Download Gut flora in health and disease

Gut flora in health and
disease
Introduction
The intestinal habitat of an individual contains
300–500 different species of bacteria.
The stomach and small intestine contain only a
few species of bacteria because of the composition
of the luminal medium (acid, bile, pancreatic
secretion), which kills most ingested
microorganisms, and because of the phasic
propulsive motor activity towards the ileal end,
which impedes stable colonisation of bacteria in
the lumen.
By contrast, the large intestine contains
a complex high densities of living bacteria.
Some of these bacteria are potential
pathogens and can be a source of infection
and sepsis under some circumstances for
instance when the integrity of the bowel
barrier is physically or functionally
breached. However, the constant interaction
between the host and its microbial guests
can infer important health benefits to the
human host.
Composition of gut flora
Colonization of GIT starts immediately
after birth and is affected by:
 Type of delivery
 Type of food
 Other environmental factors
Pioneer bacteria can modulate expression
of genes in host epithelial cells, thus:
 create a favourable habitat for
themselves.
 prevent growth of other bacteria
Conventional bacteriological analysis of
fecal flora
-
Anaerobic
Bacteroids
Bifidobacterium
Eubacterium
Clostridia
Peptocercus
Peptostreptocercus
Aerobic
- E coli
- Enterobacter
- Enterococcus
- Klebsiella
- Lactobacillus
- Proteus
anaerobic bacteria outnumber aerobic bacteria by a
factor of 100–1000.
Functions of gut flora
1.
Metabolic functions:
- Fermentation of non digestible dietary residue
e.g cellulose and strach by aerobic bacteria
short chain FA, source for energy for both host
and resident bacteria
- Putrefaction of exogenous and endogenous
protein (like sloughed epithelium and lysed
bacteria) by anerobic bacteria
short chain
FA as well as toxic substrances like ammonia
and amines.
- Production of Vitamin K
- Absorption of ions (Fe, Ca, Mg).
2- Trophic functions:
- SCFA stimulate epithelial cell proliferation
and differentiation, moreover butyrate
promote reversion of cells from neoplastic
to non neoplastic phentype.
3- Development and homeostatis of
immune system:
- Specialized epithelial cells (M cells)
sample luminal antigens as well as the
microflora and transport them to the
lymphoid follicles to develop tolerating
anti-inflammatory response (Th2 response)
through the production of IL10 and TGFB.
- Immunity is constantly reshaped by persistent
interactions between the host and its bacteria that
take place in the gut. Commensal organisms try to
circumvent the immune response by changing its
surface antigenicity to allow the organism to
escape immunosurveillance and maintain an
ecological niche of predominance in the intestinal
tract. However, host defences adapt and keep an
active control of bacterial growth.
- immune system also can discriminate
between potential pathogens from
commensal bacteria, with use of a restricted
number of preformed receptors i.e. toll-like
receptors.
4- Protective function (barrier effect):
- compete and adhere to the attachment
sites in the brush border of intestinal
epithelial.
- compete for available nutrients.
- produce antimicrobial (bacteriocins).
All of this will prevent attachment and
subsequent entry of pathogenic bacteria into
the epithelial cells
Gut flora and gut diseases
Gut flora and Malabsorption
syndrome
 In health, motility and acid are the most important
factors in keeping the number of bacteria in the
upper small bowel low.
 Factors predispose to bacterial overgrowth:
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Surgical e.g afferent loop syndrome
Anatomical e.g diverticulae, obstruction & fistulae.
Motor e.g scleroderma & DM.
Hypochlohydra e.g atrophic gastritis, post gastrectomy,
post vagotomy, PPI.
 Consequences of bacterial overgrowth:
- Fat malabsorption due to:
Bacteria deconjugation of bile acids which allows free
bile acids to be reabsorped
decrease luminal bile
acid concentration
limit micelle formation.
Patchy mucosal damage by bacteria or toxic effects of
FFA
- CHO and protein malabsorption due to mucosal
damage or bacterial metabolism of these nutrients.
- B12 malabsorption: B12 is utilized by the bacteria, in
contrast bacteria produces folic acid.
 Diagnosis of bacterial overgrowth:
- Quantitative culture of luminal contents (gold
standard).
- Hydrogen breath test.
 Treatment:
– Treatment of the cause
– Antibiotics e.g ciprofloxacin, metronidazole
– Stop acid reducing agents
– Octerotide improves motility in scleroderma
Gut flora and colorectal cancer
Colonic bacteria may initiate cancer through:
1- production of carcinogens from diets rich
in meat and fat (nitroso compounds).
2- augmentation of the damage to DNA of
colonic cells by dietary carcinogens
(heterocyclic aromatic amines found in
cooked meat).
High risk of colon cancer was associated with
presence of Bacteroides vulgatus and Bacteroides
stercoris while, low risk was associated with
presence of Lactobacillus acidiphilus,
Eubacterium aerofaciens.
Although the evidence is not conclusive, colonic
flora seem to be a major environmental factor that
modulates risk of colonic cancer in human beings.
Gut flora and IBD
 In Crohn's disease intestinal T-lymphocytes are
hyper-reactive against bacterial antigens, suggest
that local tolerance mechanisms are abrogated in
such patients.
 Increased intestinal mucosal secretion of IgG type
antibodies against a broad spectrum of commensal
bacteria. unlike normal IgA responses, IgG
activate the complement and the cascade of
inflammatory mediators
 patients with IBD have higher amounts of
bacteria attached to their epithelial surfaces
than than do healthy people. This causes
unrestrained activation of the intestinal
immune system
 Some patients with Crohn's disease (17–
25%) have mutations in the NOD2 gene
expressed in macrophages which encodes
intracytoplamic receptor for bacterial LPS.
Normally, Interaction of bacterial LPS
with NOD2 will lead to activation of NFKB
with subsequent production of cytokines
and resistance to apoptosis.
Mutation in NOD2 gene will lead to
diminished macrophage activation in
presence of bacterial LPS chronic
intracellular infection or failure to develop
tolerating immune response in presence of
commensal flora.
 Faecal stream diversion has been shown to prevent
recurrence of Crohn's disease, whereas infusion of
intestinal contents to the excluded ileal segments
reactivated the mucosal lesions.
 In ulcerative colitis, short-term treatment with an
enteric-coated preparation of broad-spectrum
antibiotics rapidly reduced mucosal release of
cytokines and eicosanoids and was more effective
in reduction of inflammatory activity than were
intravenous steroids.
Gut flora and complications of
cirrhosis
The gut flora plays a role in the
development of infections and also in
the hyperdynamic circulatory state of
cirrhosis and, although less prominently,
it also plays a role in the pathogenesis
of hepatic encephalopathy.
Bacterial translocation is the key
factor in the pathogenesis of SBP and
HCS.
Bacterial translocation
 Definition:
migration of viable micro organisms from
the intestinal lumen to mesenteric lymph
nodes and other extraintestinal organs.
 Conditions associated with BT:
– Acute liver failure
– Advanced liver cirrhosis
– Intestinal ischemia
– Intestinal obstruction
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Hemorrhagic shock
Burn injury
Acute severe pancreatitis
IBD
Laparotomy & abdominal surgery.
 Factors that facilitate BT in cirrhosis:
– Impaired immunity:
• Cirrhosis is accompanied by decrease in bactericidal
activity by phagocytic cells
• Decreased hepatic synthesis of complement
• Impaired RES activity because of porto-systemic
that bypasses the liver and because of impaired
phagocytic activity of kupffer cells.
– Intestinal bacterial overgrowth:
Due to delayed intestinal transit time especially
in patients with more severe liver disease.
- Intestinal permeability:
Cirrhosis is associated with structural and
functional alterations in intestinal mucosa
that may increase permeability to bacteria.
Gut flora and hyperdynamic
circulatory state
Vasodilatation, and the subsequent
development of the HCS, lead to a worsening
of all complications of cirrhosis.
Although several vasodilators, such as
prostacyclin, adrenomedullin, calcitonin-generelated peptide, substance P and glucagon
have been related to the pathogenesis of
HCS, nitric oxide appears to be the key
vasodilator responsible for the
haemodynamic abnormalities of cirrhosis.
NO is synthesized by different
isoforms of NO synthases (NOS);
endothelial (e) NOS and neuronal (n)
NOS which are expressed constitutively
whereas inducible (i) NOS is expressed
after induction by LPS, endotoxins and
cytokines like the TNF released from
GALT in response to translocated gut
flora.
Gut flora and hepatic
encephalopathy
Gut flora contributes to encephalopathy
through:
- Production of ammonia by urease positive
colonic flora.
- Production of GABA and benzodiazepine
like substances.
- H-pylori (urease producing) has
controversial role in pathogenesis of HE.
Gut flora and treatment of HE:
- Synthetic non-absorbable disaccharides
(e.g. lactulose and lactitol) once they reach
the colon, bacteria metabolize them,
generating organic acids. A lower colonic pH
creates an environment hostile to the survival
of urease-producing intestinal bacteria and
may promote the growth of non-ureaseproducing lactobacilli.
- Non-absorbable antibiotics with activity
against urease-producting bacteria (e.g.
neomycin, paromomycin) also reduce
bacterial ammonia production in the colon
and are clinically effective.
Probiotics, Prebiotics &
synbiotics
 Probiotics:
Living microorganisms that up on ingestion
exert health benefits beyond those of
inherent basic nutrients e.g lactobacilli and
bifidobacteria.
Recent research expand the definition of
probiotics to include genetically engineered
microbes and non viable microbes
 Prebiotics:
Non digestible food indgredients which
beneficially affect the host by selectively
stimulate the growth and/or the activity of
one or limited number of bacteria in the
colon having the potential to improve host
health.
 Synbiotics:
A mixture of probiotics and prebiotics
which beneficially affects the host.
Probiotics in practice
 In diarrheal disease:
– Prevention of diarrhea in undernourished children.
– Reduce antibiotic associated diarrhea if co-administered
with antibiotics.
– Shortening of duration of diarrhea in acute
gastroenteritis especially those caused by rotavirus.
• Through stabilization of indigenous microflora
• Through reduction of increased gut permeability
• Through enhancement of specific IgA response.
 Elemination of lactose intolerance in people who
donot efficiently absorb lactose, Lactobacilli provide
the enzyme lactase which hydrolyzes lactose. The
hydrolyzed lactose is converted to lactic acid.
 Prevention of CRC:
Putrefactive colonic microflora produce the
enzymes convert procarcinogens to carcinogens.
Lactobacilli, by competitive inhibition and the
production of acidic environment, suppress the
metabolic activity of colonic microflora and in this
manner may reduce the formation of carcinogens in
the large intestine. lactobacilli also suppress
carcinogen-induced mutations
 Treatment of IBD through:
- Production of proteases which degrade the
antigenic structure of dietary antigens, an
important step in the induction of tolerance to
dietary antigens.
- Induction of tolerating anti-inflammatory
response (Th2 response).
- Promoting the normalization of indigenous flora
and the exclusion of pathogens.
 Treatment of hepatic encephalopathy
through:
Lactobacilli produce lactic acid creating a
gastrointestinal environment which is not
suitable for the growth of putrefactive
organisms. This results in lower intestinal
urease levels and consequently lower blood
ammonia levels. In addition, the low pH due
to lactic acid production disfavors the
absorption of ammonia from the gut into the
tissues and facilitates excretion of ammonia
from the blood into the gut
 Treatment of allergic diseases e.g atopy &
food allergy:
- Through induction of tolerating antiinflammatory response (Th2 response).
- A significant improvement in the clinical
course of atopic eczema has been observed
in infants given a probiotic supplemented
diet, and in parallel, markers of systemic
and intestinal allergic inflammation were
significantly decreased. Similar results have
been obtained in milk hypersensitive adults.
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