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Abstract

Microbiota—defined as a collection of microbial organisms colonising different parts of the human body—is now recognised as a pivotal element of human health, and explains a large part of the variance in the phenotypic expression of many diseases. A reduction in microbiota diversity, and replacement of normal microbes with non-commensal, pathogenic or more virulent microbes in the gastrointestinal tract—also known as gut dysbiosis—is now considered to play a causal role in the pathogenesis of many acute and chronic diseases. Results from animal and human studies suggest that dysbiosis is linked to cardiovascular and metabolic disease through changes to microbiota-derived metabolites, including trimethylamine-N-oxide and short-chain fatty acids. Dysbiosis can occur within hours of surgery or the onset of critical illness, even without the administration of antibiotics. These pathological changes in microbiota may contribute to important clinical outcomes, including surgical infection, bowel anastomotic leaks, acute kidney injury, respiratory failure and brain injury. As a strategy to reduce dysbiosis, the use of probiotics (live bacterial cultures that confer health benefits) or synbiotics (probiotic in combination with food that encourages the growth of gut commensal bacteria) in surgical and critically ill patients has been increasingly reported to confer important clinical benefits, including a reduction in ventilator-associated pneumonia, bacteraemia and length of hospital stay, in small randomised controlled trials. However, the best strategy to modulate dysbiosis or counteract its potential harms remains uncertain and requires investigation by a well-designed, adequately powered, randomised controlled trial.

Keywords

Dysbiosis infection microbiome probiotics synbiotics

Introduction

The intricate relationship between a eukaryote and bacterium—likely Rickettsia prowazekii—started approximately 0.6–1.5 billion years ago when this aerobic bacterium was integrated into a eukaryote to become a mitochondrion, drastically shaping all advanced life forms, including humans, on our planet ever since.^1,2 A dynamic and complex relationship between diverse communities of microbes and host organisms, including humans, continues today.³

A microbiota is defined as a collection of microbial organisms colonising a habitat. The collective genome of these organisms is the microbiome. Due to availability of 16S rRNA sequencing, the microbiota is now recognised as a pivotal element of human health, and explains a large part of the variance in the phenotypic expression of many diseases.^3–5 A reduction in microbiota diversity, and replacement of normal microbes with non-commensal, pathogenic or more virulent microbes both in and on different parts of the human body—in particular the gastrointestinal tract (also known as gut dysbiosis)—is now considered to play an important part in the pathogenesis of many acute and chronic illnesses, including obesity, diabetes mellitus, inflammatory bowel disease, non-alcoholic fatty liver disease, autoimmune diseases, cancers and even mental health conditions.^5–24

The key words ‘probiotics’, ‘surgery’, ‘trauma’, ‘critical illness’, ‘burns’, and ‘microbiota’ were used to search for relevant studies published in the PubMed database between January 2014 and July 2019 to provide the most up-to-date information on the importance of gut microbiota in surgical and critically ill patients.

Factors affecting the gut microbiota

Food, antibiotics, other common medications and the effects of surgery and critical illness may all affect the gut microbiota. The human gastrointestinal tract is quickly colonised with 500–1000 species of microbes after birth from interactions with the environment.²⁵ A healthy individual’s gastrointestinal tract is predominantly colonised by Firmicutes (including Lactobacillus) and Bacteroides (>98% in total), with a smaller proportion constituted by Proteobacteria, Actinobacteria, Verrucobacteria and Fusobacteria.²⁶ Many factors can affect the diversity and relative proportion of different bacterial species in the gut. Food is the energy source for the gut microbes. Changes in the type of food ingested, including the quantity of micronutrients such as polyphenols, can modulate the gut ecosystem within one or two days (Table 1).^25,27–33

Table 1.

Factors affecting gut microbiota and its possible effects on the body.

Factors	Effects on microbiota	Possible effects on the body
Food
(a) Plant-based diet including non-digestible carbohydrates (resistant starch, dietary fibre, oligosaccharides) and polyphenols^25,28,30	Increases microbial diversity with a lower level of Clostridium perfringens, Enterococcus species, and E. coli and also increases abundance of Bifidobacterium, Lactobacillus and Akkermansia muciniphila	Generates SCFAs and stimulates mucous production which would maintain epithelial barrier functions, suppress colonic inflammation, reduce hepatic glucose production and modulate lipid metabolism and immune response
(b) Animal-based diet, particularly deep fried^25,33	Increases abundance of proteolytic bacteria such as Propionibacterium spp., Streptococcus, Prevotella, Clostridium, Bacillus and Staphylococcus	Variable, with possible decarboxylation of amino acids and peptides, resulting in generation of amines, the precursors for the formation of the carcinogenic nitrosamine, and TMAO
(c) High saturated fat plant diet (vs. high polyunsaturated fat plant diet)³²	Reduces microbial diversity and abundance of Bifidobacteria, and increases ratio of Firmicutes to Bacteroidetes	Weight gain and metabolic syndrome
(d) Fermented food²⁵	Increases abundance of Lactobacillus and Bifidobacterium	Generates SCFAs and reduces bacterial phenol production; some fermented vegetable items also contain a certain amount of SCFAs
(e) Food additives^27,29	Saccharin and emulsifiers: carboxymethylcellulose and polysorbate-80 increase the abundance of Bacteroides, Ruminococcus and Proteobacteria and reduce levels of Lactobacillus and Akkermansia muciniphilaPreservatives: sodium bisulphite and sodium sulphite are bactericidal or bacteriostatic to beneficial gut commensals, including Lactobacillus casei, plantarum and rhamnosus and Streptococcus thermophilus	Induces low-grade inflammation and metabolic syndrome
Non-antibiotic drugs^24,39–47	Atypical antipsychotics (e.g. risperidone and olanzapine): increase abundance of Erysipelotrichaceae and reduce level of Akkermansia muciniphilaProton pump inhibitors: reduce microbial diversity with increased abundance of StreptococcusMorphine and opioids: reduce gut barrier integrity and microbial diversity and increase abundance of potential pathogenic bacteria such as Flavobacterium, Enterococcus, Fusobacterium, Sutterella, Clostridium, Staphylococcaceae, Bacillaceae, Streptococcaceae and ErysipelotrichaceaeNon-steroidal anti-inflammatory drugs: increase Prevotella spp., Bacteroides spp., Family Ruminococaceae, Barnesiella spp.Chemotherapeutic agents (e.g. busulfan – a cell-cycle non-specific alkylating antineoplastic agent for haematopoietic stem cell transplantation): reduce microbial diversity, increase abundance of Enterococci and decrease abundance of members of the order Clostridiales, including Faecalibacterium spp. and Ruminococcus spp.	Weight gain and metabolic syndrome (with atypical antipsychotics); increases the susceptibility and rate of pathogenesis of mucosal infections, leading to sepsis and septic shock from Gram-positive bacteria (with chronic opioid use); increases TMA and TMAO, thus raising cardiovascular risk (with ibuprofen or celecoxib use); induces graft-versus-host disease (with busulfan)
Physical exercise^49,50,52	Increases microbial diversity and abundance of Veillonella atypica, Akkermansia muciniphila and Bacteroides	Increases muscle strength and exercise capacity

TMA: trimethylamine; TMAO: trimethylamine-N-oxide; SCFAs: short-chain fatty acids.

Antibiotics have rapid and potentially long-lasting effects on the microbiota. Even a couple of doses of perioperative antibiotics can affect the microbiota of the gut, respiratory tract and breastmilk,^34–36 and the latter could affect an infant’s gut microbiota for up to three months.³⁷ The effect of using antimicrobials to decontaminate the digestive tract selectively in the critically ill is also a concern because recolonisation of the gut by antibiotic-resistant bacteria may occur upon intensive care unit (ICU) discharge after cessation of selective decontamination.³⁸

A number of non-antibiotic drugs often used in critically ill patients, such as atypical antipsychotics and proton pump inhibitors, can have substantial direct antimicrobial activity³⁹ which would affect microbial diversity in the gut.^40–42 In addition to direct antimicrobial activity, non-antibiotic drugs such as opioids and non-steroidal anti-inflammatory drugs can also affect gut microbiota indirectly by their cytotoxic effect and by altering gut motility and biliary acid metabolism.^43–47 Although it is not easy to apply to urgent surgical and critically ill patients, physical activity, as part of prehabilitation,⁴⁸ may have beneficial effects on gut microbiota diversity, which can, reciprocally, improve patients’ muscle strength.^49–52

Finally, just the stress of surgery, injury, haemorrhage and critical illness itself, even without the use of antibiotics or therapeutic interventions, may also reduce the gut microbiota diversity within hours.^22,53,54 Conversely, use of probiotics (i.e. live bacterial cultures that confer health benefits), prebiotics (i.e. food that encourages the growth of gut commensal bacteria) or a combination of prebiotics and probiotics (which is also called synbiotics) may improve microbiota diversity.⁵⁵

Links between gut dysbiosis and organ dysfunction

The relationship between the normal commensals inhabiting the human gut and their healthy human host is known as mutualism. The host provides a conducive environment, and the microbiota provides nutrients and energy to the host from the ingested food that the host enzymes are unable to break down, as well as producing metabolic bioactive signalling molecules that can affect multiple organ systems, including the neural,^56–58 hepatic,⁵⁹ renal,^60,61 cardiovascular,^62,63 respiratory,⁶⁴ immune⁶⁵ and coagulation systems (Figure 1).^66–68 A number of biologically active gut microbiota–derived metabolites, including trimethylamine-N-oxide (TMAO), uraemic toxins, short-chain fatty acids (SCFAs), phytoestrogens, anthocyanins, bile acids and lipopolysaccharide, have been shown to have substantial effects on different organ systems.⁶⁹ In this review, we will focus on two of the most important and well-established microbiota-derived metabolites: TMAO and SCFAs.

Figure 1.

Links between dysbiosis and organ dysfunction. TMA: trimethylamine; TMAO: trimethylamine-N-oxide; SCFAs: short-chain fatty acids; vWF: von Willebrand factor; TLR-2: Toll-like receptor-2; FMO3: flavin-containing mono-oxygenase-3.

TMAO

Choline is water-soluble nutrient from food sources such as eggs, red meat, liver, soybeans and pork. It is a precursor for phospholipids (including phosphatidylcholine) which are essential components of membranes and of the neurotransmitter acetylcholine. Many species of gut bacteria, though not the major normal commensal Bacteroides, can metabolise choline into trimethylamine (TMA), which is then rapidly absorbed into the splanchnic circulation before further transformation to TMAO by the flavin-containing mono-oxygenase-3 (FMO3) enzyme in the liver. A reduction in Bacteroides and an increase in TMA-forming microbes, such as Firmicutes, in the gut microbiota will increase the production of TMA and hence also plasma TMAO. Choline itself, however, does not impact on the abundance of TMA-producing bacteria. Of the five functional FMO enzymes in the liver, FMO3 is the only one which effectively catalyses the conversion of TMA to TMAO.^70–72 In addition to choline, l-carnitine in red meat can also be converted into TMAO by gut microbiota–dependent transformations.^72,73

TMAO is normally excreted by the kidneys, but it can induce adverse systemic effects, including platelet hyper-reactivity, endothelial cell and macrophage foam cell activation, modulation of cholesterol and sterol and/or bile acid metabolism, and vascular inflammation.^{62,70,74–76} Compared to a control group, mice receiving a diet containing choline (1.2%) or TMAO (0.12%) for 12 weeks developed more pulmonary oedema, cardiac enlargement and myocardial fibrosis, and reduced left ventricular ejection fraction.⁷⁷ Similarly, patients with heart failure have elevated TMAO concentrations that correlate with plasma B-type natriuretic peptide (BNP) levels, and are predictive of five-year mortality in a dose–response fashion.⁷⁸ A large epidemiological study of 4007 patients undergoing elective coronary angiography also found a concentration-dependent relationship between elevated plasma TMAO and major adverse cardiac events of death, myocardial infarction and stroke over a three-year period, independent of traditional cardiovascular risk factors.⁷⁹ Furthermore, elevated TMAO levels were also shown to be associated with the concentrations of pro-inflammatory intermediate monocytes (CD14⁺⁺CD16⁺; correlation = 0.7)⁸⁰ and atherosclerotic burden on coronary angiography in patients with coronary artery disease.⁸¹ Similarly, microbiota-related metabolites of the TMAO pathway were reported to be associated with two important complications after heart transplantation: rejection and total atheroma volume which is a precursor of cardiac allograft vasculopathy.⁸² Interestingly, statin use is associated with a reduced level of TMAO in patients with coronary artery disease, suggesting that statins may work beyond reducing the plasma cholesterol levels by interacting with the microbiota–heart axis.^83,84

Beside inducing TMAO, dysbiosis can also generate Toll-like receptor-2 signalling which will increase von Willebrand factor synthesis by the hepatic endothelial cell, resulting in acceleration of platelet deposition and thrombus growth after vascular endothelial injury.⁶⁶ In addition to cardiovascular adverse effects, TMAO is also believed to play a role in the relationship between dysbiosis and conditions including progressive renal fibrosis,⁸⁵ insulin resistance⁸⁶ and non-alcoholic fatty liver disease.⁸⁷

SCFAs

SCFAs are now considered as one of the most important beneficial microbiota-related metabolites. SCFAs, including acetate, propionate and butyrate, are derived from the bacterial fermentation of dietary fibres, and can act as either substrates for metabolism or signalling molecules. SCFAs are rapidly absorbed (>90%) by the colonic cells into the portal circulation and then mostly used by the hepatocytes to synthesise glucose, cholesterol and fatty acids, with only small amounts of SCFAs reaching the systemic circulation. SCFAs have multiple important physiological roles in the gastrointestinal tract, including maintenance of mucosal barrier integrity by regulating the expression of tight junction proteins to reduce bacterial translocation, improving mucous production and mobility, and anti-inflammatory and immunomodulatory properties.⁵⁸ SCFAs are multi-target messengers and can stimulate three G-protein coupled receptors on many types of cells beyond those in the gastrointestinal tract, including tissue-resident (or localised) immune cells in the peripheral blood, bone marrow, lung, small intestine, adipose tissue and brain.^88–91

The actions of SCFAs on the heart have received much attention recently. In a murine model of chronic left anterior descending artery ligation, gut microbiota suppression by an oral antibiotic mixture (vancomycin, neomycin, metronidazole and ampicillin) markedly increased the rates of post myocardial infarction ventricular rupture and death in a dose-dependent fashion. Crucially, this mortality outcome could be substantially attenuated by faecal transplantation (from untreated mouse donors) before myocardial infarction, suggesting that gut microbiota are involved in the early phase of myocardial remodelling after myocardial infarction.⁹² This interesting study showed that there was a dramatic reduction in monocytic cell infiltration into the tissue affected by myocardial infarction in animals with microbiota suppressed by antibiotics compared to animals untreated with antibiotics prior to the infarction. Administering enteral SCFAs or intravenous infusion of the monocytic cell line in addition to antibiotics one day after infarction not only restored the normal monocytic infiltration into the tissue of the study animals but also improved survival of these animals with less myocardial rupture. Furthermore, administration of SCFA-producing probiotics (Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus casei, Lactobacillus paracasei and Lactobacillus rhamnosus) was associated with both improved ejection fraction and levels of monocytic infiltration in the infarcted myocardium, partially overcoming the adverse effects of microbiota suppression. This study strongly suggests that SCFAs are the key mediators through which the gut microbiota can modulate myocardial tissue repair (or left ventricular remodelling) by the tissue-resident immune cells after injury. Statins are widely used in patients with coronary artery disease, and in an animal setting, statins do not appear to affect the production of SCFAs, and the gut bacteria are not sensitive to physiological concentrations of statins.⁹³

In addition to the cardiovascular system, a lack of SCFAs due to dysbiosis is also believed to induce a wide range of adverse effects on other organ systems through a number of different receptors in the brain, sympathetic ganglia, vagal nerves, peripheral nerves, gut endocrine cells and renal juxtaglomerular apparatus, inducing neuroinflammation, disrupting the blood–brain barrier and causing a reduction in serotonin and neurotrophic factor biosynthesis. These pathological changes may, in part, contribute to the development of chronic renal, mental health and neurodegenerative diseases.^58,94–97 The fact that supplementing SCFAs can attenuate the development of some of these diseases in different experimental settings substantially strengthens the causal role of SCFA deficiency in these diseases.^92,97–101

Clinical trials of probiotics and synbiotics in surgical and critically ill patients

Although the evidence to support the causal link between dysbiosis and many chronic diseases is increasing, the relationship between dysbiosis and acute illnesses in surgical or critically ill patients is much more contentious. A number of clinical studies have shown that changes in gut microbial diversity, with a lower relative abundance of Firmicutes and Bacteroidetes and an increased relative abundance of Proteobacteria resulting in a reduction in SCFAs level, can occur within hours of an acute insult to the body.^{16,22,102,103} The effects of dysbiosis on a perioperative or critically ill patient are confounded further by medical interventions that can affect the microbiota directly, including blood transfusion,¹⁰⁴ parenteral nutrition^105,106 and the use of antibiotic and non-antibiotic drugs, including antipsychotics, proton pump inhibitors, non-steroidal anti-inflammatory drugs, hypoglycaemic agents and chemotherapy.^{34–37,43,47,107–109}

Clinical trials on surgical and critically ill patients

Ultimately, any causal link between dysbiosis and adverse outcomes after surgery or in critical illness would require confirmation by clinical trials showing a reduction in adverse outcomes after interventions to modulate dysbiosis. In patients undergoing gastrointestinal surgery, anastomotic leaks after bowel resection are a major concern because of the associated morbidity and mortality. Observational studies on patients with leaks showed that a lack of microbial diversity and abundance of mucin-degrading Lachnospiraceae are common in their microbiota,^110,111 offering a plausible mechanistic reason for the causal link between dysbiosis and leaks after bowel resection.¹¹² There are animal and human controlled trials showing that applying topical antimicrobial agents to reduce non-commensal gut microbes in the areas of bowel anastomosis would improve healing and reduce leaks after bowel resection.¹¹³ A number of small randomised controlled clinical trials, mostly published prior to 2014, also suggested that the use of pro/pre/synbiotics was associated with a reduced incidence of infection after a variety of different surgical procedures and a reduced incidence of anastomotic leaks after bowel resection.^114,115 Unfortunately, a strong conclusion cannot be drawn from these older studies because the infection endpoint was not clearly defined.¹¹⁴

More randomised controlled trials evaluating the benefits of probiotics/synbiotics involving surgical and critically ill patients in a variety of clinical settings have been reported in the past five years (Table 2).^116–140 Study probiotics were administered enterally in most controlled trials, but in two trials, topical probiotics were administered to either the oral cavity or burn wound to assess their effects against bacterial colonisation compared to standard antiseptic solutions. The use of topical Lactobacillus plantarum instead of antiseptic for burn-wound dressing resulted in similar rates of wound healing and bacterial infection, and more importantly, Lactobacillus plantarum was not recovered from either peripheral blood or wound samples.¹³² Of the 21 studies comparing enteral probiotics/synbiotics with placebo, 14 (67%), including five that were double-blinded,^{118,128–131,134,138} reported some form of clinical benefit after using probiotics/synbiotics compared to placebo: a reduction in ventilator-associated pneumonia, bacteraemia, length of mechanical ventilation and hospital stay. These studies were all relatively small (N ≤ 362), and none was powered to detect a mortality difference.¹⁴¹ In terms of safety, none of these studies reported any episodes of bacteraemia or liver abscess related to the live bacteria contained in the probiotic/synbiotic treatment, although this potential complication has been reported in the literature, particularly in patients who are immunocompromised.^142–145

Table 2.

Randomised controlled clinical trials assessing the effects of probiotics or synbiotics on outcomes of surgical and critically ill patients.

Study	Patient cohort	Intervention	Comparison	Outcomes
Klarin et al.¹¹⁶ 2018	Mechanically ventilated >24 hours (N = 137)	Oral probiotic bacterium Lactobacillus plantarum: 10¹⁰ colony-forming units twice a day	Oral topical chlorhexidine (1 mg/ml) twice a day mouth cleaning	A reduction in only oropharyngeal fungal colonisation (RR 0.53, 95% CI 0.30–0.95). No difference in staphylococcal or enteric organism colonisation in both oropharynx and trachea. VAP: probiotic 7/69 vs. control 10/68 (P = 0.45)
Shimizu et al.¹¹⁷ 2018	Septic mechanically ventilated (N = 72)	Nasogastric synbiotics: 3 g/day (Bifidobacterium breve strain 1 × 10⁸/g Yakult Lactobacillus casei strain 1 × 10⁸/g Shirota)+10 g/day galactooligosaccharides	Routine care	A reduction in VAP (synbiotics: 5/35 vs. control: 18/37, P<0.05). No statistically significant difference in the number of ventilator-free days, incidence of bacteraemia (14.3% vs. 13.5%) or mortality (8.6% vs. 10.8%) between the two groups before day 28
Mahmoodpoor et al.¹¹⁸ 2019	Mechanically ventilated >48 hours (N = 100)	2 capsules/day, each contained 10¹⁰ Lactobacillus species (casei, acidophilus, rhamnosus, bulgaricus), Bifidobacterium species (breve, longum) and Streptococcus thermophilus	Identical-looking placebo	A reduction in VAP (probiotic: 0.66 vs. 0.94 per 1000 hours of mechanical ventilation; P = 0.04), ICU (probiotic: 12 vs. control: 19 days, P = 0.007) and hospital stay (probiotic: 14 vs. control: 21, P = 0.002) but not ICU mortality (probiotic: 5/48 vs. control: 6/54, P = 0.58)
Majid et al.¹¹⁹ 2014	Exclusively treated with enteral nutrition (N = 22)	Prebiotic: 7 g/day oligofructose/inulin	Identical-looking placebo	A reduction in concentrations of F. prausnitzii (P = 0.01) and Bacteroides-Prevotella (P = 0.05) in the faeces of the oligofructose/inulin group but no significant difference between the two groups in diarrhoea
Lunia et al.¹²⁰ 2014	Cirrhosis without overt hepatic encephalopathy (N = 160)	1 capsule 3 times a day probiotics: Bifidobacterium species (breve, longum, infantis), Lactobacillus species (acidophilus, plantarum, paracasei, bulgaricus) and Streptococcus thermophiles: 110 billion colony-forming units	Routine care	A reduction in hepatic encephalopathy (probiotics: 13/86 vs. control: 19/74, P = 0.04; hazard ratio 2.1, 95% CI 1.31–6.53)
Suzuki et al.¹²¹ 2017	Treated with low dose aspirin 1 month or longer (N = 61)	112 ml of yogurt containing 10⁹ colony-forming units of Lactobacillus gasseri (LG group) twice daily for 6 weeks	Placebo twice daily for 6 weeks	Capsule endoscopy showed fewer mucosal lesions including breaks and reddened lesions in the LG group compared to the baseline prior to initiation of probiotics (P<0.002), but this improvement was not observed in the placebo group
Mayes et al.¹²² 2015	Acutely burned paediatric patients (<22 years old: mean age = 7, mean full-thickness burn areas 25%–32%; N = 20)	15 billion colony-forming units of the probiotic organism, Lactobacillus rhamnosus twice per day until 95% wound closure was achieved	Identical-looking placebo twice per day until 95% wound closure was achieved	No difference in total infection days (P = 0.54), antibiotic days (P = 0.94) and antifungal days (P = 0.29) between the two groups
Shao et al.¹²³ 2014	Upper gastrointestinal perforation (N = 96)	Bifidobacterium, Lactobacillus and Streptococcus thermophilus, 0.35 g/capsule (containing Bifidobacterium adolescent 0.5 billion): 9 capsules/day+glutamine 0.25 g/capsule): 6 capsules/day+fish oil 1200 mg/capsule)×1/day	Routine care	The incidence of postoperative infection complications in the treatment group (18.8%; 9/48) was significantly lower than that in the control group (39.6%; 19/48; P = 0.025)
Tan et al.¹²⁴ 2013	Traumatic brain injury (N = 52)	1 × 10⁹ bacteria of viable probiotics (Golden Bifid, 3.5 g×3/day) per day for 21 days	Routine care	Probiotic group had lower fasting plasma glucose levels, fewer days requiring insulin and reduced length of stay in ICU (6.8 vs. 10.7 days, P = 0.034) compared to the control group
Shao et al.¹²⁵ 2014	Symptoms of post-radiation enteritis after radiotherapy within 3 weeks and the overall radiation did not exceed 6000 rad (N = 46)	Bifidobacterium, Lactobacillus and Streptococcus thermophilus, 0.35 g/capsule (containing Bifidobacterium adolescent 0.5 billion): 9 capsules/day+glutamine 0.25 g/capsule): 6 capsules/day+fish oil 1200 mg/capsule)×1/day	Routine care	Abdominal pain (P = 0.018), bloating (P = 0.015) and diarrhoea (P = 0.002) were less common in the probiotic group compared to the control group at 14 days
Wong et al.¹²⁶ 2014	Spinal cord injury with antibiotics initiated within 24 hours (N = 158)	Lactobacillus casei a minimum of 6.5 × 10⁹ colony-forming units for the duration of the antibiotic course+a further 7 days after cessation of antibiotics	Routine care	Incidence of antibiotic-associated diarrhoea was significantly lower in the probiotic group (17.1%) than in the control group (54.9%, including one patient with Clostridium difficile–associated diarrhoea; P<0.001); routine care remained significantly associated with an increased risk of antibiotic-associated diarrhoea in the multivariable analysis (odds ratio 8.5, 95% CI 3.2–22.2; P<0.001)
Endo et al.¹²⁷ 2011	Taking low-dose enteric-coated aspirin 100 mg/day >3 months +omeprazole 20 mg/day with unexplained iron deficiency anaemia (N = 25)	Lactobacillus casei (45 × 10⁸ to 63 × 10⁹ colony-forming units in powder form) daily for 3 months	Routine care	Capsule endoscopy findings showed that the number of mucosal breaks (P = 0.039) and reddened lesions (P = 0.005) from baseline in the probiotic group were both significantly less than in the control group, but the increase in the haemoglobin concentration from the baseline to after treatment was not different between the two groups (P = 0.183)
Kotzampassi et al.^128–130 2006, 2009 and 2010	Multiple injuries (>18 years of age) requiring mechanical ventilation, with a long ICU stay and a life expectancy >15 days (N = 65)	10¹¹ colony-forming units of the following Pediococcus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei spp. and Lactobacillus plantarum once daily for 15 consecutive days	Identical-looking placebo	Probiotics reduced (a) infections compared to the placebo (overall rate: 63% vs. 90%, P = 0.01; bacteraemia: 5.6% vs. 25%, P = 0.038; pneumonia: 54% vs. 80%, P = 0.03; central venous catheter infection: 37% vs. 66%, P = 0.02; urinary tract infection: 17% vs. 43%, P = 0.02), (b) mechanical ventilation days (16.7 vs. 29.7 days, P = 0.001) and (c) ICU stay (27.2 vs. 41.3 days, P = 0.01). Probiotic group had less abundance of Enterobacteriaceae on day 4 but larger abundance of Enterococcus spp. and Lactococcus spp. on days 7 and 15 compared to placebo group in the faecal microflora analyses
Kotzampassi et al.¹³¹ 2015	Elective, open, colonic resection with primary anastomosis (N = 164)	Lactobacillus acidophilus 1.75 × 10⁹ colony-forming units, Lactobacillus plantarum 0.5 × 10⁹ colony-forming units, Bifidobacterium lactis 1.75 × 10⁹ colony-forming units and Saccharomyces boulardii 1.5 × 10⁹ colony-forming units, started one day before operation and continued until 15 days after surgery	Identical-looking placebo	Probiotics significantly decreased the rate of all postoperative major complications (28.6% vs. 48.8%, P = 0.010, including pneumonia: 2.4% vs. 11.3%, P = 0.029; surgical site infection: 7.1% vs. 20.0%, P = 0.02; anastomotic leaks: 1.2% vs. 8.8%, P = 0.031), requiring mechanical ventilation (20.2% vs. 35.0%, P = 0.037), time to first defaecation (P<0.001) and length of hospital stay (8 vs. 10 days, P<0.001)
Peral et al.¹³² 2009	Delayed second-degree burns and early and delayed third-degree burns (N = 80)	10⁵ colony-forming units of Lactobacillus plantarum in 1 ml culture solution was applied on a gauze pad per cm² of the burn wound and then covered by routine bandage each day for 10 days	Daily antiseptic bath with chlorhexidine 0.05%, and then the burn wounds received a 3 mm layer of silver sulphadiazine cream each day for 10 days	Wound healing was not different between using topical probiotic and topical antiseptic dressings (73.7% vs. 71.4% respectively, P = 0.821) for all study patients; and for a delayed second- or third-degree burn, the incidence of having bacterial load >10⁵/g tissue was also not different between using probiotic and topical antiseptic dressing (23.1% vs. 27.6%, P = 0.702)
Zeng et al.¹³³ 2016	Critically ill adults with an expected need of mechanical ventilation for >48 hours (N = 235)	Probiotic capsules (Enterococcus faecium to Bacillus subtilis at 9:1 ratio, 5.0 × 10⁸ colony-forming units per capsule) three times daily within 24 hours of admission to the ICU or within 24 hours of tracheal intubation if the intubation occurred in ICU	Routine care	Probiotic group had a lower incidence of microbiologically confirmed VAP (36.4% vs. 50.4% respectively, P = 0.031) and a longer time to develop VAP (10.4 vs. 7.5 days, P = 0.022) compared to the control; length of mechanical ventilation, ICU and hospital stay and hospital mortality were not different between the two groups
Malik et al.¹³⁴ 2016	Adult critically ill patients admitted to ICU >48 hours requiring enteral nutrition (N = 49)	30 billion colony-forming units of highly compatible, acid- and bile-resistant strains of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus lactis, Bifidobacterium bifidum, Bifidobacterium longum and Bifidobacterium infantis twice per day for 7 days	Identical-looking placebo	Probiotic group had a shorter time than the control to tolerate enteral nutrition (72 vs. 168 hours, respectively, P = 0.001), requiring mechanical ventilation (8.4 vs. 14 days, respectively, P = 0.004) and in ICU (10.9 vs. 15.8 days, respectively, P = 0.014)
Lopez de Toro Martín-Consuegra et al.¹³⁵ 2014	Medical and surgical ICU patients with multi-organ failure (N = 89)	Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus acidophilus, Bifidobacterium, E. coli, coliformes×7 days (4.8 × 10⁹ colony-forming units/ml)	Routine care	Probiotic group had a lower incidence of hospital-acquired infection (19.6% vs. 30.2%, respectively, P = 0.244) and similar incidence of mortality (41.3% vs. 41.9%, respectively, P = 0.958) to the control
Sanaie et al.¹³⁶ 2014	Critically ill patients with systemic inflammatory response syndrome+Acute Physiology and Chronic Health Evaluation score between 15 and 30+receiving enteral nutrition+expected ICU stay ≥7 days (N = 40)	Twice daily 900 billion of Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus and Lactobacillus delbrueckii subsp. bulgaricus; Bifidobacterium longum, Bifidobacterium breve and Bifidobacterium infantis; and Streptococcus salivarius subsp. thermophilus for 7 days	Identical-looking placebo	Bacteraemia incidence was similar between the probiotic and control group (10% vs. 20%, respectively, P = 0.407)
Rongrungruang et al.¹³⁷ 2015	Expected to receive mechanical ventilation ≥72 hours (N = 150)	Daily 8 × 10⁹ colony-forming units of Lactobacillus casei for 28 days or until the endotracheal tube was removed	Routine care	No difference between the probiotic and control groups in VAP (24% vs. 29.3%, P = 0.46), length of hospital stay (20 vs. 19 days, P = 0.79) and 90-day mortality (33.3% vs. 34.7%, P = 0.86)
Barraud et al.¹³⁸ 2010	Mechanical ventilation ≥2 days (N = 167)	Daily 10 × 10¹⁰ of bacteria (mainly Lactobacillus rhamnosus, but also Lactobacillus casei, Lactobacillus acidophilus and Bifidobacterium bifidum) for the duration of mechanical ventilation or a maximum of 28 days	Identical-looking placebo	Probiotic group had a lower incidence of catheter-related bloodstream infection than the control group (3.4% vs. 13.7%, respectively, P = 0.005), but no difference in 90-day mortality, length of hospital stay and mechanical ventilation–free days between the two groups
Komatsu et al.¹³⁹ 2016	Elective laparoscopic colonic surgery (N = 362)	Daily 4 × 10¹⁰ Lactobacillus casei with 2.5 g galactooligosaccharides, 1 × 10¹⁰ Bifidobacterium breve started 7–11 days before surgery and resumed at 2–7 days (duration of treatment after surgery was not described)	Routine care	No difference between the probiotic group and control in surgical site infection (17.3% vs. 22.7%, respectively, P = 0.20) and anastomotic leaks (7.1% vs. 6.2%, respectively, P = 0.72)
Sadahiro et al.¹⁴⁰ 2014	Elective open colonic resection for cancers (N = 195)	10 billion Bifidobacterium bifidum daily for 5 days before surgery, resumed on day 5 after surgery for 10 days	Routine care	No difference between the probiotic group and control in surgical site infection (18% vs. 17.9%, respectively, P = 0.99) and anastomotic leaks (12.0% vs. 7.4%, respectively, P = 0.56)

RR: risk ratio; CI: confidence intervals; ICU: intensive care unit; VAP: ventilator-associated pneumonia.

Although the evidence to support the benefits of modulating dysbiosis in acute surgical and critically ill patients is strengthening, significant challenges as to how this can be translated into improved patient-centred outcomes remain. First, not all gut commensals are equally important, and some may offer more health benefits than others.^30,39,40 Response to different types of probiotic treatment may vary and be specific to the strain of live bacteria used.^24,146,147 Although not proven, the different types and doses of live bacteria and duration of probiotic therapy used in the studies may, at least in part, explain why the benefits of probiotics/synbiotics were not consistently reported (Table 2). Second, the emerging science is almost exclusively derived from 16S rRNA sequencing. This describes the quantity but not the function of bacteria, and does not look at viruses, fungi or protozoa. Unlike animal studies, important microbiota-related metabolites in the plasma, such as TMAO and SCFAs, were not measured in most, if not all, clinical trials. It is paramount to confirm that any live bacteria used in the probiotics/synbiotics can directly tackle the likely pathogenic pathways of dysbiosis by successfully colonising the colon with healthy microbiota that can generate SCFAs and reduce TMAO in the blood.¹⁴⁸

Finally, there are other interventions that can attenuate the potential harms of dysbiosis, including faecal microbiota transplantation,¹⁴⁹ SCFA supplementation,^91,100,101 use of choline structural analogues to reduce TMA production by gut microbes,^150,151 and reducing conversion of TMA to TMAO by inhibiting FMO3 in the liver.¹⁵² In addition, early enteral nutrition,¹⁵³ a restrictive approach to using antimicrobials,¹⁵⁴ use of lactulose as a prebiotic^155,156 and use of enteral digestive protease inhibitors such as tranexamic acid to reduce generation of TMAO may also be helpful.¹⁵⁷ Whether these alternative interventions are better than probiotics or if they can have additive benefits is not known, but this deserves further investigation by adequately powered randomised controlled trials.

Probiotics in Clostridium difficile–related diarrhoea and Helicobacter pylori infection

Clinical trials evaluating the efficacy of probiotics on specific bowel-related infections have been reported with mixed results.^158–162 Although probiotics appear to be useful as an adjunct to therapeutic oral antibiotics to improve bowel symptoms in both Clostridium difficile–related diarrhoea and Helicobacter pylori infections, probiotics alone are certainly inadequate for eradicating these infections.¹⁵⁹

Conclusions

We begin to fully appreciate the importance of a healthy microbiota ecosystem in determining health and disease. In addition to antibiotics, commonly prescribed non-antibiotic drugs, acute illness and surgery all can have a substantial effect on microbiota diversity and risk of dysbiosis, which can occur within hours in surgical and critically ill patients.

Dysbiosis can affect different organ systems that are not anatomically in close proximity to the gastrointestinal tract through a number of different microbiota-derived metabolites, including TMAO and SCFAs. Results from animal and human studies are supportive of a causal role for dysbiosis in many chronic illnesses, especially cardiovascular and metabolic diseases. Using probiotics/synbiotics in surgical and critically ill patients to reduce or modulate dysbiosis has been increasingly reported to confer a number of important benefits, including a reduction in ventilator-associated pneumonia, bacteraemia and length of hospital stay. These trials are, however, small and have substantial limitations. As such, adequately powered randomised controlled trials assessing the effect of probiotics/synbiotics on mortality of surgical and critically ill patients are crucial before probiotics/synbiotics are used routinely in surgical and critically ill patients. From an ecology perspective, the most challenging—but also the best—approach to maintain our health, as a ‘supra-organism’,¹⁶³ is to achieve mutualism.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

ORCID iD

Kwok M Ho

References

Andersson

Zomorodipour

Andersson

, et al. The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature 1998; 396: 133–140.

Neupert

Mitochondrial gene expression: a playground of evolutionary tinkering. Annu Rev Biochem 2016; 85: 65–76.

Pasolli

Asnicar

Manara

, et al. Extensive unexplored human microbiome diversity revealed by over 150,000 genomes from metagenomes spanning age, geography, and lifestyle. Cell 2019; 176: 649–662.e20.

Gilbert

Lynch

SV.

Community ecology as a framework for human microbiome research. Nat Med 2019; 25: 884–889.

Gilbert

Blaser

Caporaso

, et al. Current understanding of the human microbiome. Nat Med 2018; 24: 392–400.

Luca

Di Mauro

, et al. Gut microbiota in Alzheimer’s disease, depression, and type 2 diabetes mellitus: the role of oxidative stress. Oxid Med Cell Longev 2019; 2019: 4730539.

Melhem

Kaya

Ayata

, et al. Metabolite-sensing G protein-coupled receptors connect the diet–microbiota–metabolites axis to inflammatory bowel disease. Cells 2019; 8: 450.

Pierantonelli

Svegliati-Baroni

Nonalcoholic fatty liver disease: basic pathogenetic mechanisms in the progression from NAFLD to NASH. Transplantation 2019; 103: e1–e13.

Gianchecchi

Fierabracci

Recent advances on microbiota involvement in the pathogenesis of autoimmunity. Int J Mol Sci 2019; 20: 283.

10.

Nagano

Otoshi

Hazama

, et al. Novel cancer therapy targeting microbiome. Onco Targets Ther 2019; 12: 3619–3624.

11.

McQuade

Daniel

Helmink

, et al. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol 2019; 20: e77–e91.

12.

Peirce

Alviña

The role of inflammation and the gut microbiome in depression and anxiety. J Neurosci Res 2019; 97: 1223–1241.

13.

Lee

Chico

TJA

Renshaw

SA.

The triune of intestinal microbiome, genetics and inflammatory status and its impact on the healing of lower gastrointestinal anastomoses. FEBS J 2018; 285: 1212–1225.

14.

Alverdy

Hyoju

Weigerinck

, et al. The gut microbiome and the mechanism of surgical infection. Br J Surg 2017; 104: e14–e23.

15.

Ahmad

Bromberg

JS.

Current status of the microbiome in renal transplantation. Curr Opin Nephrol Hypertens 2016; 25: 570–576.

16.

Nicholson

Merrill

Zhu

, et al. Polytrauma independent of therapeutic intervention alters the gastrointestinal microbiome. Am J Surg 2018; 216: 699–705.

17.

Mukherjee

Hanidziar

More of the gut in the lung: how two microbiomes meet in ARDS.

Yale J Biol Med 2018; 91: 143–149.

18.

Lamarche

Johnstone

Zytaruk

, et al. Microbial dysbiosis and mortality during mechanical ventilation: a prospective observational study. Respir Res 2018; 19: 245.

19.

Zhang

Ankawi

Sun

, et al. Gut–kidney crosstalk in septic acute kidney injury. Crit Care 2018; 22: 117.

20.

Fay

Ford

Coopersmith

CM.

The intestinal microenvironment in sepsis. Biochim Biophys Acta Mol Basis Dis 2017; 1863: 2574–2583.

21.

Earley

Akhtar

Green

, et al. Burn injury alters the intestinal microbiome and increases gut permeability and bacterial translocation. PLoS One 2015; 10: e0129996.

22.

Nicholson

Burmeister

Johnson

, et al. A prospective study in severely injured patients reveals an altered gut microbiome is associated with transfusion volume. J Trauma Acute Care Surg 2019; 86: 573–582.

23.

Zhu

Grandhi

Patterson

, et al. A review of traumatic brain injury and the gut microbiome: insights into novel mechanisms of secondary brain injury and promising targets for neuroprotection. Brain Sci 2018; 8: E113.

24.

Wan

Choe Uouncey

, et al. Gut microbiota, chemotherapy and the host: the influence of the gut microbiota on cancer treatment. Ecancermedicalscience 2018; 12: 868.

25.

Pham

Schoene

, et al. Interactions between food and gut microbiota: impact on human health. Annu Rev Food Sci Technol 2019; 10: 389–408.

26.

Eckburg

Bik

Bernstein

, et al. Diversity of the human intestinal microbial flora. Science 2005; 308: 1635–1638.

27.

Ruiz-Ojeda

Plaza-Díaz

Sáez-Lara

, et al. Effects of sweeteners on the gut microbiota: a review of experimental studies and clinical trials. Adv Nutr 2019; 10: S31–S48.

28.

Zmora

Suez

Elinav

You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol 2019; 16: 35–56.

29.

Irwin

Fisher

Graham

, et al. Sulfites inhibit the growth of four species of beneficial gut bacteria at concentrations regarded as safe for food. PLoS One 2017; 12: e0186629.

30.

Anhê

Nachbar

Varin

, et al. Treatment with camu camu (Myrciaria dubia) prevents obesity by altering the gut microbiota and increasing energy expenditure in diet-induced obese mice. Gut 2019; 68: 453–464.

31.

David

Maurice

Carmody

, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505: 559–563.

32.

Mokkala

Houttu

Cansev

, et al. Interactions of dietary fat with the gut microbiota: Evaluation of mechanisms and metabolic consequences. Clin Nutr. Epub ahead of print 13 May 2019. DOI: 10.1016/j.clnu.2019.05.003.

33.

Shu

Rivera

, et al. Urinary levels of trimethylamine-N-oxide and incident coronary heart disease: a prospective investigation among urban Chinese adults. J Am Heart Assoc 2019; 8: e010606.

34.

D’Haens

Zwittink

Belzer

, et al. Short term changes of intestinal microbiota composition in preterm infants after two prophylactic doses of vancomycin. Acta Paediatr 2019; 108: 1919–1920.

35.

Kosikowska

Biernasiuk

Rybojad

, et al. Haemophilus parainfluenzae as a marker of the upper respiratory tract microbiota changes under the influence of preoperative prophylaxis with or without postoperative treatment in patients with lung cancer. BMC Microbiol 2016; 16: 62.

36.

Padilha

Iaucci

Cabral

, et al. Maternal antibiotic prophylaxis affects Bifidobacterium spp. counts in the human milk, during the first week after delivery. Benef Microbes 2019; 10: 155–163.

37.

Zimmermann

Curtis

Effect of intrapartum antibiotics on the intestinal microbiota of infants: a systematic review. Arch Dis Child Fetal Neonatal Ed 2020; 105: 201–208.

38.

Buelow

Bello González

TDJ

Fuentes

, et al. Comparative gut microbiota and resistome profiling of intensive care patients receiving selective digestive tract decontamination and healthy subjects. Microbiome 2017; 5: 88.

39.

Maier

Pruteanu

Kuhn

, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 2018; 555: 623–628.

40.

Bretler

Weisberg

Koren

, et al. The effects of antipsychotic medications on microbiome and weight gain in children and adolescents. BMC Med 2019; 17: 112.

41.

Shi

Cai

Tian

, et al. Effects of proton pump inhibitors on the gastrointestinal microbiota in gastroesophageal reflux disease. Genomics Proteomics Bioinformatics 2019; 17: 52–63.

42.

Ticinesi

Milani

Lauretani

, et al. Gut microbiota composition is associated with polypharmacy in elderly hospitalized patients. Sci Rep 2017; 7: 1–11.

43.

Brusselaers

Prescribed drugs and the microbiome. Gastroenterol Clin North Am 2019; 48: 331–342.

44.

Bauman

Meng

Zhang

, et al. Enteric glial-mediated enhancement of intestinal barrier integrity is compromised by morphine. J Surg Res 2017; 219: 214–221.

45.

Banerjee

Sindberg

Wang

, et al. Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol 2016; 9: 1418–1428.

46.

Wang

Meng

Zhang

, et al. Opioid use potentiates the virulence of hospital-acquired infection, increases systemic bacterial dissemination and exacerbates gut dysbiosis in a murine model of Citrobacter rodentium infection. Gut Microbes 2019; 1–19.

47.

Rogers

MAM

Aronoff

DM.

The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect 2016; 22: 178.e1–178.e9.

48.

Heger

Probst

Wiskemann

, et al. A systematic review and meta-analysis of physical exercise prehabilitation in major abdominal surgery (PROSPERO 2017 CRD42017080366). J Gastrointest Surg. Epub ahead of print 21 June 2019. DOI: 10.1007/s11605-019-04287-w.

49.

Morita

Yokoyama

Imai

, et al. Aerobic exercise training with brisk walking increases intestinal Bacteroides in healthy elderly women. Nutrients 2019; 11: E868.

50.

Scheiman

Luber

Chavkin

, et al. Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism. Nat Med 2019; 25: 1104–1109.

51.

Nay

Jollet

Goustard

, et al. Gut bacteria are critical for optimal muscle function: a potential link with glucose homeostasis. Am J Physiol Endocrinol Metab 2019; 317: E158–E171.

52.

Barton

Penney

Cronin

, et al. The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. Gut 2018; 67: 625–633.

53.

Nicholson

Merrill

Zhu

, et al. Polytrauma independent of therapeutic intervention alters the gastrointestinal microbiome. Am J Surg 2018; 216: 699–705.

54.

Nicholson

Watts

Burmeister

, et al. Moderate traumatic brain injury alters the gastrointestinal microbiome in a time-dependent manner. Shock 2019; 52: 240–248.

55.

Sanders

Merenstein

Reid

, et al. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat Rev Gastroenterol Hepatol 2019; 16: 605–616.

56.

Wallace

Sayre

Patterson

, et al. Spinal cord injury and the human microbiome: beyond the brain–gut axis. Neurosurg Focus 2019; 46: E11.

57.

Zhang

Guo

, et al. Abnormal composition of gut microbiota contributes to delirium-like behaviors after abdominal surgery in mice. CNS Neurosci Ther 2019; 25: 685–696.

58.

Dalile

Van Oudenhove

Vervliet

, et al. The role of short-chain fatty acids in microbiota–gut–brain communication. Nat Rev Gastroenterol Hepatol 2019; 16: 461–478.

59.

Bajaj

JS.

Alcohol, liver disease and the gut microbiota. Nat Rev Gastroenterol Hepatol 2019; 16: 235–246.

60.

Meijers

Evenepoel

Anders

HJ.

Intestinal microbiome and fitness in kidney disease. Nat Rev Nephrol 2019; 15: 531–545.

61.

Gong

Noel

Pluznick

, et al. Gut microbiota–kidney cross-talk in acute kidney injury. Semin Nephrol 2019; 39: 107–116.

62.

Tang

WHW

Bäckhed

Landmesser

, et al. Intestinal microbiota in cardiovascular health and disease: JACC state-of-the-art review. J Am Coll Cardiol 2019; 73: 2089–2105.

63.

McMillan

Hazen

SL.

Gut microbiota involvement in ventricular remodeling post-myocardial infarction. Circulation 2019; 139: 660–662.

64.

Dang

Marsland

BJ.

Microbes, metabolites, and the gut–lung axis. Mucosal Immunol 2019; 12: 843–650.

65.

Nogueira

Shoenfeld

Microbiome and autoimmune diseases: cause and effect relationship. Curr Opin Rheumatol 2019; 31: 471–474.

66.

Jäckel

Kiouptsi

Lillich

, et al. Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2. Blood 2017; 130: 542–553.

67.

Reinhardt

The gut microbiota as an influencing factor of arterial thrombosis. Hamostaseologie 2019; 39: 173–179.

68.

Kiouptsi

Ruf

Reinhardt

Microbiota-derived trimethylamine. Circ Res 2018; 123: 1112–1114.

69.

Wang

Zhao

Gut microbiota derived metabolites in cardiovascular health and disease. Protein Cell 2018; 9: 416–431.

70.

Romano

Vivas

Amador-Noguez

, et al. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. MBio 2015; 6: e02481.

71.

Velasquez

Ramezani

Manal

, et al. Trimethylamine N-oxide: the good, the bad and the unknown. Toxins (Basel) 2016; 8: E326.

72.

Fennema

Phillips

Shephard

EA.

Trimethylamine and trimethylamine N-oxide, a flavin-containing monooxygenase 3 (FMO3)-mediated host–microbiome metabolic axis implicated in health and disease. Drug Metab Dispos 2016; 44: 1839–1850.

73.

Koeth

Lam-Galvez

Kirsop

, et al. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J Clin Invest 2019; 129: 373–387.

74.

Vogt

Romano

Darst

, et al. The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimers Res Ther 2018; 10: 124.

75.

Zhu

Gregory

Org

, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 2016; 165: 111–124.

76.

Roberts

Buffa

, et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med 2018; 24: 1407–1417.

77.

Organ

Otsuka

Bhushan

, et al. Choline diet and its gut microbe-derived metabolite, trimethylamine N-oxide, exacerbate pressure overload-induced heart failure. Circ Heart Fail 2016; 9: e002314.

78.

Tang

Wang

Fan

, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 2014; 64: 1908–1914.

79.

Tang

Wang

Levison

, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013; 368: 1575–1584.

80.

Haghikia

Liman

, et al. Gut microbiota-dependent trimethylamine N-oxide predicts risk of cardiovascular events in patients with stroke and is related to proinflammatory monocytes. Arterioscler Thromb Vasc Biol 2018; 38: 2225–2235.

81.

Senthong

Hudec

, et al. Plasma trimethylamine N-oxide, a gut microbe-generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J Am Coll Cardiol 2016; 67: 2620–2628.

82.

Trøseid

Mayerhofer

CCK

Broch

, et al. The carnitine–butyrobetaine–TMAO pathway after cardiac transplant: impact on cardiac allograft vasculopathy and acute rejection. J Heart Lung Transplant 2019; 38: 1097–1103.

83.

Milks

Sharkey-Toppen

, et al. Statin use is associated with lower trimethylamine-N-oxide (TMAO) level in adults at risk of atherosclerotic cardiovascular disease, independent of serum cholesterol and renal function. J Clin Lipidol 2018; 12: 567–568.

84.

Wang

, et al. Relationship between statin use and trimethylamine N-oxide in cardiovascular risk assessment. J Am Coll Cardiol 2018; 71: 115.

85.

Tang

Wang

Kennedy

, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 2015; 116: 448–455.

86.

Heianza

Sun

, et al. Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial. Gut 2019; 68: 263–270.

87.

Chen

Liu

Zhou

, et al. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci Rep 2016; 6: 19076.

88.

Bilotta

Cong

Gut microbiota metabolite regulation of host defenses at mucosal surfaces: implication in precision medicine. Precis Clin Med 2019; 2: 110–119.

89.

Farzi

Hassan

Zenz

, et al. Diabesity and mood disorders: multiple links through the microbiota–gut–brain axis. Mol Aspects Med 2019; 66: 80–93.

90.

Erny

Hrabě de Angelis

Prinz

Communicating systems in the body: how microbiota and microglia cooperate. Immunology 2017; 150: 7–15.

91.

Chang

Hao

Offermanns

, et al. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A 2014; 111: 2247–2252.

92.

Tang

TWH

Chen

, et al. Loss of gut microbiota alters immune system composition and cripples postinfarction cardiac repair. Circulation 2019; 139: 647–659.

93.

Nolan

Skuse

Govindarajan

, et al. The influence of rosuvastatin on the gastrointestinal microbiota and host gene expression profiles. Am J Physiol Gastrointest Liver Physiol 2017; 312: G488–G497.

94.

Huang

Zhou

Guo

, et al. The role of short-chain fatty acids in kidney injury induced by gut-derived inflammatory response. Metabolism 2017; 68: 20–30.

95.

Wang

Huang

, et al. Effects of regulating gut microbiota on the serotonin metabolism in the chronic unpredictable mild stress rat model. Neurogastroenterol Motil 2019; 31: e13677.

96.

Welcome

MO.

Gut microbiota disorder, gut epithelial and blood–brain barrier dysfunctions in etiopathogenesis of dementia: molecular mechanisms and signaling pathways. Neuromolecular Med 2019; 21: 205–226.

97.

Ono

Tsuji

, et al. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer’s disease-type beta-amyloid neuropathological mechanisms. Expert Rev Neurother 2018; 18: 83–90.

98.

Van De Wouw

Boehme

Lyte

, et al. Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain–gut axis alterations. J Physiol 2018; 596: 4923–4944.

99.

Pingitore

Gonzalez-Abuin

Ruz-Maldonado

, et al. Short chain fatty acids stimulate insulin secretion and reduce apoptosis in mouse and human islets in vitro: role of free fatty acid receptor 2. Diabetes Obes Metab 2019; 21: 330–339.

100.

Arnoldussen

IAC

Wiesmann

Pelgrim

, et al. Butyrate restores HFD-induced adaptations in brain function and metabolism in mid-adult obese mice. Int J Obes (Lond) 2017; 41: 935–944.

101.

Bartolomaeus

Balogh

Yakoub

, et al. Short-chain fatty acid propionate protects from hypertensive cardiovascular damage. Circulation 2019; 139: 1407–1421.

102.

Hayakawa

Asahara

Henzan

, et al. Dramatic changes of the gut flora immediately after severe and sudden insults. Dig Dis Sci 2011; 56: 2361–2365.

103.

McDonald

Ackermann

Khailova

, et al. Extreme dysbiosis of the microbiome in critical illness. mSphere 2016; 1: e00199–16.

104.

Païssé

Valle

Servant

, et al. Comprehensive description of blood microbiome from healthy donors assessed by 16S targeted metagenomic sequencing. Transfusion 2016; 56: 1138–1147.

105.

Jirsova

Heczkova

Dankova

, et al. The effect of butyrate-supplemented parenteral nutrition on intestinal defence mechanisms and the parenteral nutrition-induced shift in the gut microbiota in the rat model. Biomed Res Int 2019; 2019: 7084734.

106.

Lavallee

MacPherson

JAR

Zhou

, et al. Lipid emulsion formulation of parenteral nutrition affects intestinal microbiota and host responses in neonatal piglets. JPEN J Parenter Enteral Nutr 2017; 41: 1301–1309.

107.

Noor

Kaysen

Wilmes

, et al. The gut microbiota and hematopoietic stem cell transplantation: challenges and potentials. J Innate Immun 2019; 11: 405–415.

108.

Biagi

Zama

Nastasi

, et al. Gut microbiota trajectory in pediatric patients undergoing hematopoietic SCT. Bone Marrow Transplant 2015; 50: 992–998.

109.

Whang

Nagpal

Yadav

Bi-directional drug–microbiome interactions of anti-diabetics. EBioMedicine 2019; 39: 591–602.

110.

Van Praagh

De Goffau

Bakker

, et al. Mucus microbiome of anastomotic tissue during surgery has predictive value for colorectal anastomotic leakage. Ann Surg 2019; 269: 911–916.

111.

Van Praagh

De Goffau

Bakker

, et al. Intestinal microbiota and anastomotic leakage of stapled colorectal anastomoses: a pilot study. Surg Endosc 2016; 30: 2259–2265.

112.

Shanahan

Hill

Language, numeracy and logic in microbiome science. Nat Rev Gastroenterol Hepatol 2019; 16: 387–388.

113.

Schardey

Rogers

Schopf

, et al. Are gut bacteria associated with the development of anastomotic leaks? Coloproctology 2017; 39: 94–100.

114.

Lederer

Pisarski

Kousoulas

, et al. Postoperative changes of the microbiome: are surgical complications related to the gut flora? A systematic review. BMC Surg 2017; 17: 125.

115.

Yang

Liu

, et al. Effect of perioperative probiotics and synbiotics on postoperative infections after gastrointestinal surgery: a systematic review with meta-analysis. JPEN J Parenter Enteral Nutr 2017; 41: 1051–1062.

116.

Klarin

Adolfsson

Torstensson

, et al. Can probiotics be an alternative to chlorhexidine for oral care in the mechanically ventilated patient? A multicentre, prospective, randomised controlled open trial. Crit Care 2018; 22: 272.

117.

Shimizu

Yamada

Ogura

, et al. Synbiotics modulate gut microbiota and reduce enteritis and ventilator-associated pneumonia in patients with sepsis: a randomized controlled trial. Crit Care 2018; 22: 239.

118.

Mahmoodpoor

Hamishehkar

Asghari

, et al. Effect of a probiotic preparation on ventilator-associated pneumonia in critically ill patients admitted to the intensive care unit: a prospective double-blind randomized controlled trial. Nutr Clin Pract 2019; 34: 156–162.

119.

Majid

Cole

Emery

, et al. Additional oligofructose/inulin does not increase faecal bifidobacteria in critically ill patients receiving enteral nutrition: a randomised controlled trial. Clin Nutr 2014; 33: 966–972.

120.

Lunia

Sharma

, et al. Probiotics prevent hepatic encephalopathy in patients with cirrhosis: a randomized controlled trial. Clin Gastroenterol Hepatol 2014; 12: 1003–1008.e1.

121.

Suzuki

Masui

Nakamura

, et al. Yogurt containing Lactobacillus gasseri mitigates aspirin-induced small bowel injuries: a prospective, randomized, double-blind, placebo-controlled trial. Digestion 2017; 95: 49–54.

122.

Mayes

Gottschlich

James

, et al. Clinical safety and efficacy of probiotic administration following burn injury. J Burn Care Res 2015; 36: 92–99.

123.

Shao

Yang

Impact of microbial immune enteral nutrition on postoperative insulin resistance and infectious complication of patients with abdominal infection. Zhonghua Wei Chang Wai Ke Za Zhi 2014; 17: 676–679.

124.

Tan

Duan

, et al. Effects of probiotics on blood glucose levels and clinical outcomes in patients with severe craniocerebral trauma. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2013; 25: 627–630.

125.

Shao

Xin

Yang

, et al. The impact of microbial immune enteral nutrition on the patients with acute radiation enteritis in bowel function and immune status. Cell Biochem Biophys 2014; 69: 357–361.

126.

Wong

Jamous

O’Driscoll

, et al. A Lactobacillus casei Shirota probiotic drink reduces antibiotic-associated diarrhoea in patients with spinal cord injuries: a randomised controlled trial. Br J Nutr 2014; 111: 672–678.

127.

Endo

Higurashi

Hosono

, et al. Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study. J Gastroenterol 2011; 46: 894–905.

128.

Koutelidakis

Bezirtzoglou

Giamarellos-Bourboulis

, et al. Impact of synbiotics on the intestinal flora of critically ill patients with multiple injuries. Int J Antimicrob Agents 2010; 36: 90–91.

129.

Giamarellos-Bourboulis

Bengmark

Kanellakopoulou

, et al. Pro- and synbiotics to control inflammation and infection in patients with multiple injuries. J Trauma 2009; 67: 815–821.

130.

Kotzampassi

Giamarellos-Bourboulis

Voudouris

, et al. Benefits of a synbiotic formula (Synbiotic 2000Forte) in critically ill trauma patients: early results of a randomized controlled trial. World J Surg 2006; 30: 1848–1855.

131.

Kotzampassi

Stavrou

Damoraki

, et al. A four-probiotics regimen reduces postoperative complications after colorectal surgery: a randomized, double-blind, placebo-controlled study. World J Surg 2015; 39: 2776–2783.

132.

Peral

Martinez

Valdez

JC.

Bacteriotherapy with Lactobacillus plantarum in burns. Int Wound J 2009; 6: 73–81.

133.

Zeng

Wang

Zhang

, et al. Effect of probiotics on the incidence of ventilator-associated pneumonia in critically ill patients: a randomized controlled multicenter trial. Intensive Care Med 2016; 42: 1018–1028.

134.

Malik

Rajandram

Tah

, et al. Microbial cell preparation in enteral feeding in critically ill patients: a randomized, double-blind, placebo-controlled clinical trial. J Crit Care 2016; 32: 182–188.

135.

López De Toro Martín-Consuegra

Sanchez-Casado

Pérez-Pedrero Sánchez-Belmonte

, et al. [The influence of symbiotics in multi-organ failure: randomised trial]. Med Clin (Barc) 2014; 143: 143–149.

136.

Sanaie

Ebrahimi-Mameghani

Hamishehkar

, et al. Effect of a multispecies probiotic on inflammatory markers in critically ill patients: a randomized, double-blind, placebo-controlled trial. J Res Med Sci 2014; 19: 827–833.

137.

Rongrungruang

Krajangwittaya

Pholtawornkulchai

, et al. Randomized controlled study of probiotics containing Lactobacillus casei (Shirota strain) for prevention of ventilator-associated pneumonia. J Med Assoc Thai 2015; 98: 253–259.

138.

Barraud

Blard

Hein

, et al. Probiotics in the critically ill patient: a double blind, randomized, placebo-controlled trial. Intensive Care Med 2010; 36: 1540–1547.

139.

Komatsu

Sakamoto

Norimizu

, et al. Efficacy of perioperative synbiotics treatment for the prevention of surgical site infection after laparoscopic colorectal surgery: a randomized controlled trial. Surg Today 2016; 46: 479–490.

140.

Sadahiro

Suzuki

Tanaka

, et al. Comparison between oral antibiotics and probiotics as bowel preparation for elective colon cancer surgery to prevent infection: prospective randomized trial. Surgery 2014; 155: 493–503.

141.

Manzanares

Lemieux

Langlois

, et al. Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis. Crit Care 2016; 19: 262.

142.

Sherid

Samo

Sulaiman

, et al. Liver abscess and bacteremia caused by lactobacillus: role of probiotics? Case report and review of the literature. BMC Gastroenterol 2016; 16: 138.

143.

Pararajasingam

Uwagwu

Lactobacillus: the not so friendly bacteria. BMJ Case Rep 2017; 2017: bcr–2016.

144.

Haghighat

Crum-Cianflone

NF.

The potential risks of probiotics among HIV-infected persons: bacteraemia due to Lactobacillus acidophilus and review of the literature. Int J STD AIDS 2016; 27: 1223–1230.

145.

Land

Rouster-Stevens

Woods

, et al. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 2005; 115: 178–181.

146.

Hughes

Kable

Marco

, et al. The role of the gut microbiome in predicting response to diet and the development of precision nutrition models. Part II: Results. Adv Nutr 2019; 10: 953–978.

147.

Depommier

Everard

Druart

, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med 2019; 25: 1096–1103.

148.

Moens

Van Den Abbeele

Basit

, et al. A four-strain probiotic exerts positive immunomodulatory effects by enhancing colonic butyrate production in vitro. Int J Pharm 2019; 555: 1–10.

149.

Limketkai

Hendler

Ting

, et al. Fecal microbiota transplantation for the critically ill patient. Nutr Clin Pract 2019; 34: 73–79.

150.

Wang

Roberts

Buffa

, et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 2015; 163: 1585–1595.

151.

Roberts

Buffa

, et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med 2018; 24: 1407–1417.

152.

Schugar

Brown

JM.

Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis. Curr Opin Lipidol 2015; 26: 426–431.

153.

Schörghuber

Fruhwald

Effects of enteral nutrition on gastrointestinal function in patients who are critically ill. Lancet Gastroenterol Hepatol 2018; 3: 281–287.

154.

Bhalodi

Van Engelen

TSR

Virk

, et al. Impact of antimicrobial therapy on the gut microbiome. J Antimicrob Chemother 2019; 74: i6–i15.

155.

Wang

Bajaj

Wang

, et al. Lactulose improves cognition, quality of life and gut microbiota in minimal hepatic encephalopathy: a multi-center, randomized controlled trial. J Dig Dis 2019; 20: 547–556.

156.

Peters

Pomare

Fisher

CA.

Portal and peripheral blood short chain fatty acid concentrations after caecal lactulose instillation at surgery.

Gut 1992; 33: 1249–1252.

157.

DeLano

Chow

Schmid-Schönbein

GW.

Volatile decay products in breath during peritonitis shock are attenuated by enteral blockade of pancreatic digestive proteases.

Shock 2017; 48: 571–575.

158.

Barker

Duster

Valentine

, et al. A randomized controlled trial of probiotics for Clostridium difficile infection in adults (PICO). J Antimicrob Chemother 2017; 72: 3177–3180.

159.

Lee

Shih

, et al. Evaluation of the potential inhibitory activity of a combination of L. acidophilus, L. rhamnosus and L. sporogenes on Helicobacter pylori: a randomized double-blind placebo-controlled clinical trial. Chin J Integr Med 2017; 23: 176–182.

160.

Chen

Lee

, et al. The impact of Helicobacter pylori infection, eradication therapy and probiotic supplementation on gut microenvironment homeostasis: an open-label, randomized clinical trial. EBioMedicine 2018; 35: 87–96.

161.

McNicholl

Molina-Infante

Lucendo

, et al. Probiotic supplementation with Lactobacillus plantarum and Pediococcus acidilactici for Helicobacter pylori therapy: a randomized, double-blind, placebo-controlled trial. Helicobacter 2018; 23: e12529.

162.

Lau

Ward

Chamberlain

RS.

Probiotics improve the efficacy of standard triple therapy in the eradication of Helicobacter pylori: a meta-analysis.

Infect Drug Resist 2016; 9: 275–289.

163.

Glendinning

Free

Supra-organismal interactions in the human intestine.

Front Cell Infect Microbiol 2014; 4: 47.

Gut microbiota in surgical and critically ill patients

Abstract

Keywords

Introduction

Factors affecting the gut microbiota

Links between gut dysbiosis and organ dysfunction

TMAO

SCFAs

Clinical trials of probiotics and synbiotics in surgical and critically ill patients

Clinical trials on surgical and critically ill patients

Probiotics in Clostridium difficile–related diarrhoea and Helicobacter pylori infection

Conclusions

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

References