Modulation of Gut Microbiota in Early Sepsis: A Pilot Study
Modulation of Gut Microbiota in Early Sepsis: A Pilot Study
Background Sepsis is a common disease leading to high morbidity and mortality. Gut microbiota
 and/or gut permeability may play a crucial role in the development of organ dysfunction.

 Hypothesis The ingestion of a multispecies probiotic in early sepsis is able to modulate gut
 microbiota and/or gut permeability.
Sepsis is a systemic deleterious host response to infection causing major healthcare
 problems. Sepsis affects millions of people around the world each year, with a lethality of
 25%-50%. The incidence is increasing partly because of a raise in average age and occurrence
 of predisposing diseases in the population, and partly because of shifts in causative
 pathogens. Effectiveness of therapy administered in the initial hours of severe sepsis
 critically influences the clinical outcome of the patient.

 Lacking reliable biomarkers for early stages, the diagnosis of (severe) sepsis relies on a
 combination of surrogate parameters indicating end organ dysfunction.

 Recently, gut wall integrity has been identified as a key feature in protecting the body
 against potentially harmful compounds such as bacteria, toxins and antigens. The gut barrier
 consists of the mucus barrier, antimicrobial peptides, secretory IgA, the epithelial barrier,
 and the gut immune system. Gut permeability is reported to increase in sepsis and to play a
 key role in the development of multi-organ dysfunction. Therefore, gut permeability markers
 might have the potential to predict the risk of progression from sepsis to severe sepsis. The
 mechanisms leading to increased gut permeability are not completely clear, yet. Direct and
 indirect interactions of pathogens, hormonal imbalances, beta-adrenergic activity,
 hyperglycemia and cytokine activation as well as individual predisposition have been
 proposed. It seems that increased gut permeability is the common final pathway of a multitude
 of influencing factors.

 Furthermore, the importance of gut microbiota composition has recently been recognized in
 several diseases; however, not much is known about the role of the microbiome in sepsis to
 date. Available data suggest, that disturbances in microbiome homeostasis are present in
 sepsis, but it is yet unknown if these changes are cause or consequence of sepsis. Changes in
 gut barrier and/or gut microbiota can lead to an increase in microbial products in
 circulation, contributing to (inadequate) activation and later "paralysis" of immune cells.
 It is not yet known if the gut microbiome of a patient in early stages of sepsis differs from
 the healthy microbiome or from the microbiome of a patient in late stages of sepsis. Also,
 the possibility to modulate the gut microbiome in early sepsis has not been studied yet.

 A typical strategy to modulate the gut microbiome is the use of probiotic bacteria. In
 sepsis, the use of probiotics is well established for specific indications, such as
 necrotising enterocolitis in neonates, however, studies in adults are scarce. Therefore the
 aim of this study is to investigate if the ingestion of a multispecies probiotic in early
 sepsis is able to modulate gut microbiota and/or gut permeability and observe the clinical
 outcome of treated patients.
Inclusion Criteria:

 -  Participant is willing and able to give informed consent for participation in the
 study.

 -  Age above 18 years

 -  Sepsis as defined by the presence of a systemic inflammatory response syndrome (2 out
 of the four: elevated heart rate (tachycardia) >90 beats per minute at rest; body
 temperature either high (>100.4 F or 38 C) or low (<96.8 F or 36 C); increased
 respiratory rate of >20 breaths per minute or a reduced partial pressure of carbon
 dioxide (PaCO2) in arterial blood level; abnormal white blood cell count (>12,000
 cells/µL or <4,000 cells/µL or >10% bands [an immature type of white blood cell]) and
 a known or suspected infection

 -  Blood cultures ordered by the attending physician

 Exclusion Criteria:

 -  Severe sepsis or septic shock as defined by the Surviving Sepsis Guidelines [1]

 -  Admission to any intensive care unit or intermediate care unit for any reason

 -  soluble urokinase plasminogen activator receptor (sUPAR) level at admission >9.15
 ng/mL [19]

 -  Positive beta-D-glycan test

 -  Patients receiving (par)enteral nutrition

 -  Presence or suspicion of acute pancreatitis

 -  Inability to understand and sign an informed consent

 -  Pregnancy or women of childbearing age without adequate contraception

 -  Women who are breast-feeding

 -  Known malignancy or any other condition or circumstance, which, in the opinion of the
 investigator, would affect the patient's ability to participate in the protocol