This event is only for invited and registered medical practitioners

Sanofi India LTD., CTS No.117-B, L&T Business Park, Saki Vihar Rd, Powai, Mumbai, Maharashtra 400072, India
Dr Joura Vishal
MD (PGI ) MRCP ( UK )
Senior Consultant Internal Medicine
MAT-IN-2301411-v1.0/06/2023 SGL Superspecailaity Hospital
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Table of Contents

Gut dysbiosis & Its Clinical Significance

Link between dysbiosis & gut microbiota-derived metabolites

Effect of dysbiosis on gut microbiota derived metabolites

Implications of gut microbiota derived metabolites in various diseases

Role of probiotics in gut dysbiosis

Bacillus clausii as a probiotic therapy

Key Points
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Gut Dysbiosis

Total loss of Disease

Gut dysbiosis diversity in the progression or
microbiota severity
Disruptions
in the structure
of microbial

community
Loss of Dominance/
Inflammation
Relationship between the gut beneficial overgrowth of
and pathology
microbiota, metabolic products organisms commensals
and the host is lost in a
microbial ecosystem.

Gut dysbiosis involves loss of beneficial microorganisms and leads to expansion of pathogenic microbes,
triggers pro-inflammatory effects and immune dysregulation associated with various disease states.
References:
Iebba V, Totino V, Gagliardi A, Santangelo F, Cacciotti F, Trancassini M, Mancini C, Cicerone C, Corazziari E, Pantanella F, Schippa S. Eubiosis and dysbiosis: the two sides of the microbiota. New Microbiol. 2016 Jan;39(1):1-12
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Dysbiosis of Gut Microbiota Contributes

to Various Chronic Diseases

Most disease
stems in the digestive
tract due to dysbiosis
- when the
“good”
bacteria are no
longer able to control
the “bad” ones1

References:
1. Iebba V, Totino V, Gagliardi A, Santangelo F, Cacciotti F, Trancassini M, Mancini C, Cicerone C, Corazziari E, Pantanella F, Schippa S. Eubiosis and dysbiosis: the two sides of the microbiota. New Microbiol. 2016 Jan;39(1):1-12.
2. Gebrayel P et al Microbiota medicine: towards clinical revolution. J Transl Med. 2022 Mar 7;20(1):111. doi: 10.1186/s12967-022-03296-9. PMID: 35255932; PMCID: PMC8900094.
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Link Between Dysbiosis & Gut

Microbiota-derived Metabolites
Importance of gut microbiota-derived
Gut microbiota-derived metabolites are key
metabolites in human metabolism
mediators responsible for microbiota induced
beneficial or detrimental effects on host.
Dietary
cues

G
u
Healthy t Altered

m
i
Microbial metabolites
c
r of human metabolism
Regulation
o
b Detrimental effect of altered specific
Health- Disease-
i promoting microbiota-derived metabolites leads to
promoting o imbalanced symbiotic gut microbiota.
m
References: e
Herrema H, Jan N. Intestinal microbial metabolites in human metabolism and type 2 diabetes. Diabetologia.2020;63:2533–47. Available at: https://link.springer.com/article/10.1007/s00125-020-05268-4
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Gut Microbiota Metabolites Influences the

Intestinal Barrier and Gut Motility
During chronic diseases,
SCFAs enhance the disturbance of tights junctions
chemical barrier to prevent lead to destruction of physical
harmful bacteria. SCFAs, barrier, and further lead to
bile acids, and indole translocation of LPS and bacteria.
derivatives enhance This triggers the activation of
physical barrier via immune cells and lead to
increasing tight junction production of pro-inflammatory
proteins. cytokines

Intestinal barrier consists of Later, the epithelial cross The release of

microbial barrier, chemical of SCFAs and indole pro-inflammatory
barrier, physical barrier, and derivatives act on immune cytokines act on local
immune barrier. cells and lead to release of epithelial cells to worsen
anti-inflammatory physical barrier or can act
cytokines such as IL-10 on extraintestinal organs to
and IL-22 trigger other diseases.

Abbreviations: SCFA, short chain fatty acids;LPS, lipopolysaccharide; IL, interleukin.

References:
Liu J et al. Functions of Gut Microbiota Metabolites, Current Status and Future Perspectives. Aging and disease. 2022
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Link Between Dysbiosis & Gut

Microbiota-derived Metabolites
Microbiota-derived Metabolites
Within gut lumen, gut microbiota metabolites serve as nutrients for
Diet Gut Microbiota
A bacteria and change composition of gut microbiota.2
+
SCFAs

Mcrobial Tryptophan Catabolites

TMAO Locally act on intestinal epithelium and immune cells to further induce
Primary Bile Gut Microbiota downstream systemic functions.2
Acids
+ B
Secondary
Bile Acids
Systemically can be absorbed and transported to remote organs
Gut Microbiota C and tissues to exert diverse functions.2
BCAAs

Polyamines

Bacterial Vitamins Indirectly regulates composition and function of gut microbiota via inducing
hosts to synthesize and release anti-bacterial materials into gut lumen.2

Abbreviations: BCAAs branched-chain amino acids, TMAO trimethylamine-N-oxide.

Gut microbiota-derived metabolites are produced by:

(A) Gut microbiota from dietary components Gut microbiota-derived metabolites play a critical role in maintaining the composition
(B) Host and modified by gut bacteria and function of the gut microbiota and its alteration can cause multiple immune-related
(C) Synthesized de novo by gut bacteria inflammatory diseases.1,2

References:
1. Yang W, Cong Y. Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cell Mol Immunol. 2021 Apr;18(4):866-877.
2. Liu J et al. Functions of Gut Microbiota Metabolites, Current Status and Future Perspectives. Aging and disease. 2022
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Typical Diseases Associated With Gut

Microbiota-derived Metabolites
Groups Typical metabolites Specific functions Typical diseases associated

Regulation of gut microbiota composition,

Acetate, propionate,
butyrate, hexanoate,
Short-chain fatty acids
isovalerate, isobutyrate, 2-
methylpropionate, valerate
gut barrier integrity, appetite, energy
homeostasis, gut hormone production,
Nonalcoholic fatty liver disease,
circadian clocks; inhibit proinflammatory
Crohn's disease, colorectal cancer,
cytokines; stimulate water and sodium
absorption; modulate systemic immune
response

Cholate, hyocholate,
Facilitate lipid and vitamin absorption;
deoxycholate, Primary biliary cholangitis, primary
regulation of gut microbiota composition,
taurohyocholate, sclerosing cholangitis, ulcerative
Bile acids gut hormones, intestinal immunity,
ursodeoxycholate, colitis, cancer, hepatic
intestinal electrolyte and fluid balance,
taurocholate, tauro- a- encephalopathy,
gut motility,
muricholate

Altered microbiota-derived metabolites mediate dysregulated immune responses leading to pathogenesis of

various immune-related chronic inflammatory diseases.
Liu J et al. Functions of Gut Microbiota Metabolites, Current Status and Future Perspectives. Aging and disease. 2022
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Altered Gut Microbiota Derived Metabolites

Affects Physiological Processes
Effects of gut microbiota-derived metabolites leading to immune-related inflammatory diseases

Gut Microbiota-Derved metabolites

SCFAs Microbial Secondary TMAO BCAAs Polyamines

Gut Microbiota Tryptphan Bile Acids
Catabolites

IBD IBD IBD T2D T2D SLE

T1D T2D RA

T2D RA

RA

SLE

Specific microbiota-derived metabolites, notably SCFAs, bile acids, BCAAs and TMAO have been implicated
in pathogenesis of immune-related inflammatory diseases and metabolic disorders.
References:
Yang W, Cong Y. Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cell Mol Immunol. 2021 Apr;18(4):866-877.
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Altered Gut Microbiota Derived Metabolites

Causes Metabolic Disorders
↑ Satiety
SCFAs
• Increase satiety and browning of white adipose tissue
↑ Browning of WAT ↑ Cardiovascular risk • Induce decrease in lipogenesis and associated
inflammation
↑ Thermogenesis • Increase secretion of GLP-1 and PYY
• Participate in maintenance of intestinal barrier integrity
↑ Lipogenesis
↑ Inflammation
↑ Protein synthesis
↑ Hepatocyte proliferation
BCAAs
• Increase thermogenesis, protein synthesis and
hepatocyte proliferation.
• Associated with insulin resistance and visceral fat
accumulation
↑ GLP-1 & PYY Legend
↑ Visceral fat
↑ Barrier integrity
↑ Insulinoresistance TMAO
SCFAs

BCAAs
Increases cardiovascular risks by inducing
↑ Hyperlipidaemia
↑ Oxidative stress hyperlipidaemia, oxidative stress and pro-
TM AO
↑ Pro-inflammatory cytokines
inflammatory cytokines

Specific microbiota-derived metabolites, notably SCFAs, bile acids, BCAAs and TMAO
have been implicated in pathogenesis of metabolic disorders.
References:
Agus A, Clément K, Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut. 2021 Jun;70(6):1174-82.
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Gut Dysbiosis And Inflammatory Bowel

Diseases (IBD)
Gut microbial diversity is an essential factor for
intestinal inflammation in IBD
Gut microbiota alteration and Altered gut microbiota in IBD compared
immune responses in IBD to healthy individuals in humans
IBD Microbiota Decreased in IBD Increased in IBD
Bacteria diversity↓, Caudovirales richness↑, Fungi diversity↓
Microbial Bifidobacterium sp Proteobacteria
Composition
Escherichia coli, adherent/
Groups IV and invasivera Fusobacterium
XIVA species Ruminococcus gnavusa
Clostridium Pasteurellaceae Veillonellaceae
Caudovirales Clavispora
Faecalibacterium prausnitzii lusitaniae Kluyveromyces
Roseburia species marxianus Candida albicans
Suterella species Candida tropicalis
Abbreviations: TGF= transforming
Bacteroides Cyberlindnera jadinii
growth factor; TGF=transforming Saccharomyces cerevisiae Auxotrophy Amino acid
growth factor; MMP=matrix
metalloproteinase; DC=dendritic transport Sulfate transport
cell, INF= interferons Oxidative stress Type II secretion
Microbial SCFAs, butyrate system Secretion of toxins
function Butanoate and propanoate
metabolism
Amino acid biosynthes
References:
Zuo T, Ng SC. The Gut Microbiota in the Pathogenesis and Therapeutics of Inflammatory Bowel Disease. Front Microbiol. 2018 Sep 25;9:2247.
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Gut dysbiosis And Obesity

Dysregulation of SCFA and bile acid metabolism in obesity

SCFA production FIAF protein expression

Increases fat storage and Increases LPL activity and stores the
energy retention by binding fatty acids to adipose and muscle
to G-protein-coupled tissue.
receptors.

Gut permeability
AMPK activity
Increases LPS activity, Production
Leads to a decrease in fatty
of pro-inflammatory cytokines acid oxidation and an increase
and stimulates adipogenesis
in adipogenesis.
through activation of peripheral
endocannabinoid system.
Altered microbiota-derived metabolites, mainly SCFA and dysregulated bile acid metabolism are associated
with metabolic diseases including obesity.
Abbreviations:FIAF: Fasting-induced adipocyte factor; LPL: Lipoprotein lipase; LPS: Lipopolysaccharides.

Sanchez M, Panahi S, Tremblay A. Childhood obesity: a role for gut microbiota? Int J Environ Res Public Health. 2014 Dec;12(1):162-75.
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Gut Dysbiosis And Diabetes

Gut-derived microbial metabolites influence host responses in type 2 diabetes

↑SCFA in patients with type- 2 diabetes

↑TMAO in patients with type- 2 diabetes:

Dietary TMAO impairs glucose tolerance and
increased high-fat-induced insulin resistance.

↑BCAAs levels associated with insulin

resistance is a predictive biomarker for
development of type-2 diabetes

Altered microbiota-derived metabolites influence host responses in the context of

metabolic syndrome and type 2 diabetes.
Abbreviations: GNG, gluconeogenesis; IEC, intestinal epithelial cells.
References:
Herrema H, Jan N. Intestinal microbial metabolites in human metabolism and type 2 diabetes. Diabetologia.2020;63:2533–47.
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Gut Dysbiosis And Cardiovascular Diseases (CVD)

Cholesterol
accumulation
Hypertension
Foam cell
formation
Atherosclerosis
Platelet
hyper-responsiveness CVD
Atherosclerosis
Vascular endothelial
inflammation
TMA Heart failure
Fibrosis and

remodelling
TMAO
FMOs

Altered microbiota-derived metabolites can cause heart failure, atherosclerosis, hypertension,

myocardial fibrosis, myocardial infarction, and coronary artery disease.
References:
Xu H, Wang X, Feng W, Liu Q, Zhou S, Liu Q, Cai L. The gut microbiota and its interactions with cardiovascular disease. Microb Biotechnol. 2020 May;13(3):637-656.
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Gut Dysbiosis And Viral Respiratory Infections

Controlled Uncontrolled A healthy gut microbiota releases

Viral and bacterial Viral and bacterial
infection infection certain factors, which protect the lungs
against viral respiratory infections

Antibiotics disturb the ecological

Lung immunity Lung immunity equilibrium in the gut and alter the
Type I IFNs Defective
CD8+ T cells response lung’s defences

Aging and co-morbidities also disturb

the gut microbiota; they also enhance
Healthy microbiota Dusbiotic microbiota susceptibility to respiratory infections
LPS, NOD, SCFAs - Antibiotic Treatment
Desaminotyrosine - Aging, co-morbidity

Altered microbiota-derived metabolites impairs lungs defenses and

favors systemic damage along with bacterial superinfections.
References:
Sencio V, Machado MG, Trottein F. The lung–gut axis during viral respiratory infections: The impact of gut dysbiosis on secondary disease outcomes. Mucosal Immunology. 2021 Jan 26:1-9.
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Gut Dysbiosis And Lung Diseases

The dysbiosis of the gut microbiota in some lung diseases

Actinobacteria SCFAs
Bacteroidetes The microbes and immune cells
Proteobacteria
mediate the cross talk between
Tuberculosis the gut microbiota and lungs
Enterococcus sp.
IL-12
SCFAs
Akkermansia muciniphila Actinobacteria sp.
Bifidobacterium sp.
Faecalibacterium prausnitzii Alteration in the composition of gut
microbiome may lead to immune
responses and disease development
in the lungs

Asthma Gut Microbiota Lung Cancer

References:
Zhou A, Lei Y, Tang L, et al.. Gut Microbiota: the Emerging Link to Lung Homeostasis and Disease. J Bacteriol. 2021 Jan 25;203(4):e00454-20.
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Link Between Antibiotic Associated Dysbiosis And Microbiota-

derived Metabolites

Diverse antibiotic Alters microbiota- Alters microbial

regimens derived metabolites community structure

Antibiotic-associated dysbiosis affects the

ability of the gut microbiota to control
intestinal inflammation in experimental
colitis models.

Compelling evidence have postulated that even antibiotics treatments shape the gut microenvironment and
influence microbiota-derived metabolites.
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Antibiotic Associated Dysbiosis Leaves Patients Vulnerable

5x Susceptibility Leaves vulnerable to

Prolonged
to infections, Increased Chronic Diseases like IBD
Hospital Stay
allergies and Diabetes

Lesser compliance
Poor immune response
to antibiotic therapy
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Consequences of Antibiotic Associated Dysbiosis

Loss of potential competitors

Lower expression of antibacterials and IgG Establishment of resistant bacteria
Decrease of neutrophil-mediated killing Transfer of resistance genes to pathogens
Accumulation of antibiotic resistances
Increased susceptibility to infections
Infections by exogenous pathogens or
Gut Untreatability of bacterial infections
by opportunistic members of the
microbiota
microbiota
Disruption of Treg/Th balance Elevated inflammatory tone
Elevated inflammatory tone Altered insulin sensitivity
Compromised immune Altered metabolism of
SCFA and bile acids
homeostasis Derregulated metabolism
Atopic, inflammatory and autoimmune Obesity, metabolic syndrome, diabetes
diseases (allergies, asthma, necrotizing
enterocolitis, inflammatory bowel disease,
irritable bowel syndrome, etc)
References:
Francino MP. Antibiotics and the Human Gut Microbiome: Dysbioses and Accumulation of Resistances. Front Microbiol. 2016 Jan 12,6:1543.
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Diarrhea: A Consequence of Antibiotic Associated Dysbiosis

Diarrhea caused by: Pathological Increased receptivity to Host response to exogenous

proliferation of opportunistic infection due to loss of infectious agents amplifies/
pathogens of endogenous microbiota integrity and promotes dysbiosis status.
microbiota (Clostridium difficile barrier function.
and vancomycin-resistant
enterococci)

Impact of
Antibiotic Associated Dysbiosis
References:
Lebba V et al. Eubiosis and dysbiosis: the two sides of the microbiota. New Microbiol. 2016 Jan;39(1):1-12.
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Role of Probiotics in Gut Dysbiosis

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Probiotics and Its Significance

Live microorganisms that confers health benefits to the host
PROBIOTICS when administered in adequate amounts.

Significance of probiotics
Probiotics plays an important role in maintaining normal
PROBIOTICS microbial composition, metabolism and immunity of gut.
Immunomodulation: Enhances systemic immunity and
Immunomodulation Normalized gut
Metabolic
reduces the chances of allergy and inflammation.
microbiota composition
effects
Restoration of normal gut microbiota composition:
Decreased allergic Improved mucosal
Vitamin synthesis Strengthens mucosal immunity and decreases gut
reactions immunity
infections and disorders.
Decreased gut
Reduced Lower
disorders
inflammation cholesterol Normal metabolic effects: Helps in vitamin K synthesis,
Decreased gut Improved lactose
Strengthened Immunity
infections tolerance metabolism of lactose and lowers cholesterol level.
Importance of gut probiotics in human All these functons of probiotics are correlated to each other.
health
Singh Y, Ahmad J, Musarrat J, et al. Emerging importance of holobionts in evolution and in probiotics. Gut Pathog. 2013 May;5(1):12.
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Gut Dysbiosis And Cardiovascular Diseases (CVD)

Role of probiotics relevant to intestinal diseases via recovery
of dysbiosis in the intestinal microbiota.
Prevention and Treatment

• Antimicrobial activity
• Anticarcinogenic activity
Probiotics
• Anti-inflammatory activity
• Antibiotic-associated diarrhea (AAD)
Intestinal • Inflammatory bowel disease (IBD)
Disease • Crohn’s disease (CD)
Health • Colorectal cancer (CRC)

Intestinal microbial homeostasis

Intestinal
microbiota
Microbial dysbiosis
• Short-chain fatty acid (SCFA)
• Microbial metabolites

Probiotics possess antimicrobial, anti-inflammatory, and anti-carcinogenic activities which may assist in
recovering unbalanced intestinal microbiota to reduce these intestinal diseases or alleviate their symptoms.
References:
Kim SK, Guevarra RB, Kim YT, et al. Role of probiotics in human gut microbiome-associated diseases. J. Microbiol. Biotechnol. (2019), 29(9), 1335–40.
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Bacillus clausii (O/C, SIN, N/R, T) : The

“Trusted” Probiotic Species
B. Clausii (O/C, SIN, N/R, T)

40 years Excellent
tolerability and no
Resistant to
commonly used
Absence in normal
resident intestinal flora
Survives the acid
gastric environment,
of clinical use documented antibiotics and the sporogenic activate and reach the
adverse effects activity intestinal tract

B. clausii possess unique physiological properties beneficial against

microbial dysbiosis to restore intestinal homeostasis.
References:
Sanders ME et al. An update on the use and investigation of probiotics in health and disease. Gut. 2013 May 1;62(5):787-96.
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Clinical Properties of Bacillus clausii (O/C, SIN, N/R, T)

Lysis of vegetative cell

Bacillus clausii
Spores
life cycle
Vegetative cells

Germination Sporulation

Inhibition Proliferation of Serine protease Altered levels of Production of Increase in mucin Other Antibiotic Vitamin Enhance gut Tolerance to
enteropathogens CD4+ T cells activity on pro and lantibiotics secretion and biochemical and resistance synthesis barrier heat, acid,
enterotoxins anti-inflammatory reduction in gut metabolic function salt
cytokines permeability properties

Antimicrobial and immunomodulatory activity Physiological properties

Beneficial effects of B. clausii on intestinal health includes their capacity to relieve gastrointestinal
distress and their immunomodulatory effects.
References:
Ghelardi E, Abreu Y Abreu AT, et al. Current Progress and Future Perspectives on the Use of Bacillus clausii. Microorganisms. 2022 Jun 17;10(6):1246.
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B. clausii (O/C, N/R, SIN and T) Mechanisms In Strengthening

Gut Health

Bacterial species Immunomodulatory Secretion of

harbor probiotic action on gut- antimicrobial
effect associated
compounds
lymphoid tissue

Probiotic action of B. clausii Exclusion Suppress

(O/C, N/R, SIN and T)1,2 of GI pathogens pathogen
through competitive numbers or
Modulation of immune adherence metabolism
system to gut wall of toxins

1. Lee YY et al. Gut microbiota in early life and its influence on health and disease: a position paper by the Malaysian Working Group on Gastrointestinal Health. Journal of
paediatrics and child health. 2017 Dec;53(12):1152-8. 2. Acosta-Rodríguez, Abreu Y, Guarner I, et al. Bacillus clausii for Gastrointestinal Disorders: A Narrative Literature Review. Adv
Ther. 2022 Nov;39(11):4854-74.
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B. clausii: Effective Therapeutic Probiotic In Acute Childhood

Diarrhea
Meta-analysis on 6 randomized controlled trials were conducted to
assess the efficacy of Bacillus Clausii in acute childhood diarrhea

Reduced the • B. clausii significantly reduced duration of

Analysis revealed
duration of diarrhea (mean difference = -9.12 h; p = 0.015)
that Bacillus Clausii
compared with control.
diarrhea
was well-tolerated,
without causing
Reduced the • B. clausii significantly reduced duration of serious adverse
duration of hospitalization (mean difference = -0.85 days; events.
p = 0.017), compared with control.
hospitalization
Ianiro G, Rizzatti G, Plomer M, et al. Bacillus clausii for the treatment of acute diarrhea in children: A systematic review and meta-analysis of randomized controlled trials.
Nutrients. 2018 Aug;10(8):1074.
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Role of Probiotics in Antibiotic Associated Diarrhea

Prevents antibiotic-associated diarrhea (AAD)

Common adverse effect Probiotic use by normalization of an unbalanced
of antibiotic use gastrointestinal flora

Table: Effect of probiotics on the incidence of antibiotic-associated diarrhea

Probiotics Control Risk ratio Risk ratio
Study or Subgroup Events Total Events Total Weight M.H.Random,95%CI Year M.H.Random,95%CI
2.2.3 WHO definition of diarrhea
Arvola et al., 1999 3 61 9 60 8.7% 0.33 (0.09, 1.15) 1999
Duman et al., 2005 14 204 28 185 24.4% 0.45 (0.25, 0.83) 2005
Conway et al., 2007 9 131 17 120 18.4% 0.48 (0.22, 1.05) 2007
De Vrese et al., 2011 4 30 3 29 7.2% 1.29 (0.32, 5.26) 2011
Chatterjee et al., 2013 19 198 26 198 26.9% 0.73 (0.42, 1.28) 2013
Probiotics yielded a Fox et al., 2014
Olek et al., 2017
0
6 218
34 16
9 220
36 2.0%
12.3%
0.03 (0.00, 0.51)
0.67 (0.24, 1.86)
2014
2017
significant reduction Subtotal (95% CI) 876 848 100.0% 0.54 (0.36, 0.82)
in incidence of AAD Total events 55
Heterogeneity. Tau²= 0.08, Ch 108
vec r ^ 2 = 8.27 . df = 6 (P = 0.22) ; I ^ 2 =27\%
Test for overall effect Z = 2.95 (P = 0.003)
Total (95%CI) 876 108 848 100.0% 0.54
Total
[0.36,events
0.82] 55 0.01 0.1 1 1.0 100
Heterogeneity.
108 Tau²= 0.08, Ch vec r ^ 2 = 8.27 . df = 6 (P = 0.22) ; I ^ 2 =27\% Favours [probiotics] Favours [control]
Test for overall effect Z = 2.95 (P = 0.003)
Test for subgroup differences: Not applicable

References:
Blaabjerg S, et al. Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Outpatients-A Systematic Review and Meta-Analysis. Antibiotics (Basel). 2017 Oct 12;6(4):21.
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Bacillus clausii (O/C, SIN, N/R, T) Reduces Incidence &

Severity of Antibiotic Associated Diarrhea
Figure: Incidence of side effects associated with anti H. pylori antibiotic therapy
Marked improvements at 1st week of
70
treatment with B. Clausii vs. placebo: 64
60 P<0.05

Better tolerability to multiple 50 48

44
antibiotic treatment

INCIDENCE (%)
40

B. clausii reduced the incidence of 30

30 24
most common side-effects related
20
to anti-H. pylori antibiotic therapy.
10
10

0
Nausea Placebo

B. clausii probiotic reduces incidence of most common side-effects related to

anti-H. pylori antibiotic therapy in H. pylori-positive patients.
References:
Acosta-Rodríguez, Abreu Y, Guarner I, et al. Bacillus clausii for Gastrointestinal Disorders: A Narrative Literature Review. Adv Ther. 2022 Nov;39(11):4854-74.
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Clinical outcomes of Bacillus clausii Treatment in Adult Diarrhea

bring down B. clausii Treatment in Adult Diarrhea
Study design Study outcomes

Prospective, phase II, uncontrolled
study; In adults treatment with one
capsule of B. clausii (2 X 109 CFU)
b.i.d. for 10 days
 Significantly reducing efficacy outcomes of mean duration of diarrhea
(from 34.8 to 9.3 min/day), frequency of defecation (from 7.0 to 1.8
times/day), abdominal pain (from 3.2 [severe] to 0.7 [absent]) and
improved stool consistency (from 3.9 [watery] to 1.2 [soft]) (all p < 0.0001).
 With no significant changes in safety parameters.

Prospective, phase II study in adults
with acute diarrhea given B. clausii
treatment (one capsule containing 2
X 109 CFU/ml b.i.d. for 7 days)
 Decrease in mean duration of diarrhea (from 94.2 to 5.8 min/day) and
frequency of defecation (from 4.2 to 1.4 times/day).
 Stool consistency also improved (from 2.7 [watery] to 1.6 [soft]), while
severity of abdominal pain was reduced.
 No significant side effects observed.

B. clausii probiotic represent an effective option for alleviating diarrhea symptoms in adult patients.
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B. clausii Treatment in Undiagnosed GI Discomfort

B. clausii therapy
showed significant
improvements in
severity of
dyspepsia
Subscores for pain
assessment scores
(p = 0.003), non-
for B. clausii probiotic
pain (p = 0.04) and
burping/belching was well tolerated
satisfaction (p =
(p = 0.025), with no adverse
0.03) also
bloating (p = events.
improved with B.
0.048), sour taste
clausii.
(p = 0.025) and
total score (p =
0.007) vs. placebo
(day 30 after
treatment start).
B. Clausii probiotic is an effective option for treating general symptoms in the
management of GI discomfort.
Study design: Prospective, randomized, double-blind, placebo-controlled, parallel group study in 60 adults (mean age 34.9 years) with symptoms of GI discomfort who were randomized to receive either a multi-strain probiotic blend (containing three Bacillus strains, including B. clausii [SNZ 1971]) or placebo.

Acosta-Rodríguez, Abreu Y, Guarner I, et al. Bacillus clausii for Gastrointestinal Disorders: A Narrative Literature Review. Adv Ther. 2022 Nov;39(11):4854-74.
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Bacillus clausii Treatment in Irritable Bowel Syndrome (IBS)

Following treatment with B. Proportion of children with

clausii, 93% children showed Pain intensity (median 6 vs 2; p normalization of bowel
overall improvement in = 0.04) and pain events (median movements increased (93% vs
symptoms vs. 33% children after 17 vs 3; p = 0.03) were also 13%; p = 0.01), following B.
initial conventional treatment significantly reduced. clausii treatment relative to
alone (p = 0.04). conventional treatment alone.

Study design: Using a prospective, pre-test/post-test study design, investigated B. clausii as an adjuvant treatment for pediatric IBS. Following 6 weeks of conventional treatment, children (n = 15, aged
6–16 years) then additionally received B. clausii (O/C, N/R, SIN and T; 6 9 109 CFU/day) for 6 weeks.

.
Acosta-Rodríguez, Abreu Y, Guarner I, et al. Bacillus clausii for Gastrointestinal Disorders: A Narrative Literature Review. Adv Ther. 2022 Nov;39(11):4854-74
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Protective Action of B. clausii (O/C,SIN,N/R,T)

in Rotavirus (RV) Infection
Effective mucosal barrier function by B. clausii1
Protective action against RV
infection; restore cell proliferation,
B. clausii
inducing a restart in cell cycle
Rotavirus progression and protecting against
apoptosis, in RV-infected human
Cytokines enterocytes.

Inhibits release of pro-inflammatory

cytokines (IL-8 and IFN-β) In
Enterocytes RV-infected cells.

Limit RV infection; block cell

Protection against R-induced reduction of trans-epithelial electrical replication and secretion of various
resistance upregulation of mucin 5AC and tight junctions
cytokines and chemokines.
Downregulation of pro-inflammatory cytokines and pathways

Mixture of four B. clausii (O/C,SIN,N/R,T) probiotic strains has protective effects and stimulates various non-immune
mucosal barrier and innate immune system defense mechanisms in a human enterocyte model of RV infection.
References:
Bacillus clausii`s mechanisms to protect the gut microbiome activity and composition after proton-pump inhibitor treatment, using the in vitro SHIME® technology. Poster presented at 54th Annual Meeting of European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) in Copenhagen, 2022
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Change in Microbial Composition In Ileum, Proximal And Distal Colon

After
B. clausii Treatment in Proton Pump Inhibitor (PPI) Induced
Dysbiosis
di st al
l a nd
xi
ma
co
Triple-Mucosal-Simulator of

lo
o

n
the Human Intestinal

*pr
Christensenellaceae Anaerostipes Prevotellaceae
# hadrus Microbial Ecosystem)
Total SCFA
experiment, an in vitro
Lactobacillaceae Bifidobacteriaceae Streptococcaceae model of GIT was used.
Butyrate Bacillus clausii Ileum* Propionate (SCFA) levels
unaffected by B. Clausii
Enterococcus faecium Lactobacillus reuteri
probiotic, but significantly
Acetate increased due to increase in
Streptococcus bovis
nutrients reaching ileum and
Streptococcus intermedius
colon as a side effect of
omeprazole treatment
*The change in microbial composition was statistically significant (P<0.05) compared to control and also between the experimental treatment arms during the
*Propionate levels
treatment and were not
wash-out affected by Enterogermina supplementation
period

B. clausii probiotic showed immunomodulatory and metabolic benefits by

increased production of butyrate in PPI induced dysbiosis.
References:
Bacillus clausii`s mechanisms to protect the gut microbiome activity and composition after proton-pump inhibitor treatment, using the in vitro SHIME® technology. Poster presented at 54th Annual Meeting of European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) in Copenhagen, 2022
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Clinical Studies on Probiotic Effects of B. clausii in

Various Infections
Strain (Dose) Study Design Disease Efficacy
O/C, SIN, N/R, T
Reduced frequency and duration of
(2 x 109 to 4 × 109 Meta-analysis; n = 898 from 6 studies Rotavirus infection
diarrhea Shortened hospital stay
CFU/day)
Single-center, double blind,
randomized, placebo-controlled
Reduced nausea, diarrhea, and
O/C, SIN, N/R, T (6 x prospective study; n = 120 Helicobacter pylori
epigastric pain Fewer days of diarrhea
109spores/day) Randomized, double blind, single- treatment
Lower incidence of diarrhea
center, placebo-controlled, parallel
group, phase 3b study; n = 130

Necrotizing
Randomized, double-blind, placebo-
O/C, SIN, N/R, T enterocolitis and Faster attainment of full feeds
controlled. trial; n = 244
late-onset sepsis
Randomized, single-blind, multi-
Upper respiratory Fewer and shorter duration of
O/C, SIN, N/R, T center, two arm parallel group study;
tract infections infections
n = 80
Reduction in pro-inflammatory
Single-blind, non-controlled study;
O/C, SIN, N/R, T Allergic rhinitis cytokines, higher levels of anti-
n = 10
inflammatory cytokines

Ghelardi E, Abreu Y Abreu AT, et al. Current Progress and Future Perspectives on the Use of Bacillus&nbsp;clausii. Microorganisms. 2022 Jun 17;10(6):1246.
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Comparative Study of Bacillus clausii Treatment

in Acute Diarrhea

Aim
• To compare efficacy of 3 single-strain probiotics, Bacillus clausii, Saccharomyces boulardii,
and Lactobacillus rhamnosus GG, as adjuvant therapy along with oral rehydration
solution and zinc supplements in management of acute gastroenteritis.

Study design
• Open label, randomized, comparative study, a total of 150 children (aged 6 months to 16
years) were assigned to 3 groups (50 in each group) of S. boulardii CNCMI-1745, B. clausii
(O/C, N/R, SIN and T) and L. rhamnosus ATCC 15503.

Kesavelu D. Single-Strain Probiotics For The Management Of Acute Diarrhea In Children: A Randomized Comparative Study. Neuro Quantology. September 2022;20(9):5277-83.
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Comparative Study Outcomes: Reduction in Duration of

Vomiting with B. clausii Treatment in Acute Diarrhea

FREQUENCE OF VOMITING
40 38
26
35
Mean duration of diarrhea: 3.19 ±
32
30
32
30
0.65 days, 3.04 ± 0.57 days, and 3.68
30 28 ± 0.35 days in S. boulardii, B. clausii,
26 26
25 and L. rhamnosus groups,
respectively.
20
B. clausii: More efficient in reducing
15
10 duration of vomiting (p = 0.016).
10
6 6 Similar efficacy in reducing loose
5 stool frequency by all 3 probiotics in
0 acute diarrhea
0 1 2 3

S. boulardii B. clausii L. rhamnosus

References:
Kesavelu D. Single-Strain Probiotics For The Management Of Acute Diarrhea In Children: A Randomized Comparative Study. Neuro Quantology. September 2022;20(9):5277-83.
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Comparative Study Outcomes: Normal Stool

Consistency with B. clausii Treatment in Acute Diarrhea
STOOL CONSISTENCY
24 HRS DAY 2 DAY 3 DAY 4 DAY 5
120 No change in loose stools during first
24 h among 3 groups.
100

100

100
98
100 94
88 88 Stool consistency: On day 5, in S.
84
80
78 boulardii group, only 10% patients
70 68 passed loose stools, while 50%
60 passed normal stools; in B. clausii
50
44 group, 88% and 6% passed normal
40
40
30
36 36 36 and loose stools, respectively; and in
28
26
20
24 26
18
24 L. rhamnosus group, 88%, 26%, 24%
20
10 10 10 12 14 14 passed normal, loose, and
6 6
02 2
0
4
0 0 0 2 0 0 2 semisolid stools, respectively.
0
LOOSE SEMI NORMAL LOOSE SEMI NORMAL LOOSE SEMI
SOLID SOLID NORMAL
STOOL STOOL STOOL SOLID
S. boulardii B. clausii
L. rhamnosus
References:
Kesavelu D. Single-Strain Probiotics For The Management Of Acute Diarrhea In Children: A Randomized Comparative Study. Neuro Quantology. September 2022;20(9):5277-83.
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Comparative Study Outcomes: Safety Profile of

B. clausii Treatment in Acute Diarrhea

CESSATION OF LOOSE STOOLS (FREQUENCY) Significant cessation of loose

50
46
stools by B. clausii.
45
40
40 No life-threatening events
35 32
triggered by any probiotics
30
26 studied.
25 24 22
20
20
18 18
20 Negligible readmission/revisit to
15
10 10
hospital rates.
10
5
6
2
6
Lowest rate of antibiotic use
0 0 0
0 observed among children
1 2 3 4 5 >5
administered B. clausii (p=0.04).
S. boulardii B. clausii L. rhamnosus

B. clausii probiotic achieved high efficacy along with good safety profile and should be
strongly recommended as adjuvant therapy in children with acute diarrhea.
References:
Kesavelu D. Single-Strain Probiotics For The Management Of Acute Diarrhea In Children: A Randomized Comparative Study. Neuro Quantology. September 2022;20(9):5277-83.
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B. clausii: Probiotic Therapy In Childhood Obesity

It is reported that more than 9 exposures to antibiotics by age of 48

months, increased the risk for obesity 2.4 times.

Alters gut microbiota

(Gut dysbiosis)

Side-effects Diarrhea

Treatment with a probiotic : Bacillus Clausii

References:
Petraroli M, Castellone E, Patavni L, et al. Gut microbiota and obesity in adults and children: The state of the art. Front Pediatr. 2021 Mar;9:657020.
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B. clausii: Recommended in Pediatric Diarrhea

by Asian Consensus
Acute diarrhea
• Recommended as adjunct therapy to ORS and zinc in acute diarrhea.
• Safe in children.
• Efficacious in reducing duration and frequency of diarrhea, hospital stay, and

Bacillus financial burden.

Chronic diarrhea

clausii • Recommended for management of chronic/persistent diarrhea in children.

Antibiotic-associated diarrhea

• Recommended as co-adjuvant therapy for Helicobacter pylori eradication.

De Castro JA et al. Recommendations for the adjuvant use of the poly-antibiotic–resistant probiotic Bacillus clausii (O/C, SIN, N/R, T) in acute, chronic, and antibiotic-associated diarrhea in children: consensus from Asian experts. Trop Dis, Travel Med Vaccines. 2020 Oct;6:21.
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Key Points

 Gut microbiome composition is significantly different in healthy individuals compared

to affected individual with chronic diseases . Lower Microbiome diversity is common
theme across the chronic diseases
 Detrimental effect of altered specific microbiota-derived metabolites leads to imbalanced
symbiotic gut microbiota.
 Altered microbiota-derived metabolites notably SCFAs, bile acids, BCAAs and TMAO can
cause multiple immune-related inflammatory and metabolic diseases.
 Compelling evidence have postulated that even antibiotics treatments shape the gut
microenvironment and influence microbiota-derived metabolites.
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Key Points

 Gut microbiome composition is modifiable through various therapeutic approaches

 Dietary Interventions can help to make robust changes and make a shift in outcomes
in chronic diseases
 Beneficial effects of B. clausii (O/C, N/R, SIN, and T) probiotic on intestinal health are well
known, including their capacity to relieve gastrointestinal distress and their
immunomodulatory effects.
 Current clinical evidences most strongly supports the use of B. clausii probiotic preparations
for treating diarrhea in adults and children and in improving metabolic effects.
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