Patients prescribed antibiotics in hospital are more likely to get fungal infections because of disruption to the immune system in the gut, according to a new study from the University of Birmingham and National Institutes of Health.
Using immune-boosting drugs alongside the antibiotics could reduce the health risks from these complex infections say the researchers.
The life-threatening fungal infection invasive candidiasis is a major complication for hospitalized patients who are given antibiotics to prevent sepsis and other bacterial infections that spread quickly around hospitals (such as C. diff). Fungal infections can be more difficult to treat than bacterial infections, but the underlying factors causing these infections are not well understood.
A team in the University’s Institute of Immunology and Immunotherapy, in conjunction with researchers at the National Institutes of Health, discovered that antibiotics disrupt the immune system in the intestines, meaning that fungal infections were poorly controlled in that area. Unexpectedly, the team also found that where fungal infections developed, gut bacteria were also able to escape, leading to the additional risk of bacterial infection.
The study, published in Cell Host and Microbe, demonstrates the potential for immune-boosting drugs, but the researchers also say their work also highlights how antibiotics can have additional effects on our bodies that affect how we fight infection and disease. This in turn underscores the importance of careful stewardship of available antibiotics.
Lead author Dr. Rebecca Drummond said: “We knew that antibiotics make fungal infections worse, but the discovery that bacterial co-infections can also develop through these interactions in the gut was surprising. These factors can add up to a complicated clinical situation—and by understanding these underlying causes, doctors will be better able to treat these patients effectively.”
In the study, the team used mice treated with a broad-spectrum antibiotic cocktail and then infected these animals with Candida albicans, the most common fungus that causes invasive candidiasis in humans. They found that although infected mice had increased mortality, this was caused by infection in the intestine, rather than in the kidneys or other organs.
In a further step, the team pinpointed what parts of the immune system were missing from the gut after antibiotic treatment, and then added these back into the mice using immune-boosting drugs similar to those used in humans. They found this approach helped reduce the severity of the fungal infection.
The researchers followed up the experiment by studying hospital records, where they were able to show that similar co-infections might occur in humans after they have been treated with antibiotics.
“If we limit or change how we prescribe antibiotics we can help reduce the number of people who become very ill from these additional infections – as well as tackling the huge and growing problem of antibiotic resistance.”
Human Gut Microbiota
Microbiota is defined as the assemblage of microorganisms present in a particular environment, while the term “microbiome” refers to the entire habitat, including the microorganisms (bacteria, archaea, lower and higher eurkaryotes, and viruses), their genomes and the environmental conditions that obtain in that habitat (Marchesi and Ravel, 2015). Bacteria, archaea, eukaryotes (fungi and protists), and viruses that inhabit the gastrointestinal tract of humans are collectively referred to as the human gut microbiota.
The genome of a single symbiotic microbial species is likely to be insufficient for survival (Guarner, 2015). As a result, multispecies communities organized around a complex network of metabolic interdependencies, such as those found in the human gut, represent the natural environment for most symbiotic microbes (Guarner, 2015).
The development of culture-independent research methods that combine genetic sequencing with bioinformatics has led to rapid advances in the study of the human gut microbiota (Guarner, 2015). One of the most common methods used for taxonomic identification and assessment of species diversity of prokaryotes (Bacteria and Archaea) is sequencing of the gene that encodes the small subunit of ribosomal RNA (16S rRNA) (Guarner, 2015). Of the 55 phyla that comprise the domain Bacteria, only seven to nine are found in the human gut, with the majority (90%) belonging to the Bacteroidetes and Firmicutes phyla (Eckburg et al., 2005). Other phyla consistently identified in the human gut include Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia, while very few Archaea species have been detected (Eckburg et al., 2005).
Another culture-independent research method is whole genome sequencing, which yields an inventory of all the genes present in a sample. Whole genome sequencing also allows the analysis of the functional and metabolic networks, as well as the detection of genes that belong to non-bacterial members of the microbial community, such as viruses, yeasts, and protists. In total, approximately 10 million non-redundant microbial genes have been identified in human fecal samples (Li et al., 2014). On average, 600,000 non-redundant microbial genes are present in the gastrointestinal tract of a human, of which 300,000 genes are shared by people living in Europe, North America, and China (Li et al., 2014).
There are differences between the microbial communities inhabiting the lumen and mucosa within the same individual (Eckburg et al., 2005; Donaldson et al., 2016). Furthermore, bacterial species found in the lumen vary from the cecum to the rectum. In the cecum, slow transit time and lack of simple sugars promote the proliferation of fermentative polysaccharide-degrading anaerobes, notably Prevotella, Roseburia, Faecalibacterium, Lachnospira, and Eubacterium. In distal sections of the colon, mucolytic and proteolytic species are common (e.g., Bacteroides, Ruminococcus, Akkermansia, Bifidobacterium, Methanobrevibacter, Desulfovibrio, Proteus, and Escherichia). Mucosa-associated bacteria from the terminal ileum to the rectum tend to be more stable at the phylum and genus level, but patches of heterogeneity within the same intestinal area have been described (Donaldson et al., 2016).
Most strains that comprise the gut microbiota are resident for decades, although their relative abundance varies over time in a given individual (Donaldson et al., 2016). However, longitudinal studies show that factors such as diet, drug intake, lifestyle (smoking, travelling, physical activity), co-morbidities, or colonic transit time have an impact on the microbial composition of fecal samples obtained from a unique host (Gilbert et al., 2018; Allaband et al., 2019; Zmora et al., 2019). Although intra-individual changes in gut microbiota composition can be significant, for example, due to an episode of acute infectious diarrhea or after antibiotic treatment, over time it tends to return to its pre-disturbance state, a quality known as resilience (Gilbert et al., 2018; Allaband et al., 2019). The diversity of gut microbiota also changes with age, increasing from infancy to adulthood and decreasing in the elderly. Gut microbial changes in elderly individuals correlate with measures of frailty, nutritional status, and markers of inflammation, suggesting that diet-driven microbiota alterations play a role in the varying rates of age-associated health decline (Kuipers, 2019).
The gut microbiota of each individual person contains many unique strains not found in other individuals, and inter-individual differences in microbiota composition are much larger than intra-individual variations (Allaband et al., 2019). Sex, ethnicity and geographic location affect the taxonomic composition of the microbiome (Gaulke and Sharpton, 2018). For example, the fecal microbiota of adults from the metropolitan areas of Europe and North America is less diverse compared with adults from rural populations in Africa and South America (Clemente et al., 2015; Sonnenburg and Sonnenburg, 2019).
Despite intra- and inter-individual differences, an analysis of the microbial composition of fecal samples from American, European, and Japanese individuals showed similarities in the structure of gut microbiota at the genus level (Arumugam et al., 2011). Multidimensional scaling and principal coordinates analysis revealed the existence of three clusters, or enterotypes, each of which was characterized by the predominance of one genus: Bacteroides (enterotype 1), Prevotella (enterotype 2), or Ruminococcus (enterotype 3). Clustering was not driven by age, sex, nationality, or body mass index (Arumugam et al., 2011). The results of this study indicate that there are a limited number of well-balanced, host-microbiota symbiotic states. In addition, the discrete nature of these states suggests that the structure of the human gut microbiota is primarily determined by interactions between various bacterial genera (Guarner, 2015).
The clinical implications of enterotypes have been the subject of several studies (Costea et al., 2018). The Bacteroides enterotype has been associated with decreased microbial genetic diversity, insulin resistance, and the risk of obesity and non-alcoholic steatohepatitis (Le Chatelier et al., 2013; Costea et al., 2018). Perhaps unsurprisingly, long-term dietary patterns may be one of the factors that determine the enterotype (Wu et al., 2011). Diets rich in animal protein and fat are associated with the Bacteroides enterotype, while diets characterized by the predominance of plant carbohydrates are associated with the Prevotella enterotype (Wu et al., 2011).
Functions of human gut microbiota.
The metabolic function involves the fermentation of non-digestible dietary substrates and recovery of energy and nutrients. In humans, digestion of vegetables, fruits, nuts, and wholegrain cereals is mostly performed by gut microbes since our enzymatic resources for the digestion of carbohydrates are limited to amylases and disaccharidases. In addition, fermentation of complex carbohydrates in the colon produces short-chain fatty acids that are absorbed by the host (Litvak et al., 2018). Butyrate produced by Faecalibacterium prausnitzii and others inhibits interleukin-17, generates regulatory T cells and has anti-inflammatory effects in experimental models (Litvak et al., 2018). Colonic microorganisms also break down xenobiotics and other foreign compounds, contribute to amino acid and vitamin synthesis, and provide a variety of nutrients in individuals on monotonous diets (Zmora et al., 2019).
The gut microbiota performs a defensive function by competing for attachment sites and nutrients with indigenous fungi or bacteria with pathogenic potential, such as Candida and Clostridioides difficile, thereby preventing invasion or overgrowth of these organisms (McFarland, 2008). Resident microorganisms also inhibit the growth of their competitors by producing bacteriocins (McFarland, 2008).
The trophic function of gut microbiota includes promotion of epithelial cell proliferation and differentiation, stimulation of intestinal motor activity and neuro-endocrine pathways of gut origin, and regulation of the immune system and the central nervous system (Mayer et al., 2015).
Induction and regulation of the adaptive immune system is one of the major aspects of the trophic function of the gut microbiota. The large surface area of the gastrointestinal tract is constantly exposed to a variety of antigens. As a result, intestinal immunity is the largest and most complex part of the overall immune system, with at least 80% of all antibodies produced in adults originating in the intestinal mucosa (Brandtzaeg, 2010). The intestinal immune system must be able to discriminate between pathogens and antigens derived from food or from commensal non-pathogenic microbes, because an inflammatory reaction to a foreign antigen can also harm the host (Tanoue et al., 2016). The gut microbiota affects the development of the adaptive immune system by stimulating the growth of lymphoid structures, T- and B-cell differentiation and the establishment of immune tolerance (Zhao and Elson, 2018).
Perturbation of the Gut Microbiota
The term dysbiosis refers to a persistent perturbation of the gut microbiota, and has been defined as an alteration in both the composition and function of the microbiota caused by host-related and environmental factors that overwhelms the resistance and resilience capabilities of the microbial ecosystem (Levy et al., 2017). Alterations in gut microbiota may be implicated in the pathogenesis of several non-communicable diseases and in the transition of these conditions to chronicity. Numerous studies have shown links between changes in the composition of the gut microbiota and diseases, including recurrent diarrhea associated with C. difficile, some bowel disorders (including IBD), colorectal cancer, non-alcoholic steatohepatitis, type 2 diabetes, obesity, and advanced chronic liver disease (Duvallet et al., 2017; Wirbel et al., 2019). However, for some of these examples, the studies are inconsistent, possibly because the methodology has not been standardized. Furthermore, rather than necessarily indicating a causative role in the pathogenesis of a disease, these associated microbiota changes could be a consequence of the disease itself. Thus, follow-up cohort studies are needed, particularly studies of interventions that may restore the composition of gut microbiota.
Nevertheless, studies in rodents have shown that it is possible to use fecal transplants to transfer certain disease phenotypes, including insulin resistance, obesity, anxiety, and intestinal inflammation. This suggests that some gut microbiota changes may have a causative role in those diseases. In humans, fecal microbiota transplantation has a well-established role in the treatment of recurrent diarrhea caused by C. difficile infection (CDI) (Cammarota et al., 2017). Fecal transplant has become standard therapy for this condition as recommended by national guidelines (Mullish et al., 2018). Less successful results have been observed with attempts to treat IBD. There are four randomized trials that evaluated fecal transplant as induction therapy for achieving remission in active ulcerative colitis, and these collectively show statistical improvement compared with control. At 8 weeks, 37% of participants in the stool transplant group were in remission compared with 18% of participants in the control group (Imdad et al., 2018). Additional studies are needed to further define transplant material rich in microbial populations identified as missing in the patient, and avoiding transplants rich in aggressive, over-represented microbes.
A loss of species diversity seems to be a common feature of a disturbed gut microbiota. Low microbial richness is associated with an overabundance of pro- versus anti-inflammatory microbial species, and this may lead to intestinal inflammation and disrupted function of the mucosal barrier. In a study that used the number of microbial genes in fecal samples as a proxy for diversity, individuals with low gene counts were more likely to have insulin or leptin resistance, adiposity, or dyslipidemia, and a more marked inflammatory phenotype, compared with those with high gene counts (Le Chatelier et al., 2013). This association might indicate that low microbial richness increases an individual’s risk of developing metabolic syndrome (i.e., obesity, arterial hypertension, type 2 diabetes, dyslipidemia, and non-alcoholic steatohepatitis).
In terms of the functional capacity of the gut microbiota, a low microbial gene count appears to be associated with a reduced production of short-chain fatty acids (particularly butyrate) for the host (Le Chatelier et al., 2013). Failure to produce butyrate increases the flow of oxygen towards the mucosa and perturbs the micro-ecosystem in a way that favors the survival of oxygen-resistant bacteria and precludes recovery of strict anaerobes (Litvak et al., 2018). In this way, dysbiosis has been described as disruption of the symbiotic balance between microbiota and host. Such changes critically affect the resilience capacity of the ecosystem and increase the likelihood that the imbalance will become chronic.Go to:
Effects of Antibiotics on Gut Microbiota
Antibiotic treatment reduces the overall diversity of gut microbiota species, including loss of some important taxa, which causes metabolic shifts, increases gut susceptibility to colonization, and stimulates the development of bacterial antibiotic resistance (Lange et al., 2016).
Antibiotic use is associated with reduced microbiota diversity. In children, restoration of microbial diversity following antibiotic treatment has been reported to take approximately 1 month (Yassour et al., 2016). In adults, administration of a combination of meropenem, gentamicin, and vancomycin resulted in an increase in the prevalence of Enterobacteriaceae and other pathobionts, and a decrease in Bifidobacterium and butyrate-producing species (Palleja et al., 2018) (Figure 2). While the baseline composition of the gut microbiota was mostly restored within 1.5 months, several common species remained undetectable for the rest of the observation period (180 days) (Palleja et al., 2018).
Four-day antibiotic treatment induced large shifts in bacterial abundances. Graphs show relative abundance of representative species according to their pattern of change after four-day antibiotic treatment over a 180-day follow-up period. Adapted from Palleja et al. (2018).
Antibiotics can also disrupt the balance that normally exists between the various species of gut microbiota. For instance, by causing a decrease in species diversity, antibiotics can lead to the overgrowth of pathobionts, such as toxigenic C. difficile (Ianiro et al., 2020).
It should be noted that reduced diversity does not necessarily mean a reduced number of bacteria overall. As the antibiotic-susceptible bacteria are eliminated, antibiotic-resistant bacteria multiply and take their place. In fact, the total microbial load may increase after antibiotic treatment, even though species diversity is reduced. In a study of patients treated with broad-spectrum antibiotics, treatment with β-lactams over the course of 7 days increased the microbial load in fecal samples two-fold (Panda et al., 2014). In this study, broad-spectrum antibiotic use also increased the ratio of Bacteroidetes to Firmicutes (Panda et al., 2014).
The complete set of small molecules (<1500 Da) found in a biological system is referred to as the metabolome of that system (Lamichhane et al., 2018). The effects of antibiotics on the gut metabolome are less well studied than their effects on gut microbial diversity. One factor that makes research into this connection more complex is metabolomic redundancy. Despite these challenges, some of the effects of antibiotics on the gut metabolome in mice have been described (Cho et al., 2012; Choo et al., 2017). In a study in young mice, low-dose antibiotics led to increased adiposity and elevated hormones associated with the metabolism of carbohydrates, lipids and cholesterol (Cho et al., 2012). In another study, vancomycin-imipenem administration resulted in increased levels of arabinitol and sugars (e.g. sucrose) in feces (Choo et al., 2017). Elevated levels of these compounds have been associated with an increased susceptibility to CDI, potentially by serving as a growth substrate. Vancomycin/imipenem also reduced the relative abundance of Lachnospiraceae and Ruminococcaceae bacteria that normally convert arabinitol to pentose sugars. Immediately after the cessation of vancomycin/imipenem, a small but significant reduction in the level of arginine was observed that correlated with increased prevalence of Escherichia and Shigella species and reduced prevalence of Ruminococcaceae and Bacteroides. An increase in arginine observed 9 days after the end of vancomycin/imipenem was correlated with increased prevalence of organisms from the Enterobacter genus and reduced prevalence of Alistipes. Arginine serves as a precursor for a number of immunomodulatory compounds (Choo et al., 2017).
Antibiotic exposure produces changes in the gut metabolome that may or may not correlate with changes in the microbiome. In patients with metabolic syndrome, oral administration of vancomycin decreased fecal secondary bile acids, with a simultaneous postprandial increase in primary bile acids in plasma. Concomitantly, vancomycin affected host physiology by decreasing peripheral insulin sensitivity (Vrieze et al., 2014). Antibiotic-induced changes in bile acid metabolism may affect host physiology and susceptibility to infection.
Antibiotic resistance is defined as the capacity of a species of bacteria to survive antibiotic concentrations that inhibit or kill other bacteria of the same species (Sabtu et al., 2015). It first evolved in antibiotic-producing bacteria as a way to defend against their own products and compete with other microbes (Rolain, 2013). Worldwide, antibiotic resistance has emerged as a significant public health concern. Between 2000 and 2015, global antibiotic consumption increased by 65% (Klein et al., 2018), with amoxicillin and amoxicillin/clavulanic acid being the most commonly used antibiotics (World Health Organization, 2018). Between 2000 and 2015, the greatest increases in antibiotic use were observed in developing countries and the gap between developing and developed countries decreased. Antibiotic resistance is responsible for an estimated 35,000 deaths in the US and 25,000 deaths in Europe each year (European Medicines Agency and European Centre for Disease Prevention and Control, 2009; Centers for Disease Control and Prevention, 2019). According to one estimate, by 2050 the number of deaths per year caused by antibiotic resistance will be 317,000 in North America, 390,000 in Europe, 392,000 in Latin America, 4,150,000 in Africa, and 4,730,000 in Asia (Sugden et al., 2016). The World Health Organization estimates that the number of antibiotic resistance-related deaths could reach 10 million by 2050 (World Health Organization, 2019). In China, resistance has increased dramatically due to large-scale antibiotic use in livestock (Van Boeckel et al., 2015). Inappropriate use of antibiotics, facilitated by their availability over the counter and on the internet, is the primary driver of antibiotic resistance (Sabtu et al., 2015). The increased prevalence of antibiotic-resistant bacteria results in infections that are difficult and expensive to treat. As older antibiotics lose effectiveness due to resistance, newer antibiotics must be used. However, these drugs are more expensive and may not be available to many of those who need them, particularly in countries with a high burden of infectious diseases (Klein et al., 2018).
Bacteria have developed a range of processes to elude the effects of antibiotics, including protection against the uptake of antibiotics through their cell membranes, developing enzymatic processes that modify or degrade the antibiotic, altering the molecules that antibiotics target, and actively removing antibiotics from the cell via specialized efflux proteins (Giedraitiene et al., 2011). Bacterial enzymes that are able to neutralize antibiotics include β-lactamases, aminoglycoside-modifying enzymes, and chloramphenicol acetyltransferases (Giedraitiene et al., 2011). Bacteria are also able to mutate the molecular targets of antibiotics, interfering with the highly specific interaction between the antibiotic and its target molecule through small structural modifications. For example, mutations in penicillin-binding proteins reduce the efficacy of β-lactams, mutations in 23S rRNA confer resistance to macrolides, lincosamides and streptogramin B, and mutations in DNA topoisomerase II and IV lead to resistance to quinolones and fluoroquinolones (Giedraitiene et al., 2011). Bacteria can eliminate antimicrobial agents by pumping them out via efflux proteins located in the bacterial cell membrane. Although these proteins can be antibiotic-specific, most are multidrug transporters. Another mechanism of resistance is reduced outer membrane permeability, which results in a decreased uptake of antibiotics (Giedraitiene et al., 2011).
In humans, the gut microbiota contains a pool of antibiotic resistance genes. Antibiotic treatment rapidly increases the pool of resistance genes present in the gut, which slowly declines after treatment is discontinued (Rolain, 2013). Antibiotic-resistant gut bacteria can be transferred to a newborn from his/her mother at birth and thereafter may persist for weeks. In a Swedish study, tetracycline resistance was detected in 12% of commensal E. coli strains from infants who had not received tetracycline (Karami et al., 2006).
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732679/
More information: Long-term Antibiotics Promote Mortality After Systemic Fungal Infection by Driving Lymphocyte Dysfunction and Systemic Escape of Commensal Bacteria, Cell Host & Microbe (2022).