Effect of antibiotics and other drugs on the microbiota
Because of the critical illness of admitted patients, antibiotics are frequently used in intensive care units [
20]. Recent advances in understanding the role of intestinal microbiota spotlight potential harmful effects of these medications [
21,
22] in that these therapies target pathogenic bacteria, but also the commensal ones making our microbiota [
23] (Fig.
4). The impact of antibiotics is multifactorial: it depends on the antibiotic’s intrinsic characteristics (class, pharmacokinetic and pharmacodynamic properties) and the way in which it is used (e.g., dosage, duration, administration route) [
24]. With its substantial biliary excretion (> 80%) and its activity against many anaerobic bacteria, clindamycin is a good example to illustrate the consequences of antibiotics on the microbiota. This drug alters bacterial diversity [
25,
26] and favors the growth of intrinsically resistant microorganisms (e.g.,
Clostridioides difficile,
Enterococcus spp. or Enterobacterales) making clindamycin a major risk factor for the development of
C. difficile infection (CDI) [
27]. In a similar way, macrolides [
28], glycopeptides [
29] or fluoroquinolones [
30] have been shown to significantly modify the composition of the intestinal microbiota. Conversely, rifaximin (typically used in hepatic encephalopathy) seems to have a limited effect on microbial diversity while favoring the growth of beneficial bacteria [
31‐
34]. Still in routine clinical settings, ranking the antibiotics according to their potential impact on the intestinal microbiota remains driven by expert opinions [
35]. Indeed, while the impact of antibiotics has been extensively studied, the lack of standardization between studies hampers any type of comparison [
36,
37]. In our opinion, an important point is that the antibiotic spectrum and the impact of the antibiotic on gut microbiota are not necessarily correlated [
37]. To date, there is no hard data comparing the importance of microbiota dysbiosis between extended-spectrum antibiotics such as carbapenems and other broad-spectrum antibiotics [
38,
39].
Bearing a special status because of its direct action on the microbiota, selective digestive decontamination (SDD) or selective oral decontamination (SOD) are also well-used in critically ill patients and can be cited in treatments modifying the microbiota [
40]. Contrary to the patients not treated, the main variations in those treated with SDD are a decrease of
Enterobacteriaceae, an increase of enterococci, and an impact on anaerobic bacteria [
41]. Conversely, SOD seems to have a limited impact on the microbiota [
40].
By analyzing the gut microbiomes of 1,135 Dutch patients exposed to various commonly used drugs, Zhernakova et al. showed that non-antibiotic drugs may also impact the gut microbiota [
42]. Among them, proton pump inhibitors [
43,
44], metformin [
45], nonsteroidal anti-inflammatory drugs [
46], or statins exerted a detectable effect on the composition of the gut microbiota. In addition to all cited molecules, many intensive care-specific therapies such as artificial feeding [
47], mechanical ventilation, proton pump inhibitors [
48], and vasopressors may also contribute to the microbiota dysregulation [
3]. Among them, opioids, which also contribute to the slowing down of the intestinal transit, are widely used in ICU patients and possibly modulate the microbiota by increasing
Enterococcus and
Staphylococcus species and favoring their extra-intestinal dissemination as shown in a murine model of sepsis [
49].
Consequences of the alteration of the gut microbiota
MDRO are a growing burden in intensive care structures [
50,
51]. An unaltered microbiota seems to be a key element in the fight against resistant organisms because of its ability to confront exogenous bacteria, including the resistant ones: this concept is called colonization resistance and protective organisms are beginning to be studied in greater detail [
4,
52] (Fig.
4). A major study touching on the relation between the antibiotic use and the emergence of MDR bacteria was published by Donskey et al. [
53] in the 2000s, showing that the intestinal concentrations of vancomycin-resistant
Enterococcus spp. were correlated to the use of antibiotics with a marked activity on anaerobic bacteria, thereby altering the bacterial protective barrier and allowing the growth of resistant microorganisms. In animal models,
Clostridium scindens was shown to slow the growth of
C. difficile infection [
54],
Blautia producta and
Clostridium bolteae that of vancomycin-resistant
Enterococcus inhibition [
55] and Lactobacilli, Clostridiales and anaerobes that of
Listeria monocytogenes infection [
56]. Several studies have analyzed and confirmed the increase of resistant bacteria after antibiotic administration, the latter altering colonization resistance, provoking, at the expense of the susceptible bacteria, a selection of MDR organisms, such as Enterobacterales [
57,
58] (including extended-spectrum beta-lactamase-producing
E. coli [
59,
60]) or vancomycin-resistant
Enterococcus spp. [
59]
. However, colonization with beta-lactamase-producing strains in high abundance may be also helpful: a recent animal study showed that a prior colonization by these strains may inactivate antibiotics in the gut after systemic treatment, protecting thus the microbiota from dysbiosis [
61,
62]. Such observations have paved the way for the development of solutions aiming at protecting the microbiota [
63,
64]. As a specific form of antibiotic therapy, SDD does not appear to increase the emergence of bacterial resistance in ICU [
65], and seems to be paradoxically associated with a lower prevalence of rectal carriage of antibiotic-resistant Gram-negative bacteria in ICU [
66,
67]. However, some observations have pointed to the SDD’s responsibility in the emergence of bacterial resistance after ICU stay [
68]. A high relative abundance of resistant microorganisms in microbiota has an important clinical impact, because it favors their involvement in infections [
36,
57,
60,
69], the duration of rectal carriage and shedding [
70], insofar as high concentrations of MDRO in stools correlates with environmental contamination and may play an important role in MDRO transmission [
71].
The microbiota is also a cornerstone for immunity development [
72,
73] with mucosal gut immunity on the one hand and systemic immunity on the other hand. Indeed, many structures (e.g., Peyer’s patches) are involved in immune modulation for instance via immunoglobulin A (IgA) which constitutes a major gut immune component potentially targeting some gut microorganisms [
74,
75]. The alteration of the gut microbiota may also lead to the dysregulation of the immune system [
76]. A reduction of mucosal IgA concentration has been shown to be associated in mice with an increased abundance of gamma-Proteobacteria (which include Enterobacterales) associated with pro-inflammatory properties [
77]. Similarly, an absence of IgA allows
Bacteroides thetaiotaomicron to induce a pro-inflammatory state [
78]. An alteration of the microbiota could also have consequences on the T cells and notably on T
H-17 cells, which are involved in antimicrobial defense and have an action on intestinal epithelial cells, enabling production of antimicrobial peptides [
79,
80]. The connection between dysbiosis and the immune system is illustrated by the increased susceptibility to asthma through dysregulation of T effector cells and IgE production in patients frequently exposed to antibiotics in their early infancy [
81]. The interactions between gut bacteria and the host immune system can also occur via the production of specific bacterial metabolites [
82]. SCFA concentration is associated with a reduced risk of colorectal adenoma and patients with inflammatory bowel disease present high levels of medium-chain fatty acids in feces comparatively to healthy subjects [
83,
84]. Butyrate is also an energy source for the gut cells, and their shortage because of dysbiosis in critically ill patients may provoke immune dysregulation and cell death [
85‐
87].
Alteration of microbiota and abnormalities of the immune system have consequences on the presence of bacteria with anti-inflammatory properties, creating a pro-inflammatory state in the guts of critically ill patients. At the species level, the decrease or even disappearance of some bacteria such as
Faecalibacterium prausnitzii has been associated with the promotion of a pro-inflammatory state, as seen in other patients with inflammatory bowel diseases or digestive cancers [
88‐
90]. Specifically in SARS-CoV-2 infection, a dysbiosis could be connected to the severity of COVID_19, with the drop of above-mentioned
Faecalibacterium prausnitzii being associated with disease severity [
91]. Furthermore, microbiota may be involved in certain types of inflammatory conditions [
92]. Dysbiosis may alter the intestinal barrier, allowing systemic passage of bacterial components, metabolites or pathogen-associated molecular patterns (PAMPs) [
93,
94], resulting in the production of pro-inflammatory mediators such as cytokines or chemokines [
95]. This pathophysiological process is involved, for example in patients with type 2 diabetes via imidazole propionate, a microbial metabolite which contributes to insulin resistance [
96]. Other inflammatory states may also be promoted by disturbances in the microbiota. The angiotensin converting enzyme 2 (ACE2) hydrolyses angiotensin II, which participates in pro-inflammatory events such as vascular permeability increase, or recruitment of infiltrating cells into the tissues [
97]. In healthy patients, ACE2 is expressed in the small intestine, and the absence of this expression (e.g., malnutrition, gut injuries during critical illness), leads to an aberrant production of antimicrobial components induces modifications of the colon microbiota, favoring local inflammatory reactions, colitis, and even other organ dysfunctions [
98]. Indeed, animal studies have shown the importance of the mesenteric lymph nodes in the gut-mediated lung injury and neutrophil activation, probably via toll-like receptor 4 stimulation or other pattern recognition receptors activation [
99]. As an example, in the case of SARS-CoV-2 infection, specific modifications of the microbiota are correlated with a pro-inflammatory state: the presence of
Ruminococcus gnavus and
Clostridium spp. were correlated positively and negatively, respectively, with inflammatory markers [
100]. Yeoh et al. [
101] discretely corroborated these observations in finding associations between underrepresented gut bacteria with immunomodulatory properties and high concentrations of blood cytokines and biomarkers in severe patients; however, the small number of critically ill patients and the large proportion of patients who received antibiotics hinder the extrapolation of the results. Through analyses of viral transcriptional activity of fecal samples, those with a signature of high SARS-CoV-2 infectivity had higher abundances of bacteria with enhanced capacity for biosynthesis of nucleotide and amino acid, and carbohydrate metabolism. By contrast, fecal samples with a signature of low infectivity had higher abundances of short-chain fatty acids producing bacteria [
102].
Association with infections and outcome
The prognosis of critically ill patients is determined, among many other things, by the occurrence of healthcare-associated infections, which may occur in up to 25% of critically ill patients during ICU stay, with significant consequences on survival or morbidity [
107]. The rectal carriage of specific cultivable bacteria—especially Enterobacterales or
Enterococcus spp.—detected at ICU admission seems to be associated with a higher rate of subsequent infection with the same micro-organism [
69,
108,
109]. These observations are corroborated by a very recent study in ICU patients, which shows that throat or rectal carriage of extended-spectrum beta-lactamase producing Enterobacterales (ESBL-E) is a risk factor for developing ESBL-E ventilator-associated pneumonia [
110]. Specifically in non-ventilated patients, the modification of oral and oropharyngeal microbiota with presence of
E. coli,
P. aeruginosa or
S. aureus increase the risk of unspecific hospital-acquired pneumonia (HAP) [
111]. Microbiota-associated considerations are also significant: altered fecal diversity is common in ICU patients and may also increase the rate of infections [
86,
112]. First, in animal studies, gut microbiota seems to have a direct protective role against infections, notably pneumonia due to
S. pneumoniae [
113]. In ICU patients, ventilator-associated pneumonia (VAP) constitutes a common nosocomial complication. Gut bacteria seem to play a role in the pathogenesis of these VAP as they can colonize the oropharyngeal microbiota and then the respiratory tract, potentially leading to the development of an infection [
114]. A recent study by Dickson et al. [
115] showed that the gut microbiome influence the respiratory microbiome, and found an increased abundance of
Bacteroides spp., an anaerobic bacteria from the gut in patients developing acute respiratory distress syndrome. Moreover, the most recent studies are beginning to show associations between VAP and the tracheal microbiota; in mechanically ventilated patients, the patients developing VAP seem to present a different microbiota compared to those who did not develop VAP [
116]. As well as infections, altered gut microbiota seems to have an impact on the host’s outcome in critically ill situations. In animal studies, germ-free or antibiotic-treated mice (i.e., in which dysbiosis was induced) seem to be more susceptible to severe colitis [
117]. In ICU patients, the use of SDD has been associated with a better patients’ outcome, notably in ICUs with low prevalence of antibiotic resistance [
66,
67,
118,
119], but these observations have not been confirmed in ICUs with moderate-to-high prevalence of antibiotic resistance and when a parenteral cephalosporin was not associated [
120]. A major study published by Freedberg et al. finally showed that a dominance of
Enterococcus spp. at ICU admission is associated with short-term outcomes [
69]. Recently, our group observed a strong correlation between the diversity of the intestinal microbiota of ICU patients and the relative abundance of
Enterococcus spp., supporting that the quantification of
Enterococcus spp. could be a potential biomarker for dysbiosis in that a high relative abundance seems to be associated with worse outcome [
121]. Moreover, a recent study in patients who received allogeneic hematopoietic cell transplantation showed that the type of diet may influence the dysbiosis severity by modifying among others the abundance of
Enterococcus spp. which causes GVHD [
122].