Intestinal Overgrowth Bacteria and Translocation

in Critically Ill Children

Badriul Hegar
Keywords
• Intestinal Overgrowth Bacteria
• Translocation bacteria

Critically ill Children

 Critically ill Children
Children who need or potentially need close monitoring and
intensive care, both medical and surgical

Pediatric Early Warning • monitor clinical deterioration of children

• quick identify critically ill patients, so treatment can be
Scores started without delay.

Pediatric Critical Care : Pediatric Emergency & Pediatric

Intensive.

Vredebregt SJ, Mall HA, Smit FJ, Verhoeven JJ. Recognizing critically ill children with a modified pediatric early warning score at the emergency department,
a feasibility study. Eur J. Pediat . 2019 Feb;178(2):229-234
 Gastrointestinal complications in
critically ill children

• Very variable : the absence of unified diagnostic criteria

• The volume of gastric residues
• No differences between gastric and transpyloric nutrition

Lopez-Herce. Gastrointestinal complications in critically ill patients: what differs between adults and children?. Curr Opin Clin Nutr Metab Care.
2009 Mar;12(2):180-5.
 The most important risk factors
for digestive tract complications

• Shock
• The administration of drugs : catecholamines, muscle
relaxants, sedatives

Lopez-Herce. Gastrointestinal complications in critically ill patients: what differs between adults and children?. Curr Opin Clin Nutr Metab Care.
2009 Mar;12(2):180-5.
 attenuated migrating motor complex activity

Available data

Altered gastrointestinal motility

The principal mechanism underlying

Excessive gastric residue

Overgrowth bacteria

Abdominal distension
Translocation bacteria

Constipation

absorption and nutrition

Lopez-Herce. Gastrointestinal complications in critically ill patients: what differs between adults and children?.
Curr Opin Clin Nutr Metab Care. 2009 Mar;12(2):180-5.
 The criteria for
Critically ill Patient Children an intestinal motility disorder likely to
result in bacterial overgrowth

The definition : excessive gastric residues,

Gastrointestinal Complication constipation, diarrhea ?

Consensus
limit the efficacy of
enteral nutrition
Research

Morbidity and mortality Efficacy of prokinetic on GI motility

The effects of diet & laxatives on
constipation

Lopez-Herce. Gastrointestinal complications in critically ill patients: what differs between adults and children?.
Curr Opin Clin Nutr Metab Care. 2009 Mar;12(2):180-5.
 a broad range of predisposing small surgical procedures that result in
Critical Ill children bowel stasis
intestinal motility disorders

an abnormally high number of bacteria in

the small bowel

The most common symptoms

diarrhea, flatulence, abdominal pain, bloating

No single valid Quantitative culture of small bowel contents

test for SIBO Variety of indirect tests SIBO
(breath tests and biochemical tests )

• The failure of culture to be a gold The ideal approach to treat SIBO

standard
• treat the underlying disease,
• The lack of standardization of the • eradicate OGB
normal bowel flora in the small intestine • address nutritional deficiencies
Intestinal Overgrowth Bacteria

bacterial population in Normally, < 10 organisms/mL

upper small intestine,
the small intestine the majority Gram-positive organisms

> 105-106 organisms/mL

abnormal or postsurgical anatomy Systematic review :
Stagnant loop syndrome many GI conditions : Increased
bacterial counts > healthy controls
≥1 × 103 bacteria cfu/ml in the small bowel but
SIBO < 1 × 105cfu/ml

Dukowicz A, Lacy BE, Levine GM. Small intestinal bacterial overgrowth.

Gastroenterol Hepatol 2007;3(2):112-22
Clinical problem associated with clinical features

• bacteria that metabolize bile salts to fat malabsorption or

unconjugated or insoluble compounds bile acid diarrhea

• bacteria metabolize carbohydrates to bloating without diarrhea

short-chain fatty acids & gas because the metabolic products
can be absorbed

• >> gram-negative aerobes and

anaerobic. E. coli, Enterococcus spp., Klebsiella interfering with
pneumonia, Proteus mirabilis, …
absorptive function causing
secretion
produce toxins
damage the mucosa
 Causes of Gastrointestinal BOG

• diabetes neuropathy, Classic gastrointestinal surgical

• scleroderma, blind loop
• chronic intestinal pseudo-
obstruction
• adhesions,
• intestinal diverticulosis, Stasis in The Gut
• irritable bowel syndrome Coliform bacteria opportunity to proliferate locally

Small intestine motility disorder oral microbe penetration of

Bacterial overgrowth the proximal gut

Gastrocolic or coloenteric fistula Certain medication

Anatomic abnormality of
the small intestine with stagnation • narcotics cause intestinal
• Crohn’s diseases, slowing
• Malignancy
• surgical resection • afferent loop gastrojenunostomy • proton pump inhibitors (PPIs)
• small intetsine diverticulosis reduce acid
• obstruction
• surgical blind loop
• radiation enteritis
Bacterial Translocation
The migration of bacteria or bacterial products
from the intestinal lumen to
mesenteric lymph nodes (MNL) or other extra-intestinal organs

• a disruption of the normal host flora equilibrium

• leads to a self-perpetuating inflammatory response and
• ultimately to infection

inert particles and other macro molecular antigens (endotoxin and

peptidoglycan lipopolysaccharide) across the intestinal mucosal barrier
 attractive
Bacterial translocation as a direct cause of sepsis hypothesis

failure of the intestinal barrier

Critically ill children

bacteria cross
the intestinal barrier
bloodstream
infections

Predisposing factors
the systemic circulation
• intestinal obstruction,
• obstructive jaundice,
• intra-abdominal hypertension,
• intestinal ischemia/ reperfusion
injury systemic inflammatory response
• secondary ileus Sepsis syndrome.
• immaturity of the intestinal
barrier
 live bacteria and /or their products

Translocation : between cells or

through intestinal epithelium cell
after loss of tight junctions
cross
Bacterial translocation
the intestinal barrier
May be a physiological process,
luminal antigens produce immuno-
competent cells

immune system • bacterial translocation from the gut

occurs regularly even in 5-10%
infection healthy individuals
massive inflammatory • bacteremia is generally limited by
reaction an intact immune system

diffuse organ damage

organ failure and death

Bacteria translocation may in fact be
a normal phenomenon

‘Oral tolerance’

a controlled local intestinal immune response helps keep antigens away

from the internal environment
 ‘Gut origin of sepsis hypothesis’
1
splanchnic hypoperfusion The gut becoming a major site of pro-inflammatory factor production

resuscitation

leads to an injury to the intestine : loss of gut barrier function and an ensuing
ischaemia-reperfusion enhanced gut inflammatory response

bacteria or endotoxin cross the mucosal barrier

a pro-inflammatory organ, releasing chemokines, cytokines, other pro-inflammatory

augmented immune response
intermediates , affect local and systemic immune systems

2
macrophages & other immune cells in the gut wall
SIRS and MODS ‘Gut-lymph theory’ submucosal lymphatics or MLNs trap the majority of
translocating bacteria
 The gut origin of sepsis hypothesis,
with bacterial translocation as a potential stimulus for
ongoing inflammation
 bacteria intra lumen Methodological Problems in Confirming
Bacterial Translocation in human
route
transcellular and or the paracellular
• Culture of MNLs
laminal propria the most reliable method of assessing bacterial translocation

destroyed by macrophages • limited sampling at laparotomy, aseptic techniques

• appropriate media.

cross
• Techniques limitations
the mucosal epithelium
• in vivo studies : surgical patients, laparotomy
• other clinical conditions : necessitated extrapolations
MLNs
from animal models
portal venous system

solid organs Peritoneal cavity
Assessment of BT in humans difficult as it
necessitates invasive tissue sampling
The understanding of this phenomenon ?
• Ethical and logistical limitation : number of lymph
nodes that can be safely sampled in humans.
• Prevalence bacterial translocation : 10–15% of
surgical patients, >90% in some animal studies report
Advances Molecular Microbiology
opened new frontiers in identifying bacterial translocation by non‐interventional
methods

• Isolation and sequencing of DNA fragments

belonging to enteric bacteria from peripheral blood and other body fluids

• Studies : Surrogate measures of intestinal barrier function

• blood cultures with concomitant fecal cultures
• intestinal immune markers
• bowel scrapings
Do not represent level 1 evidence of
• intestinal permeability measurements
bacterial translocation,
• culture of nasogastric aspirates
The findings of such studies should be
interpreted with caution
Factors that Predispose to Translocation
Factors that influence bacterial translocation affect the delicate homeostatic equilibrium between luminal
organisms and intestinal barrier, the entry of antigens across the intestinal barrier

• intestinal obstruction
• jaundice Number and complexity of factors
• inflammatory bowel disease
• malignancy to conclude the 'independent’ factors
• pre‐operative total perenteral nutrition (TPN) that are important for translocation
are very difficult.
• emergency surgery
• gastric colonization with microrganisms.

Much of the evidence

to substantiate these claims is available
from animal studies
Factors that Predispose to Translocation
Total perenteral nutrition
• to patients with non‐functioning intestines
• cannot tolerate or absorb enteral nutrition
• BT ~ underlying gut failure
Univariate analysis
intestinal obstruction,
jaundice,
inflammatory bowel disease,
malignancy,
pre‐operative TPN and
emergency surgery
associated with an increased prevalence of
bacterial translocation
Opinion rechearer
The enhanced translocation probably
represented little more than underlying gut
dysfunction, with TPN representing nothing more
than a confounding factor.
One study :
to assess factors independently ~ bacterial
ingress across the intestinal barrier, 927
surgical patients
Multivariate analysis
Emergency surgery and pre‐operative TPN
Independently associated with translocation
Measures to Reduce Bacterial Translocation

• Bacterial Translocation may be modulated both quantitatively

(decreasing the prevalence of translocation) and qualitatively
(changing the spectrum of translocating organisms)

• No available ‘level 1’ evidence

that can be used to recommend therapeutic interventions to
decrease or somehow modulate bacterial translocation in humans

• Number of factors may be of significance in modulating gut barrier

function and consequently bacterial translocation in clinical practice
 Factors which may affect bacterial translocation
Specific interventions that might preserve intestinal barrier function or limit bacterial translocation
in the intensive care setting

Pre‐epithelial Epithelial Post‐epithelial Miscellaneous

Enteral nutrients immunonutrient vagus nerve stimulation Genomes

Glutamine and Increased

Selective bowel Nicotine and
other gut specific intra‐abdominal
decontamination cholinergics
nutrients pressures

Splanchnic blood Granulocyte colony Melatonin

Gastric colonization
flow stimulating factor Octreotide

Direct haemoperfusion lactulose

Probiotics and
Exogenous IgA and haemofiltration
prebiotics
(CHF) opiat, etc
A number of assumptions are implicit in
these commonly held views about TPN
1. Bacterial translocation occurs in
impaired intestinal barrier function & is
associated with increased incidences
of sepsis.
2. Septic morbidity is proved to be
significantly higher in patients receiving
TPN
3. The absence of enteral nutrients
(starvation, malnutrition or TPN) is
associated with mucosal atrophy,
increased intestinal permeability,
damage of intestinal barrier, which
predispose to translocation
• There is no strong evidence :
• to suggest that bacterial translocation is
reduced by the use of enteral nutrition.
• to confirm that short‐term TPN is associated
with villus atrophy or significant changes in
intestinal permeability
• Starvation or malnutrition by themselves do not
induce bacterial translocation.
• Alterations in intestinal permeability may
indicate certain changes in intestinal barrier
function but do not necessarily equate with
alterations in the prevalence of bacterial
translocation.
• Exception of trauma patients, there is no firm
evidence that septic morbidity is increased in
patients receiving parenteral as opposed to
enteral nutrition
The nature of the nutritional support that should be provided
to critically ill patients

• A functioning GIT remains an essential prerequisite for maintaining

the integrity of the immune system and gut barrier function

• Should be determined by their tolerance to enteral nutrition

• Should not be withheld on the wrong assumption that TPN will

promote bacterial translocation.

• The precise role of luminal nutrients when compared with gut

failure from whatever cause cannot be distinguished
Selective gut decontamination

• to decrease sepsis from enteric bacteria by means of selective

gut decontamination (SGD).

• Oral non‐absorbable antibiotics and/or short‐term systemic

preparations with microbial surveillance

• Antimicrobial regimes have been used separately or in

combination : vancomycin, neomycin, tobramycin, polymyxin E,.
Selective gut decontamination
Data : conflicting results in relation to
the effects on septic complications and mortality

• The increased free endotoxin load (and subsequent endotoxin

translocation) associated with the death of so many bacteria

• Decontamination regimes are not specific enough to preferentially

eliminate pathogens, upset the balance of indigenous flora,
diminish the effects of bacterial antagonism

• To date, there are no published papers to indicate that SGD may

influence BT
Gastric colonization

• Proximal GIT contains only a modest number of microorganisms,

comprising mainly acid‐tolerant (lactobacilli and streptococci)

• The presence of enteric organisms in gastric aspirates (gastric

colonization) has been shown to be associated with an
increased prevalence of bacterial translocation.

• Positive nasogastric aspirates may have a role as a surrogate

marker of altered intestinal barrier function.
Gastric colonization

Critical illness is often associated with proximal gut

overgrowth with enteric organisms

• These organisms have been linked to nosocomial infection

• the similarity of organisms identified in septic foci and those

cultured from gastric aspirates suggests that the infecting
organisms are of gut origin.
Gastric colonization

It would seem logical to adopt measures that discourage

bacterial overgrowth in the proximal gut

• the use of acid suppressing medications,

• acidified enteral feeding,
• continuous vs. intermittent enteral nutrition,
• broad spectrum antibiotics
• ….
Probiotics

• They selectively stimulate the growth and activity of beneficial

strains of bacteria while also directly benefiting the gut.

• They may help in promoting gut transit which has been shown
to be a determining factor for bacterial translocation (animal
models)

• Some strain significantly decrease the prevalence of potentially

pathogenic organisms in the upper GIT although this had no
effect on gut barrier function as assessed by intestinal
permeability measurements.
Epithelial factors

• Gut‐specific nutrients and Immune enhancing feeds

• Immunonutrients : glutamine and arginine
• Arginine
• Vitamin A

• Splanchnic blood flow, dopexamine, inotropes and

ischaemia‐reperfusion injury
Post‐epithelial and miscellaneous factors

• Increased intra‐abdominal pressures may result in increased

ingress of luminal bacteria,

• measures to control acute abdominal compartment syndrome

may lead to a decrease in translocation, and the eventual
development of multisystem organ failure
Post‐epithelial and miscellaneous factors
Effect on bacterial translocation, mucosa integrity
• Melatonin
• Octreotide and lactulose
• Enteral feeds supplemented with IgA

The effects on bacterial translocation in humans are unknown.

• Immunoglobulin G or lactoferrin
• growth hormone
• insulin‐like growth factor 1 (IGF‐1) recombinant human IGF‐1
• glucagon‐like peptide 2
Post‐epithelial and miscellaneous factors

Intraoperative bowel manipulation has been shown to adversely

affect gut barrier function and increase bacterial translocation in
humans

• It is advisable to implement methods aimed at curtailing

operative times and bowel manipulation

• The need for laparotomy in the critically ill

Post‐epithelial and miscellaneous factors

Opiate for analgesia are known to reduce nausea and vomiting,

enhance transit times, preserve intestinal migratory motor
complexes, and attenuate post‐operative gut dysfunction

• The use of opiates may increase bacterial translocation

• Best current evidence :
it would seem wise to decrease the use of opiates in the
critically ill when suitable alternatives are available
Conclusion

• There would seem to be little doubt that gut function in general, and
intestinal barrier function in particular, are important determinants of
outcome in critically ill patients.

• Methodological problems in confirming bacterial translocation,

which is a direct measure of intestinal barrier function, has restricted
investigations to patients undergoing laparotomy

• There is only limited data available relating to specific interventions

that might preserve intestinal barrier function or limit bacterial
translocation.
Conclusion
• Based on the best currently available knowledge, glutamine
supplementation, aggressive and targeted nutritional intervention, maintaining
good splanchnic flow whilst limiting other inotropic support, the judicious use of
antibiotics and directed SGD regimes hold some promise of limiting
bacterial translocation.

• Future potential in decreasing bacterial translocation and

preserving intestinal barrier function may lie in targeted
immunomodulation of GALT as well as other gut‐directed therapies
aimed at attenuating gut failure and encouraging the earlier return
of normal gut function
BHegarS