Advanced surgical and medical treatments, as well as medical and surgical emergencies, are, despite some breath-taking advances in medico-pharmaceutical and surgical treatment, still accompanied by an unacceptably high morbidity and also mortality. Worse than this, morbidity and mortality in these conditions is fast increasing and has done so all over the world for several decades. Apart from the suffering associated with this, it is also extremely costly to the individual and the health care system.

Dominating among the treatment-induced morbidities is sepsis due to bacterial, fungal or viral infections. Recent observations in the US suggest that not only the incidence, but also the severity of sepsis, has significantly increased during the last decades [1,2,3]. Especially advanced surgery carries a high rate of septic morbidity and especially esophageal, pancreatic, and gastric procedures are particularly known to represent great risk for the development of sepsis, but thoracic, adrenal, and hepatic procedures are those that have the highest sepsis-induced mortality [1,2]. It is also documented in the literature that elderly patients, men, and nonwhites are the most likely to develop sepsis as a complication to surgical treatment [1,2]. Sepsis is by far the most common medical and surgical complication, and estimated only in the US to annually affect as many as 751,000 [4,5], and cause death of app 215,000 patients (29% of treated patients) [5], making sepsis the tenth most common cause of death in this country.

Post-surgical morbidity and due to septic manifestations is only partly attributed to the surgeon and the surgical technique. Increasing evidence suggests instead that it is the patient’s ability to resist disease/immune defense and especially supportive measures during and around the treatment, such as mechanical ventilation, use of implants, drains and intravascular lines, but also choice of content and routes to provide nutrition, blood transfusions, choice of anesthesia and prescription of drugs, also antibiotics and immune-suppressives, that are the largest contributors to the development of septic manifestations.

Mechanical ventilation in association with management of emergencies and surgical procedures has in recent years received increasing attention as a major contributor to chest-infections, but also to general and localized septic manifestations in the body; according to a recent study applied in the US in about 800,000 individuals every year. It is estimated to represent no less than 12% of total hospital costs, no less than $27 billion in the US alone [6]. This treatment is responsible for, not only a disproportional amount of resources used, but also for the unacceptably high morbidity and mortality associated with the treatment, especially in elderly people [6].

A main contributor to intensive care unit (ICU)-associated sepsis is also artificial nutrition, both enteral and parenteral; catheter-related sepsis is reported to occur in about 25% of patients fed via intravenous feeding-tubes [7]. Numerous drugs used in the ICUs including antibiotics are known to derange the immune functions, impair macrophage functions, bactericidal efficacy as well as production and secretion of cytokines. For example, supply of an antibiotic, Mezlocillin (Bayer, 150 mg/kg body weight) is demonstrated to significantly suppress essential macrophage functions and derange chemiluminescence response, chemotactic motility, bactericidal and cytostatic ability and impair lymphocyte proliferation [8]. Other common perioperative practices like use of artificial feeding regimens, preoperative antibiotics [9], and mechanical bowel preparation [10,11] will also, according to recent studies, instead of the expected prevention as expected, contribute to increased rates of treatment-associated infections.

Most of the surgical infections originate in areas with the most exposure to the exterior world, i.e., the gut (63%) and chest (20%) and are pure gram-negative (22%), pure gram-positive (15%), mixed (23) or fungal (8%) [12]. It is also here that the dominating parts of the immune functions are localized: between 70–80% of the Ig-producing immunocytes of the body are found in the gut [13]. It was Marshall and his group who, in 1993, directed attention to the gut as a special source of surgical sepsis and especially to its most severe form—multiple organ failure (MOF) [14]. They observed that the most common organisms to cause ICU-acquired infections—Candida, Streptococcus faecalis, Pseudomonas, and coagulase-negative Staphylococci—were also the most common species that seemed to colonize especially the proximal GI tract. They reported that this colonization correlated well with development of invasive infection within one week: Pseudomonas (90% vs. 13% in non-colonized patients, p < 0.0001) and Staphylococcus epidermidis (80% vs. 6%, p < 0.0001). As a consequence of these observations, they coined the phrase: “the gut—the undrained abscess”. Studies during subsequent years focused mainly on microbial translocation as the major course of sepsis.

Important observations had, however, been made by Baue, Faist and their groups already ten years earlier, and their finding that a significant portion of patients, who develop multiple organ dysfunction syndrome (MODS), and do not have an identifiable infection [15], should have a great impact on future understanding of treatment and emergency-associated sepsis. It was Goris and his collaborators, who, in 1986, based on observations like those of Baue and Faist, but also after extensive studies in animals, suggested inflammation precedes septic manifestations and an “auto-destructive inflammatory response” with or without bacterial infection, is a major cause of this severe condition [16].

Patients who develop severe septic complications are known to respond to physical and mental stress with an early exuberant acute, or chronic, super-inflammation, with signs of exaggerated and prolonged release of pro-inflammatory cytokines such as interleukin-6 (IL-6), acute phase proteins such as C-reactive protein, and plasminogen activator inhibitor 1 (PAI-1)—see [17]—a reaction strongly associated with subsequent severe exacerbation of disease, including acute respiratory distress syndrome (ARDS), and MOF. Among the observed changes associated with an exuberant inflammation in the early nervous phase are: augmented endothelial adhesion of polymorphonuclear (PMN) cells, increased production of intracellular adhesion molecule-1 (ICAM-1), priming of the PMNs for an oxidative burst, release of pro-inflammatory platelet activating factor (PAF), and a delay in PMN apoptosis [18]. Visceral adipocytes are, compared to subcutaneous fat cells, known to secrete per gram tissue much more of free fatty acids but also about three times as much IL-6, and PAI-1; observations that well explain the high risk of both chronic and acute diseases in individuals with visceral obesity [19]. The stress-induced load of these and other proinflammatory and procoagulant molecules on organs, such as the lung and the liver, can vary a thousand times or more, as the amount of fat in the abdomen can vary from a few milliliters in a lean subject to about six liters in gross obesity [20].

An increase in growth of Gram-negative bacteria of up to 100,000 times (5 logs of order) has been demonstrated in animals exposed to noradrenaline; see Lyte’s review [21]. Old observations suggest a strong and significant association between higher blood levels of noradrenaline and adrenaline and development of severe septic conditions [22]. Luminal release of noradrenaline is a documented strong inducer of virulence of luminal bacteria [23], and much suggests that potentially pathogenic microorganisms (PPMs), normally indolent colonizers, under stress change their phenotype and become life-threatening pathogens [24]. These observations are particularly interesting as classical studies published already in the 1940s demonstrated that a 10,000 times lower dose of Clostridium welchii is needed to induce death in gas-gangrene in animals, when also adrenaline is administered to the animals [25]. Most likely similar potentiating effects exist when stress and stress-hormones are applied also to other pathogenic bacteria.

Microbiota is significantly reduced in Westerners. A study published in the US in 1983 reported that Lactobacillus plantarum, a dominating lactic acid bacterium (LAB) among plant eaters, is found in only about 25% of omnivorous Americans and in about two thirds of vegetarian Americans [26]. A more recent Scandinavian study suggest that also in healthy individuals, the most common colonic LAB are present in only half or less of the individuals: Lactobacillus plantarum in 52%, Lactobacillus rhamnosus in 26% and Lactobacillus paracasei ssp. paracasei 17% [27]. Western lifestyle with frequent mental and physical stress, and eating of processed foods with high content of saturated fats and trans-fatty acids, lack of dietary fibers, containing chemicals and pharmaceuticals, but also lack of microorganisms content in food, will significantly reduce the microbiota both with regard to diversity and extent of existing flora. Recent studies report that in Westerners, a significant shift in balance from gram-positives to gram-negatives, and subsequent increase in production of endotoxins/lipopolysaccharide (LPS) [28]. Magnesium (Mg) requirements are known to be much higher for Gram+ than for Gram− bacteria and Mg deficiency, common in Westerners, was recently shown to induce decreased content in the gut especially of Bifidobacteria, to increase colonic and systemic inflammation, and increase intestinal permeability. These observations are of particular interest as Mg deficiency is associated with systemic inflammation and common metabolic disorders such as type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension [29], but also observed in ICU patients. Mg-deficient patients, in comparison to patients with normal magnesium levels, are reported to exhibit a higher prevalence of severe sepsis and septic shock (57 vs. 11%, p < 0.01), a longer ICU stay (15.4 ± 15.5 vs. 2.8 ± 4.7 days, p < 0.01), and a higher mortality rate [30].

A several log-fold decrease in the commensal bacteria like Bifidobacteria and Lactobacilli are reported in trauma patients in parallel to increased populations of pathogenic bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus [31]. The Western lifestyle-induced derangement of the microbiota is associated with increased permeability of intestinal mucosa, increased LPS absorption, increased endotoxemia, exaggerated inflammation, and strongly associated with metabolic disorders such as obesity and diabetes [32]—conditions, which also are commonly associated with increased surgical morbidity, surgical infections and MOF.

Severe trauma, major surgery and severe sepsis will, parallel to a significant decrease in lymphocytes, induce a significant, sometimes disproportionate, increase in circulating and tissue neutrophils, and be accompanied by persistent decline in T-4 helper lymphocytes and elevation of T-8 suppressor lymphocytes [33]. It is suggested that a T-4/T-8 lymphocyte cell ratio of <1 is a sign of severe immunosuppression and predictor of complication, such as multiple organ dysfunction syndrome, myocardial infarction, acute pancreatitis, multiple severe trauma and chemotherapeutic treatment, especially in oncology patients [34]. An early and large increase in circulating neutrophils is accompanied by tissue infiltration of neutrophils, and responsible for common posttrauma/postoperative dysfunctions such as paralytic ileus [35,36], bone marrow suppression, endothelial cell dysfunction, and to lead to tissue destruction and organ failure, particularly in lungs [37,38,39], intestines [40], liver [41] and kidney [42]. Neutrophil infiltration of distant organs [16], especially the lungs [37], is a characteristic finding in patients dying of sepsis. The extent of neutrophil infiltration is significantly aggravated by mechanical therapeutic efforts such as handling of the bowels during operation [35], and ventilation of the lungs [43]. Poor nutritional status, preexisting immune deficiency, obesity, diabetes and high levels of blood sugar [44] contribute to immune deterioration and to increased expressions in the body of molecules such as NF-κB, COX-2, LOX and iNOS [45,46]. The disproportionate increase in circulating neutrophils is to a great extent inhibited by supplementation of antioxidants [47,48] and specific probiotics [49].

Supplementation of probiotics will effectively prevent neutrophil infiltration of the lung and also reduce the subsequent tissue destruction, as demonstrated in studies with inflammation induced by cecal ligation and puncture (CLP). A synbiotic formulation, Synbiotic 2000 Forte (see further below), was administered orally before the induced trauma and effectively prevented both neutrophil accumulation and tissue destruction in the lungs [50]. Most interestingly, these effects were obtained also when the LAB of the composition were injected subcutaneously (Figure 1,Figure 2,Figure 3) [51].

The average neutrophil count in the lungs (average of five fields) was: mixture of LAB and bioactive fibers 9.00 ± 0.44 (1), only LAB 8.40 ± 0.42 (2), only bioactive fibers 31.20 ± 0.98 (3), placebo (non-fermentable fiber) 51.10 ± 0.70 (4). The reduction of inflammation by the treatment was also demonstrated by significant reductions in myeloperoxidase (MPO), malondialdehyde (MDA), and nitric oxide (NO): MPO being 25.62 ± 2.19 (1), 26.75 ± 2.61 (2), 56.59 ± 1.73 (3), and 145.53 ± 7.53 (4) respectively (resp.), MDA 0.22 ± 1.31 (1), 0.28 ± 3.55 (2), 0.48 ± 5.32 (3) and 0.67 ± 2.94 (4) resp. and NO 17.16 ± 2.03 (1), 18.91 ± 2.24 (2), 47.71 ± 3.20 (3) and 66.22 ± 5.92 (4) resp.—all differences being statistically significant (>0.05).

My interest in microbiota and probiotics stems back to 1986. Since 1963, I was a surgeon focusing my interest on liver surgery, and was actively searching for new tools to combat the unacceptably high rate of perioperative infections associated with major surgery and particularly with extensive liver resections. A review of our last 81 liver resections yielded some unexpected information, which directed my interest to human microbiota and probiotics. It was standard practice at that time, in connection with surgery, to provide the patients with an antibiotic umbrella for at least five days with the hope that this treatment might somewhat reduce the rate of infections. The shocking information from this study was that only 57/81 patients had in fact received this treatment, while the treatment had been neglected in as many as 24/81 patients [52,53]. However, the unexpected information from this review was that there were no cases of sepsis reported in the patients who had not received prophylactic antibiotics. As a matter of fact, all manifestations of sepsis had occurred in the antibiotic-treated patients. A growing awareness of the importance of human microbiota [54] and the eventual possibility of reconditioning of the gut through probiotic treatment [55] was at that time visible. It was also increasingly understood that lifestyle, chemicals and pharmaceuticals, in addition to the disease per se, could impair the microbiota and immune defense.

It seemed likely that powerful probiotic treatment could constitute an effective prevention of unwanted infections in disease and also in surgical and emergency medical cases. That was the reason why I established collaboration with experts in microbiology, chemistry, nutrition, experimental and clinical science to seek opportunities find, develop and test, experimentally and clinically, probiotics, which could be expected to be powerful tools to prevent sepsis. Our first efforts resulted in a one LAB/one fiber composition, produced by fermentation of oat meal with Lactobacillus plantarum strain 299 [56,57,58]. I worked with this synbiotic composition for more than ten years. This formula is produced and marketed by Probi AB, Lund, Sweden.

After 1999 and until today, I have continued my research with a four LAB/four fiber composition, which consists of a mixture of 10¹⁰ (standard version—Synbiotic2000™) and a mixture of 10¹¹ (forte version—Synbiotic 2000 forte™) of four different LAB: Pediococcus pentosaceus 5-33:3, Leuconostoc mesenteroides 32-77:1, Lactobacillus paracasei subsp paracasei 19, and Lactobacillus plantarum 2362 combined with 10 g of fibers; 2.5 g of each of four fermentable fibers: betaglucan, inulin, pectin and resistant starch [59,60]. The standard Synbiotic 2000 contains thus 4 × 10 billion LAB = 40 billion and the stronger version, Synbiotic 2000 forte, 4 × 100 billion LAB = 400 billion resp. of lactic acid bacteria. The formula is marketed by Ionian Pharma, Glyka Nera, Greece and Synbiotic AB, Höganäs, Sweden.

In a recent study twenty-nine SIRS patients with a serum C-reactive protein (CRP) level above 10 mg/dL, received a synbiotic composition consisting of Bifidobacterium breve and Lactobacillus casei, in combination with galactooligosaccharides. The incidence of infectious complications such as enteritis, pneumonia, and bacteremia were (compared to historical controls) significantly lower in the treated group [72]. Analysis of fecal flora demonstrated significantly higher levels of Bifidobacteria and Lactobacillus, and also of total organic acids, particularly short-chain fatty acids.

Critical care units are in general a highly artificial environment and the burden of environment-induced physical and mental stress and subsequent status of systemic hyper-inflammation on the patient is unbearable. Patients treated under these conditions are in many aspects dysfunctional, the whole microbiota is gone and probiotic bacteria supplied will most often be killed already before they have reached its target organ. This artificiality seems to vary from country to country, and sometimes also from hospital to hospital, observations that might explain the great variation in outcome from studies undertaken in different regions and countries.

Probiotic treatment has never been given the chance as an alternative treatment; it has only been tried as a treatment complementary to all the other standard treatments. As discussed above, a series of auxiliary measures and particularly mechanical ventilation [7] and treatment with various drugs, including antibiotics [8,9], but also clinical nutrition solutions belong to those factors which promote super-inflammation and, indirectly, infection. Enteral nutrition formulas are also known to induce loss of intestinal barrier function, promotes bacterial translocation, and impairs host immune defense [81], a phenomenon, observed in humans and further elucidated in animal studies. The incidence of bacterial translocation to the mesenteric lymph node was in such studies significantly increased when the animals were fed nutrition formulas such as Vivonex (53%), Criticare (67%), or Ensure (60%) (p < 0.05) [82,83,84]. Similar observations have also been made in patients. Significant elevations in pro-inflammatory cytokines were observed in patients, who after pancreatoduodenectomy are fed a standard enteral nutrition solution (Nutrison): IL-1beta—day 7 (P < 0.001), day 14 (P = 0.022); TNF-alpha—day 3 (P = 0.006), day 7 (P < 0.001) [85]. Of special interest are the observations that such changes were not observed when the standard nutrition was replaced with a formula that claimed to have immune-modulatory effects (Stresson). Instead anti-inflammatory cytokines were seen significantly elevated: IL-1ra/s: day 7 (P < 0.001), IL-6: day 10 (P = 0.017), IL-8: day 1 (P = 0.011) days 3, 7, 10, and 14 (P < 0.001) and IL-10: days 3 and 10 (P < 0.001).

The type of bacteria to be chosen for probiotic purpose is also critical. Only a few LAB strains have demonstrated ability to influence the immune system, reduce inflammation and/or eliminate or reduce unwanted pro-inflammatory molecules from foods. Even strains, which carry sometimes the same name have often different and sometimes opposite effects. A recent study selected 46 strains of Lactococcus lactis from about 2600 LAB and compared their ability to induce cytokines. It was demonstrated that the inter-strain differences in ability to produce pro- and anti-inflammatory cytokines were great [86], an observation which underlines the importance of extensive animal and preclinical studies before a LAB or combination of LAB be chosen as probiotic.

Especially desirable as probiotics are strains that improve immune function by increasing the number of IgA-producing plasma cells, improve phagocytosis, and influence the proportion of Th1 cells and NK cells [87]. Among the strains with a strong anti-inflammatory record are Lactobacillus paracasei subsp. paracasei, Lactobacillus plantarum, and Pediococcus pentosaceus. Especially Lactobacillus paracasei seems to have a solid record. It has been shown to induce cellular immunity, stimulating the production of suppressive cytokines such as TGFβ and IL-10; to suppress Th2 activity, CD4 T-cells [88,89], and splenocyte proliferation [90]; and to decrease antigen-specific IgE and IgG1 [91]. Lactobacillus paracasei was shown to be the strongest inducer of Th1 and repressor of Th2 cytokines when more than a hundred LAB strains were compared [92]. A recent study in rats compared the ability of four different strains: Lactobacillus paracasei, Lactobacillus johnsonii, Bifidobacterium longum, or Bifidobacterium lactis to control Trichinella spiralis-induced infection. Lactobacillus paracasei, but none of the others, were able to reduce infection-associated Th2 response, muscle levels of TGF-β, COX-2 and PGE2 and to attenuate infection-induced muscle hyper-contractility [93]. Another recent study compared the ability to reduce stress-induced changes in gut permeability and sensitivity to colorectal distension of three probiotic strains: Bifidobacterium lactis NCC362, Lactobacillus johnsonii NCC533, and Lactobacillus paracasei NCC2461. Lactobacillus paracasei but none of the other LAB, significantly restored normal gut permeability, and reduce visceral hyperalgesia and visceral pain [94].

Lactobacillus plantarum has also an excellent record. When the ability of fifty different LAB to control twenty-three different Clostridium difficile (C diff) strainswere studied, Lactobacillus paracasei and Lactobacillus plantarum were the only strains with ability to effectively eliminate all C. diff strains—more than half of the tried LAB strains were totally ineffective, and some only against a few [95]. Some LAB can be potentiated in their efficacy by simultaneous supply of prebiotic fibers (probiotics + prebiotics ≥ synbiotics). However, there are great differences in the ability of different strains to ferment and utilize plant fibers, especially when it comes to semi-fermentable fibers such as oligofructans. Only a handful of LAB from the 712 tested strains demonstrated in a study ability to ferment inulin and phlein, namely: Lactobacillus plantarum (several strains), Lactobacillus paracasei subsp. paracasei, Lactobacillus brevis and Pediococcus pentosaceus [96].

Two recent studies provide a fascinating insight into the future. Gene expression of human duodenal mucosa cells were studied after exposure to one of the following four lactic acid bacteria: Lactobacillus plantarum WCFS1 [97], Lactobacillus acidophilus L10, Lactobacillus casei CRL-431 and L. rhamnosus GG [98], administered in a cross-over study to healthy volunteers in a dose of 10¹⁰. Mucosal biopsies were taken from duodenum after 6 h and compared to control biopsies. The interventions did not impair immune and metabolic homeostasis. Nevertheless, a fascinating and most distinct influence on expression of several hundred genes (transcriptome) was reported after administration of each of the LAB. For seemingly the first time, different probiotic lactobacilli are reported to induce more or less strain-specific and markedly different expression profiles, much similar to what is known to occur with ingestion of various foods, especially plant ingredients [99,100], but also similar to the effects observed after supplying certain pharmaceuticals. Thus L. plantarum was reported to modulate overt adaptive immune responses [97], L. acidophilus to suppress inflammation , L. casei to stimulate Th1 response and improve the Th1-Th2 balance, L. rhamnosis to influence cellular growth and proliferation [98]. The effects were suggested to resemble, although distinctly milder, those obtained by specific pharmaceuticals: L. acidophilus—antagonists of α-receptor activity, guanine antagonists, synthetic corticosteroids and flavonoids, L. casei—modulators of GABA receptors, cholinergic blocking agents, antagonists of β-adrenergic receptors, L. rhamnosus—glycoside steroids, alkaloids, protein synthesis inhibitors and protein kinase C inhibitors. A large person-to-person variation in response was also reported.

The responsiveness to ingestion of various LAB seems to be strongly influenced, not only by eventual genetic background and existing resident microbiota, but also by lifestyle, and particularly by diet, which might explain the person-to-person differences in response observed in the above studies [97,98], but also differences in outcome, when applied in critically ill patients, as reported in this review.

In the immediate future, probiotics will most likely continue to find its dominating niche as treatment given to rather healthy and health-concerned individuals with the main aim to promote health and prevent disease. However, it is likely that probiotics, as our knowledge in nutragenomics and therapeutic microbiology increases, will be generally regarded also as valuable tools for treatment of various acute and chronic diseases, also in critically ill patients. The review of studies reported to date and presented in this review supports such an assumption. Probiotics will, however, not be generally accepted and utilized as clinical tools until radical and profound changes in treatment practices in care of the critically ill and other patient groups are implemented.