.18194161
Ciprandi G, Vizzaccaro A, Cirillo I, Tosca MA. Bacillus clausii effects in children with allergic rhinitis. Allergy. 2005;60(5):702-703.15813820
Di Caro S, Tao H, Grillo A, et al. Bacillus clausii effect on gene expression pattern in small bowel mucosa using DNA microarray analysis. Eur J Gastroenterol Hepatol. 2005;17(9):951-960.16093873
Elmer GW. Probiotics: "living drugs." Am J Health Syst Pharm. 2001;58(12):1101-1109.11449853
Enterogermina (Bacillus clausii) [product information]. Milan, Italy: Sanofi-Aventis; December 2008. http://www.pediatridunyasi.org/common/getCommonFile.aspx?KUB=197065. Accessed September 23, 2016.
Erceflora (Bacillus clausii) [product information]. Taguig City, Philippines: Sanofi-Aventis; June 2015. http://www.mims.com/philippines/drug/info/erceflora?type=full. Accessed July 1, 2016.
FDA Safety Alert. MedWatch. Dietary supplements containing live bacteria or yeast in immunocompromised persons: warning – risk of invasive fungal disease. Food and Drug Administration website. https://wayback.archive-it.org/7993/20170722064337/https://www.fda.gov/Food/RecallsOutbreaksEmergencies/Outbreaks/ucm423830.htm. Published December 9, 2014. Accessed December 11, 2014.
Gabrielli M, Lauritano EC, Scarpellini E, et al. Bacillus clausii as a treatment of small intestinal bacterial overgrowth. Am J Gastroenterol. 2009;104(5):1327-1328.19352343
Ghelardi E, Celandroni F, Salvetti S, Gueye SA, Lupetti A, Senesi S. Survival and persistence of Bacillus clausii in the human gastrointestinal tract following oral administration as spore-based probiotic formulation. J Appl Microbiol. 2015;119(2):552-559.25973914
Hill C, Sanders ME. Rethinking "probiotics." Gut Microbes. 2013;4(4):269-270.23778363
Hooijmans CR, de Vries RB, Rovers MM, Gooszen HG, Ritskes-Hoitinga M. The effects of probiotic supplementation on experimental acute pancreatitis: a systematic review and meta-analysis. PLoS One. 2012;7(11):e48811.23152810
Lopetuso LR, Scaldaferri F, Franceschi F, Gasbarrini A. Bacillus clausii and gut homeostasis: state of the art and future perspectives [published online ahead of print June 22, 2016]. Expert Rev Gastroenterol Hepatol. 2016;10(8):943-948.27291780
Marseglia GL, Tosca M, Cirillo I, et al. Efficacy of Bacillus clausii spores in the prevention of recurrent respiratory infections in children: a pilot study. Ther Clin Risk Manag. 2007;3(1):13-17.18360611
McFarland LV. Use of probiotics to correct dysbiosis of normal microbiota following disease or disruptive events: a systematic review. BMJ Open. 2014;4(8):e005047.25157183
Nista EC, Candelli M, Cremonini F, et al. Bacillus clausii therapy to reduce side-effects of anti-Helicobacter pylori treatment: randomized, double-blind, placebo controlled trial. Aliment Pharmacol Ther. 2004;20(10):1181-1188.15569121
Oelschlaeger TA. Mechanisms of probiotic actions—A review. Int J Med Microbiol. 2010;300(1):57-62.19783474
Ripert G, Racedo SM, Elie AM, Jacquot C, Bressollier P, Urdaci MC. Secreted compounds of the probiotic Bacillus clausii strain O/C inhibit the cytotoxic effects induced by Clostridium difficile and Bacillus cereus toxins. Antimicrob Agents Chemother. 2016;60(6):3445-3454.27001810
Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics—approaching a definition. Am J Clin Nutr. 2001;73(2)(suppl):361S-364S.11157342
Sudha MR, Bhonagiri S, Kumar MA. Efficacy of Bacillus clausii strain UBBC-07 in the treatment of patients suffering from acute diarrhoea. Benef Microbes. 2013;4(2):211-216.23443952
Tewari VV, Dubey SK, Gupta G. Bacillus clausii for prevention of late-onset sepsis in preterm infants: a randomized controlled trial. J Trop Pediatr. 2015;61(5):377-385.26246087
Ohland CL, Macnaughton WK. Probiotic bacteria and intestinal epithelial barrier function. Am J Physiol Gastrointest Liver Physiol. 2010;298(6):G807-G819.20299599
Upadrasta A, Pitta S, Madempudi RS. Draft genome sequence of Bacillus clausii UBBC07, a spore-forming probiotic strain. Genome Announc. 2016;4(2). pii: e00235-16.27103711
US Department of Health and Human Services. Human microbiome project. National Institutes of Health website. http://commonfund.nih.gov/hmp/index. Updated March 6, 2014. Accessed March 26, 2014.
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