microbiata-----.pptx

The neglected organ
(Microbiata) therapeutic application
By
Mohie-Aldien Elsayed Sherief
Professor of pharmacology, Faculty of Medicine, Benha University

Intestinal microbiota
(1012-16 microorganisms ; > 1500
different species)
Total abundance of
bacteria according to the
different body sites.
Willem M de Vos et al. Gut 2022;71:1020-1032

Spatial and temporal aspects of intestinal microbiota composition.
Inna Sekirov et al. Physiol Rev 2010;90:859-904
©2010 by American Physiological Society

The increasing number of publications on
microbiota/microbiome worldwide
February 2021 ;Qatar
Medical Journal 2020(3):4
Pubmed:microbiome Egypt: 656 results

Egypt probiotics market is estimated to be valued at US$-111.829 million
and is estimated to grow at a CAGR of 6.64% to reach a market size of US$-
164.442by 2025

The history of microbiome research from seventieth century until our days,
highlighting the shift of the paradigm from microbes as unsocial organisms causing diseases to
the holistic view of microorganisms being the center of the One Health Concept: positively
interconnecting all areas of our lives

Methods for assessing microbiata functions
Microbiome volume 8, Article number: 103 (2020)

Nature volume 569, pages641–648 (2019); Microbiome, Health & Biomarkers Volume 3(2); 2018
The human microbiome project (HMP)
-$170 million in funding by the NIH Common Fund from 2007 to 2016

SCIENCE•5 Oct 2018•Vol 362, Issue 6410•pp. 33-34•DOI: 10.1126/science.aau8816
Associative links between Western lifestyle, Human conditions, and
loss of microbial diversity (LOMD).

AJP-Gastrointest Liver Physiol doi:10.1152/ajpgi.00093.2020 www.ajpgi.org

Development of the gut microbiome

Main beneficial
functions of the
human gut
microbiota.
Circles represent the three
principal classes of
functions performed by the
bacteria that inhabit the
gut. Arrows represent
causal relationships.
Abbreviation: SCFA, short
chain fatty acid
July 2011Biologics: Targets &
Therapy 5(default):71-86
DOI:10.2147/BTT.S19099

Microbiota diversity—a measure of how many different species and, dependent on the diversity
indices, how evenly distributed they are in the community.
Lower diversity is considered a marker of dysbiosis (microbial imbalance) in the gut and has
been found in autoimmune diseases and obesity and cardiometabolic conditions, as well as in
elderly people

Schematic
representation of
the role of the gut
microbiota in
health and
disease giving
some examples of
inputs and
outputs.
Ana M Valdes et al. BMJ 2018;361:bmj.k2179
IPA=indolepropionic acid;
LPS=lipopolysaccharide;
SCFA=short chain fatty acids;
TMAO=trimethylamine N-oxide

Taxonomic distribution, prevalence and abundance of microbial taxa that inhabit healthy
human body sites as defined in the human microbiome projects (HMP).

Depiction of various diseases associated with different microbiome (gut, oral, skin, vaginal)
and the major upregulated and downregulated microbes involved in said diseases
https://link.springer.com/chapter/10.1007/978-981-16-3156-6_10

Antibiotics affect colon flora
Jernberg C, Löfmark S, Edlund C, Jansson J. Long-term impacts of antibiotic exposure on the
human intestinal microbiota. Microbiology (Reading, England). 2010;156:3216–23.

Schematic representation of the impact of healthy vs. unhealthy microbiota on
COVID-19 outcome

Overview of candidate
biomarkers for diagnosis of gut
microbiota dysbiosis and
associated human diseases.
↓
Biomark. Med. (2021) 15(2), 139–150
decrease

Oral microbial biomarkers investigated for selected oral and systemic diseases

Therapeutic-Microbiota/ Microbiome-
modulation

Beta-Glucan;inulin;fructane
Bifidobacterium;LactoBacilis
Subtractive therapy
•Bacteriocins are ribosomally synthesized peptides exhibiting antimicrobial activity . By
membrane rupture, toxins, inhibition of the respiratory mechanism, and overall cell lysis.
•Bacteriophages

PLOS ONE |https://doi.org/10.1371/journal.pone.0247039 February 25, 2021
Exerciseinterventions

PLOS ONE |https://doi.org/10.1371/journal.pone.0247039 February 25, 2021
Exercise interventions

Immunology& Cell Biology 2021; 99: 255–273

Impact of metformin on the gut
microbiota. Various in vitro and in
vivo studies demonstrated that
metformin might exhibit glucose-
modulating effects by interacting
with the gut microbiome. Each box
presents the putative mechanism
suggested in this review
Int. J. Mol. Sci. 2021, 22, 3566.
https://doi.org/10.3390/ijms22073566

Description of
(poly)phenols direct
antibacterial and
prebiotic effects
.Front Nut 2021‫ك‬Jun .8:689456;28doi: 10.3389/fnut. 2021.689456

NonspecificProbiotics:
e.g. Fecalmicrobiata transplantation (FMT)

Major factors in
using Faecal
Microbiota
Transplantation
treatment to
restore the
microbiome.

registered clinical trials using faecal microbiota transplantation

recipient and negative inter-actions with the recipient’s existing microbial
community,
-FMT has encountered safety issues. In March 2020, the FDA issued a safety alert following
infections with pathogenic Escherichia coli strains detected in 6 patients who received
investigational FMT products supplied by a stool bank company as treatment for C
difficile infection. Additionally, 2 patients with chronic medical conditions died after
receiving the FMT product from the stool bank; however, the FDA said the E coli infection
was not detected in the stool of 1 of the patients and it was unclear whether the infection
contributed to the death of the other. The FDA now mandates additional screening of
donor feces for these dangerous strains.25-27
- Substantial microbial community variability between individuals and the limited
long-term stabilization of a foreign microbial configuration.
-Side effects, including the following: bacterial stability and translocation, genetic
factors of individual recipients that may influence the success of FMT and bacterial
colonization, or transplant rejection similar to organ transplantation
LIMITATIONS of FMT:
- They need to be ingested in a dosage high enough to cause an effect.
-The beneficial effects of a given probiotic is specific to that strain, and cannot be
regarded as general for other strains of the same species, or other species, of
bacteria or yeast.
-owing to the many unknown components presented in the donor’s samples, it also
carries the risk of transmitting pathogens or disease-causing genes to the

Screening sections involved in each stage for the functional and
safety aspects of probiotics(FAO/WHO guidelines)
Probiotics and Antimicrobial Proteins (2021)

Animal Physiology Nutrition, Volume: 104, Issue: 6, Pages: 1835-1850, First published: 29 September 2020, DOI: (10.1111/jpn.13454)
The possible mechanisms of probiotic action.
(1) Competitive exclusion of pathogenic micro‐organisms.
(2) Production of antimicrobial substances.
(3) Competition for growth factors and nutrients.
(4) Enhancement of adhesion to intestinal mucosa.
(5) Improvement of epithelial barrier function.
(6) Improvement of secretion of IgA

Probiotics: 21st Century Wonder Drug Re-discovered?
Probiotics claim to resolve/reduce > 20 human maladies from diarrhea to cancer and multiple sclerosis (MS
Diarrhea Helicobacteria pylorus
Increase in Anti-allergic Cytokines Decrease in frequency of “common cold”

Brand name Strain Producer
Linex’ Bifidobacterium lactis BB-12 sandoz
Dicoflor Lactobacillus rhamnosus GG AGPHARMA
Enterogermina Bacillus clausii SANOFI
Enterolactis Lactobacillus casei SOFAR
Nutriflor Lactobacillus acidophilus DDS-1, Lactobacillus bulgaricus
DDS-14 Bifidobacterium bifidum, Lactobacillus rhamnosus
NUTRIGEA
Probactiol duo Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-
37 Bifidobacterium lactis Bi-07, Bifidobacterium lactis Bi-04
METAGENETICS
VSL#3 Streptococcus thermophilus, Bifidobacterium
breve, Bifidobacterium longum, Bifidobacterium infantis
lactobacillus acidophilus, Lactobacillus plantarum,
Lactobacillus paracasei, Lactobacillus delbrueckii subsp.
bulgaricus
FERRING
FARMACEUTICI
Yakult Lactobacillus casei Shirota YAKULT (Tokyo)
List of a few commercially available probiotic preparations
ink.springer.com/chapter/10.1007/978-981-16-3156-6_10/tables/1

Type Delivery Product phase Recent outcomes Clinical trial ID
Faecal
microbiota
transplanta
tion or
fractionate
d, partially
undefined
communiti
es
Enema
Rebiotix RBX2660
for recurrent CDI
III
29.4% relative risk reduction of CDI recurrence
compared with placebo (week 8)a
NCT03244644
(PUNCHCD3)169,170,
171,172,173
Oral capsule
Finch Therapeutics
CP101 for recurrent
CDI
II
21% relative risk reduction of CDI recurrence
compared with placebo (week 8)b
NCT03110133
(PRISM3)
Oral capsule
(Firmicutes
spores)
Seres Therapeutics
SER-109 for recurrent
CDI
III
73% relative risk reduction (week 8)
54% relative risk reduction of CDI recurrence
compared with placebo (week 24)a
NCT03183128
(ECOSPORIII)
Oral capsule
(lyophilized stool
suspension)
Rebiotix RBX7455
for recurrent CDI
I
Microbiota shifts after treatment, no CDI
recurrence in 80–100% of participants
depending on treatment (8 weeks)
NCT02981316
(ref.174
)
Prebiotics
Dietary
supplement (with
chickpea, peanut,
soybean flours
and green
banana)
Microbiota-directed
complementary food
prototype (MDCF-2)
for moderate acute
malnutrition
II
MDCF-2 increased measures of weight-for-
length and weight-for-age compared with
ready-to-use supplementary food
NCT04015999
(ref.111
)
Symbiotic
microbial
consortia
Oral capsule (40
lyophilized
isolates)
NuBiyota MET-2 for
CDI
I
Increased microbiota alpha diversity
CDI absent in 79% of participants (day 40)
NCT02865616
(ref.175
)
Oral capsule (8
lyophilized
isolates)
Vedanta Biosciences
VE303 for CDI
II
Promoted microbiota recovery in healthy
volunteers after antibiotics
NCT03788434
(CONSORTIUM)176
Examples of microbiome-based therapeutics in development and clinical trials
Microbiome-based therapeuticsnature reviews microbiology; Published: 06 January 2022

Studied methods of microbiota normalization in CS-born infants.
CS, C-section; FMT, faecal microbiota transplantation.
. Ann Nutr Metab; 2021 Aug 30;1-9. doi: 10.1159/000518498

Delivery system Pros Cons
Fermented dairy
-Affordability and easy Availability
-Ease of incorporation into daily patterns
-Additional nutritional benefits
-Enhanced bacterial survival-through upper
GI tract (100× less bacteria can be given per
dose)
-Effective in the upper GI tract
-Contains dairy proteins and
lactose
-Taste can be issue
-Not suitable when travelling
-Not suitable for vegans
Capsules
-Ease of administration
-Contain no binders
-Not therapeutic in upper GI tract
(unless opened or chewed)
-May contain allergenic excipients
-Higher cost
Tablets
-Ease of administration
-May contain allergenic or
otherwise problematic binders and
excipients (e.g., gluten)
-Higher cost
Powders
-Dosages can be easily adjusted
-Can be incorporated into foods or drinks
-Contain no binders
The pros and cons of different probiotic delivery systems
https://www.intechopen.com/chapters/50992

•is chemical compounds of probiotic microbial origin including
short chain fatty acids, acetate, butyrate, and propionate mixture ,
peptides, teichoic acids, endo- and exo-polysaccharides, cell
surface proteins, vitamins, plasmalogens, and organic acidsis.
•Dosage and routes of administration follow the principles of
pharmacokinetics. Metabolites are present at most body sides and
thus suitable for different routes of administration.
•Metabolites are generally stable in the systemic circulation and
thus amenable for scalable modulation of their concentration.
•In contrast to the administration of live organisms, the effects of
some microbiome-associated metabolites are pleiotropic and
highly cell type specific. further characterization of the full effects
of different metabolites is necessary in order to understand
potential side effects of postbiotics
post-biotic / small molecule,

POSTBIOTICS
Molecules and metabolites produced by the gut microbiota according to the nutrients or metabolic
source and their derived compounds.
BSCFA, branched SCFA;
LPS, lipopolysaccharides;
PAMPs, pathogen-associated
molecular patterns;
SCFA, short chain fatty acids.

Colonocytes and endocrine
cells express a variety of
receptors able to sense and
transmit signals from the
microbial environment.
(PAMPs), Microbial/Pathogen-associated molecular
patterns .
(LPS) lipopolyscaccharides;
(eCBs), endocannabinoids .
CB1, CB2, cannabinoid receptor type 1 and type 2;
TRPV1, transient receptor potential cation channel
subfamily V member 1;
FXR, farnesoid X receptor;
AhR, aryl hydrocarbon receptor;
GPR119, GPR43, GPR41, G-protein coupled receptor 119,
43 and 41;
MYD88, myeloid differentiation primary response 88;
PPARα/γ, peroxisome proliferator-activated receptors alpha
and gamma;
TGR5, Takeda G protein-coupled receptor 5.

Typical gut microbiota metabolites in modulation of host metabolism

Schematic representation of various health benefits of postbiotic molecules
Microbial Cell Factories volume 19, Article number: 168 (2020)

Adv Nutr, Volume 10, Issue suppl_1, January 2019, Pages S49–S66, https://doi.org/10.1093/advances/nmy063
Potential biological effects of SCFAs in humans. AMPK, AMP kinase;
ANGPTL, angiopoietin-like; GLP1, ...
AMPK, AMP kinase; ANGPTL, angiopoietin-like; GLP1, glucagon-like peptide 1; GPR, G protein–coupled receptor; HSL, hormone-
sensitive lipase; LPL, lipoprotein lipase; PPAR-γ, peroxisome proliferator-activated receptor-γ; PYY, polypeptide YY

Groups Typical metabolites Typical targets Specific functions Typical diseases associated
Short-
chain fatty
acids
Acetate, propionate,
butyrate, hexanoate,
isovalerate, isobutyrate, 2-
methylpropionate,
valerate
Directly act on GPR41, GPR43,
GPR109A, GPR81, GPR91,
HDAC1 and HDAC3
Regulation of gut microbiota composition, gut
barrier integrity, appetite, energy
homeostasis, gut hormone production,
circadian clocks; inhibit proinflammatory
cytokines; stimulate water and sodium
absorption; modulate systemic immune
response
Diabetes, obesity, pancreatitis, nonalcoholic
fatty liver disease, hypertension,
atherosclerosis, chronic kidney disease,
ulcerative colitis, radiation proctitis, Crohn’s
disease, colorectal cancer, autism spectrum
disorder, sclerosis, Parkinson’s disease,
asthma, diarrhea
Bile acids Cholate, hyocholate, deoxy-
cholate, taurohyocholate,
ursodeoxycholate,
taurocholate, tauro-α-
muricholate,glycocholate,
hyodeoxycholate,tauro-β-
muricholate, lithocholate,
taurodeoxylcholate
Directly act on FXR, VDR,
PXR/SXR, constitutive
androstane receptor (CAR),
TGR5, sphingosine 1-phosphate
receptor 2 (S1PR2), formyl-
peptide receptor (FPR),
(mAChR)
Facilitate lipid and vitamin absorption;
regulation of gut microbiota composition, gut
hormones, intestinal immunity, intestinal
electrolyte and fluid balance, gut motility,
lipid homeostasis, glucose homeostasis,
amino acid homeostasis, circadian clocks;
influence neurotransmission and physiology
Primary biliary cholangitis, primary
sclerosing cholangitis, obesity, nonalcoholic
fatty liver disease, non-alcoholic
steatohepatitis, atherosclerosis, ulcerative
colitis, cancer, hepatic encephalopathy,
multiple sclerosis, Alzheimer's disease,
Parkinson's disease, traumatic brain injury,
stroke and amyotrophic lateral sclerosis
Gases H2S, H2, CO2, CH4, NO NO targets soluble guanylate
cyclase, H2S cause
conformational changes of
target proteins by sulfhydration
CH4 slows gut motility; H2S regulates gut
inflammation, motility, epithelial secretion
and susceptibility to infections; NO mediates
gastric mucosal protection and regulate
mucosal blood flow
Parkinson’s disease, colitis, ulcer
Tryptophan
and indole
derivatives
Indole-3-lactic acid, indole
acetic acid, indole-3-
acetamide, indole pyruvic
acid,indoxyl sulfuric acid,
indole, serotonin
Directly targeting on AhR and
PXR
Influence the gut microbial spore formation,
drug resistance, biofilm formation, and
virulence; regulate intestinal barrier
functions, gut hormone secretion, gut motility,
systemic immune response
Ulcerative colitis, Crohn’s disease, obesity,
stroke, mucosal candidiasis, autism spectrum
disorder, Alzheimer’s disease, Parkinson's
disease, migraine, schizophrenia, irritable
bowel syndrome
Choline
metabolites
TMA, methylamine,
dimethylglycine,
dimethylamine,
Direct target unknown, but can
activate NF-кB, protein kinase C
(PKC), NLRP3 inflammasome
Inhibits bile acid synthesis; promote
inflammation, thrombosis; affects myocardial
hypertrophy and fibrosis; exacerbates
mitochondrial dysfunction
Nonalcoholic fatty liver disease, obesity,
atherosclerosis, diabetes, heart failure,
hypertension
Vitamins Vitamin B2, Vitamin B3,
Vitamin B5, Vitamin B6,
Vitamin B9, Vitamin B12,
vitamin K
Vitamin receptors Involved in cellular metabolism; modulate
immune function and cell proliferation;
supply vitamins for hosts
Vitamin associated diseases such as
schizophrenia, autism, and dementia
Neurotrans
mitters
Dopamine, catecholamines, 5-
HT, and GABA
Adrenergic receptors, 5-HT
receptors, GABA receptors
Regulate gut motility, memory and stress
responses, immune function of nervous
system
Parkinson's disease, autism
Lipids Conjugated fatty acids,
cholesterol,
phosphatidylcholines,
triglycerides, LPS
LPS targets directly on TLR4 LPS triggers systemic inflammation;
conjugated fatty acids regulate
hyperinsulinemia, immune system,
lipoprotein profiles; cholesterol acts as
material bases for bile acid synthesis.
Diabetes, obesity, nonalcoholic fatty liver
disease, hyperinsulinemia,
hypercholesterolemia, chronic hepatitis C.
Others Ethanol; triphosadenine;
lantibiotic ( ruminococcin Aand
Triphosadenine activate P2X and
P2Y receptors
Enhance or damage gut barrier; regulate intestinal
or systemic immune response; act as antibiotics to
Fatty liver disease, C. difficile and H.
pylori infections, irritable bowel syndrome,

Possible diagnosis and therapy using the interaction with gut microbiome and epigenetic.
Disease Links to gut microbiome Links to epigenetics Diagnosis and therapy
Colorectal
Cancer
(CRC)
↑ abundance
of Fusobacterium
nucleatum and Providencia but
↓adabundance Lactobacillus a
nd butyrate-producing
bacteria such
as Roseburia and Fecalibacteri
um in CRC .
Butyrate, one of the most abundant
SCFAs, is well known as HDACi which
have antiangiogenic and
antimetastatic effects in cancer by
epigenetically activating tumor-
suppressor genes such
as p21 and bax or suppressing
carcinogenetic genes including Cox-2
• Oral administration
of Bifidobacterium and Bacteroides which
were suggested as therapeutic probiotics
for cancer immunotherapy .
• Butyrate or the prebiotic sources such as
acemannan in Aloe vera gel with their
chemopreventive effect.
Diabetes High ratio of
Firmicutes/Bacteroidetes in
type 2 diabetes with high
abundance of lactic acid
bacteria but low
of Faecalibacterium prausnitzii
Changes in cell wall components
such as LPS and peptidoglycan
resulting from dysbiosis are involved
in the epigenetic regulation of the
inflammatory response
• Improved diets targeting to recover
dysbiosis and epigenetic changes of pro-
inflammatory genes in metabolic syndrome
• Transplantation of gut microbiota from
lean and healthy donors to patients with
metabolic syndrome .
Obesity Decreased production of
butyrate by gut microbiota and
lower diversity of the
microbiota with low
abundance of F.prausnitzii ].
Hypomethylation at the promoter
regions of SCFAs receptor
GPR41/FFAR3 in obese patients.
• GLP-1 agonist who contributed to the
moderate increase of F.prausnitzii and the
reverse of a hypomethylation of the
promoter regions of GPR41/FFAR3 in
patients with obesity and type 2 diabetes
IBD Lower abundance
of Streptococcus and the
increased abundance
of Bacteroides, Parabacteroide
s, and Roseburia Lower
abundance of Akkermansia
muciniphila in UC patients
Hypomethylation at the differentially
methylated regions (DMR) of KHDC3L
(C6orf221) in UC patients, which
were highly correlated with the
dysbiosis Modulation of Fiaf, GPR43,
HDACs, and PPARγ expression by A.
muciniphila and propionate
• Identification of colonic mucosal DMRs
can provide epigenetical and
metagenomical targets for therapeutic
measures [107].
• Assessment of the gut microbial dysbiosis
at the early stage of CD
Epigenet. 2017, 3:2. doi: 10.21767/2472-1158.100048

U.S. Microbiome therapeutics market, by application, 2016 & 2025 (USD Million)

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