The Gut Microbiome - Source of Sepsis and Novel Target in Intensive Care Units?

Here, the investigators propose to study host responses to reduced microbiome complexity driven by treatment with broad spectrum antibiotics in patients with severe infections or sepsis. The proposal aims to combine holistic approaches with emerging experimental technologies to investigate the complex interactions between the gut microbiota and its host and assess the impact of specific bacterial communities on longevity and stress responses. A strong focus of this study will also be placed on microbiome dysbiosis and secondary impacts on short- and long-term brain dysfunction using clinical, laboratory and imaging procedures.

Prospective observational study to obtain faeces, rectal swabs, and plasma samples from critically ill patients with and without broad spectrum antimicrobial therapy as well as from long-term survivors after sepsis. Furthermore, clinical, neuropsychological and neuroimaging data will be collected to assess short- and long-term brain dysfunction.

Furthermore it will be to correlate metagenomic and metabolomic data analysis from stool and blood samples of ICU patients with clinical outcomes (including the trajectory of neuro-cognitive deficits) and stress-related parameters.

Additionally, the study aims to identify if microbiome dysbiosis is connected to short- and long-term brain dysfunction and to assess which microbiome metabolic products influence brain dysfunction.

Moreover, the investigators aim to explore immune cell diversity through single cell whole transcriptome analysis in order to establish new hypotheses on specific bacteria species and metabolites to affect the immune cell type composition of patients (single cell immuno-profiling) and integrate single cell RNA sequencing with clinical symptoms in critically ill patients.

Finally, the question is addressed whether there are differences between blood cell composition and activation between younger and older patients with and without sepsis.

In this regard, blood- and stool samples will be taken from participants at five time points as follows: three time points during ICU treatment respectively (at study inclusion day 1, day 7 and day 14) and as well as two follow-up surveys (3 and 6 months after inclusion). Brain dysfunction will be assed by daily delirium screening tests (CAM-ICU and ICDSC) and at the time of discharge from hospital by MoCa and Mini Mental Status Examination. At the follow-up survey functional MRI as well as neuropsychological measures will be performed.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 18 years
* One of the following criteria

  1. Critically ill patients treated with meropenem or piperacillin/tazobactam started within the last 72 h
  2. Critically ill patients without systemic antimicrobial therapy within the last 72 hours and an expected ICU length of stay of more than 3 days
  3. Long-term survivors of sepsis, e.g. from pre-existing sepsis cohorts

Exclusion Criteria:

* Inflammatory bowel disease
* Major bowel resection
* Selective decontamination of the oral and digestive tract
* Oral vancomycin therapy
* Immunocompromised patients
* History of chemotherapy during the last 6 months.
* Known travel history to countries to areas of high antimicrobial resistance (\>5% according to the report of the European Centre for Disease Prevention and Control and all countries except USA and Canada) within the last 4 weeks
* Acute neurological diseases (e.g., brain ischemia, hemorrhage, meningoencephalitis, tumor)
* Manifest dementia, pre-existing psychiatric diseases (schizophrenia, psychosis)
* Acute brain surgery
* MRI contraindications: pacemakers, hearing aids, neurostimulation, insulin pumps, other potentially ferromagnetic implants, screws, clips, prostheses, metal splinters, etc., pregnancy, claustrophobia, extensive tattoos.