An increasing number of microorganisms are classified as 'pathobionts' (i.e., organisms that can cause harm under certain circumstances) but there exist no universally used criteria for this ...definition. In particular, the term is often used for categorizing disease-associated taxa without proof of 'causality'. This creates confusion and distracts from explicitly searching for beneficial functions of these organisms that they may in fact have. Here, we discuss why this term in its current use, and its apparent simplicity, may obscure the complexity of microbe–host and microbe–microbe interactions that define (the status of) the gut ecosystem.
Pathobionts can cause or promote disease only when specific genetic or environmental conditions are altered in the host.Conditions under which pathobionts exhibit virulence include impaired host immune defenses and altered microbiota composition.Several microorganisms classified as pathobionts can also exert beneficial functions on their host in different scenarios.Currently the term 'pathobiont' does not comprise a well-defined concept and should therefore be revised. In this opinion article, we suggest an alternative terminology.
Colonization resistance (CR), the ability to block infections by potentially harmful microbes, is a fundamental function of host-associated microbial communities and highly conserved between animals ...and humans. Environmental factors such as antibiotics and diet can disturb microbial community composition and thereby predispose to opportunistic infections. The most prominent is Clostridioides difficile, the causative agent of diarrhea and pseudomembranous colitis. In addition, the risk to succumb to infections with genuine human enteric pathogens like nontyphoidal Salmonella (NTS) is also increased by a low-diverse, diet or antibiotic-disrupted microbiota. Despite extensive microbial community profiling efforts, only a limited set of microorganisms have been causally linked with protection against enteric pathogens. Furthermore, it remains a challenge to predict colonization resistance from complex microbiome signatures due to context-dependent action of microorganisms. In the past decade, the study of NTS infection has led to the description of several fundamental principles of microbiota-host-pathogen interaction. In this review, I will give an overview on the current state of knowledge in this field and outline experimental approaches to gain functional insight to the role of specific microbes, functions and metabolites in Salmonella-microbiota-host interaction. In particular, I will highlight the value of mouse infection models, which, in combination with culture collections, synthetic communities and gnotobiotic models have become essential tools to screen for protective members of the microbiota and establishing causal relationship and mechanisms in infection research.
The healthy human intestine is colonized by as many as 1014 bacteria belonging to more than 500 different species forming a microbial ecosystem of unsurpassed diversity, termed the microbiota. The ...microbiota's various bacterial members engage in a physiological network of cooperation and competition within several layers of complexity. Within the last 10 years, technological progress in the field of next-generation sequencing technologies has tremendously advanced our understanding of the wide variety of physiological and pathological processes that are influenced by the commensal microbiota (1, 2). An increasing number of human disease conditions, such as inflammatory bowel diseases (IBD), type 2 diabetes, obesity, allergies and colorectal cancer are linked with altered microbiota composition (3). Moreover, a clearer picture is emerging of the composition of the human microbiota in healthy individuals, its variability over time and between different persons and how the microbiota is shaped by environmental factors (i.e., diet) and the host's genetic background (4). A general feature of a normal, healthy gut microbiota can generate conditions in the gut that disfavor colonization of enteric pathogens. This is termed colonization-resistance (CR). Upon disturbance of the microbiota, CR can be transiently disrupted, and pathogens can gain the opportunity to grow to high levels. This disruption can be caused by exposure to antibiotics (5, 6), changes in diet (7, 8), application of probiotics and drugs (9), and a variety of diseases (3). Breakdown of CR can boost colonization by intrinsic pathogens or increase susceptibility to infections (10). One consequence of pathogen expansion is the triggering of inflammatory host responses and pathogen-mediated disease. Interestingly, human enteric pathogens are part of a small group of bacterial families that belong to the Proteobacteria: the Enterobacteriaceae (E. coli, Yersinia spp., Salmonella spp., Shigella spp.), the Vibrionaceae (Vibrio cholerae) and the Campylobacteriaceae (Campylobacter spp.). In general, members of these families (be it commensals or pathogens) only constitute a minority of the intestinal microbiota. However, proteobacterial "blooms" are a characteristic trait of an abnormal microbiota such as in the course of antibiotic therapy, dietary changes or inflammation (11). It has become clear that the gut microbiota not only plays a major role in priming and regulating mucosal and systemic immunity, but that the immune system also contributes to host control over microbiota composition. These two ways of mutual communication between the microbiota and the immune system were coined as "outside-in" and "inside-out," respectively (12). The significance of those interactions for human health is particularly evident in Crohn's disease (CD) and Ulcerative Colitis (UC). The symptoms of these recurrent, chronic types of gut inflammation are caused by an excessive immune response against one's own commensal microbiota (13). It is assumed that deregulated immune responses can be caused by a genetic predisposition, leading to, for example, the impairment of intestinal barrier function or disruption of mucosal T-cell homeostasis. In CD or UC patients, an abnormally composed microbiota, referred to as "dysbiosis," is commonly observed (discussed later). This is often characterized by an increased relative abundance of facultative anaerobic bacteria (e.g., Enterobacteriaeceae, Bacilli) and, at the same time, depletion of obligate anaerobic bacteria of the classes Bacteroidia and Clostridia. So far, it is unclear whether dysbiosis is a cause or a consequence of inflammatory bowel disease (IBD). In fact, both scenarios are equally conceivable. Recent work suggests that inflammatory immune responses in the gut (both IBD and pathogen-induced) can alter the gut luminal milieu in a way that favors dysbiosis (14). In this chapter, I present a survey on our current state of understanding of the characteristics and mechanisms underlying gut inflammation-associated dysbiosis. The role of dysbiosis in enteric infections and human IBD is discussed. In addition, I will focus on competition of enteric pathogens and the gut microbiota in the inflamed gut and the role of dysbiotic microbiota alterations (e.g., "Enterobacterial blooms" (11)) for the evolution of pathogenicity.
Hundreds of bacterial species make up the mammalian intestinal microbiota. Following perturbations by antibiotics, diet, immune deficiency or infection, this ecosystem can shift to a state of ...dysbiosis. This can involve overgrowth (blooming) of otherwise under-represented or potentially harmful bacteria (for example, pathobionts). Here, we present evidence suggesting that dysbiosis fuels horizontal gene transfer between members of this ecosystem, facilitating the transfer of virulence and antibiotic resistance genes and thereby promoting pathogen evolution.
Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with systemic inflammation and acquired immunodeficiency, which promote cardiovascular disease, body wasting, and ...infections as leading causes of death. This phenomenon persists despite dialysis-related triggers of immune deregulation having been largely eliminated. Here we propose a potential immunoregulatory role of the intestinal microbiota in CKD/ESRD. We discuss how the metabolic alterations of uremia favor pathogen overgrowth (dysbiosis) in the gut and an increased translocation of living bacteria and bacterial components. This process has the potential to activate innate immunity and systemic inflammation. Persistent innate immune activation involves the induction of immunoregulatory mediators that suppress innate and adaptive immunity, similar to the concept of ‘endotoxin tolerance’ or ‘immune paralysis’ in advanced sepsis or chronic infections. Renal science has largely neglected the gut as a source of triggers for CKD/ESRD-related immune derangements and complications and lags behind on the evolving microbiota research. Interdisciplinary research activities at all levels are needed to unravel the pathogenic role of the intestinal microbiota in kidney disease and to evaluate if therapeutic interventions that manipulate the microbiota, such as pre- or probiotics, have a therapeutic potential to correct CKD/ESRD-related immune deregulation and to prevent the associated complications.
The intestinal microbiota can protect efficiently against colonization by many enteric pathogens (‘colonization resistance’, CR). This phenomenon has been known for decades, but the mechanistic basis ...of CR is incompletely defined. At least three mechanisms seem to contribute, that is direct inhibition of pathogen growth by microbiota-derived substances, nutrient depletion by microbiota growth and microbiota-induced stimulation of innate and adaptive immune responses. In spite of CR, intestinal infections are well known to occur. In these cases, the multi-faceted interactions between the microbiota, the host and the pathogen are shifted in favor of the pathogen. We are discussing recent progress in deciphering the underlying molecular mechanisms in health and disease.
Microbial communities that colonize the human gastrointestinal (GI) tract defend against pathogens through a mechanism known as colonization resistance (CR). Advances in technologies such as ...next-generation sequencing, gnotobiotic mouse models, and bacterial cultivation have enhanced our understanding of the underlying mechanisms and the intricate microbial interactions involved in CR. Rather than being attributed to specific microbial clades, CR is now understood to arise from a dynamic interplay between microbes and the host and is shaped by metabolic, immune, and environmental factors. This evolving perspective underscores the significance of contextual factors, encompassing microbiome composition and host conditions, in determining CR. This review highlights recent research that has shifted its focus toward elucidating how these factors interact to either promote or impede enteric infections. It further discusses future research directions to unravel the complex relationship between host, microbiota, and environmental determinants in safeguarding against GI infections to promote human health.
Intestinal symbiont communities play a crucial role in providing colonization resistance against enteric pathogens. The dynamic interplay between microbes and their host gives rise to protection, influenced by metabolic, immune, and environmental factors. Recent research discussed by Woelfel et al. emphasizes how these contextual factors promote or hinder enteric infections.
Trillions of bacteria inhabit the mammalian gastrointestinal tract. In the majority of hosts, these symbionts contribute largely to beneficial functions promoting microbe-host homeostasis. However, ...an increasing number of human diseases is associated with altered microbiota composition and enrichment of certain bacterial species. A well-known example of this is
Mucispirillum schaedleri
, which has been associated with inflammatory conditions in the intestine.
Mucispirillum
spp. belong to the phylum Deferribacteres and are prevalent but low abundant members of the rodent, pig and human microbiota. Recently,
M. schaedleri
was causally linked to the development of Crohn’s disease—like colitis in immunodeficient mice. While this study certifies a considerable pathogenic potential, the same organism can also promote health in the immunocompetent host:
M. schaedleri
protects from
Salmonella enterica
serovar Typhimurium (
S.
Tm)-induced colitis by interfering with the expression of the pathogen´s invasion machinery. In this review, we summarize the current knowledge on the mammalian gut symbiont
M. schaedleri
and its role in intestinal homeostasis and discuss open questions and perspectives for future research.
Acute brain ischemia induces a local neuroinflammatory reaction and alters peripheral immune homeostasis at the same time. Recent evidence has suggested a key role of the gut microbiota in autoimmune ...diseases by modulating immune homeostasis. Therefore, we investigated the mechanistic link among acute brain ischemia, microbiota alterations, and the immune response after brain injury. Using two distinct models of acute middle cerebral artery occlusion, we show by next-generation sequencing that large stroke lesions cause gut microbiota dysbiosis, which in turn affects stroke outcome via immune-mediated mechanisms. Reduced species diversity and bacterial overgrowth of bacteroidetes were identified as hallmarks of poststroke dysbiosis, which was associated with intestinal barrier dysfunction and reduced intestinal motility as determined by in vivo intestinal bolus tracking. Recolonizing germ-free mice with dysbiotic poststroke microbiota exacerbates lesion volume and functional deficits after experimental stroke compared with the recolonization with a normal control microbiota. In addition, recolonization of mice with a dysbiotic microbiome induces a proinflammatory T-cell polarization in the intestinal immune compartment and in the ischemic brain. Using in vivo cell-tracking studies, we demonstrate the migration of intestinal lymphocytes to the ischemic brain. Therapeutic transplantation of fecal microbiota normalizes brain lesion-induced dysbiosis and improves stroke outcome. These results support a novel mechanism in which the gut microbiome is a target of stroke-induced systemic alterations and an effector with substantial impact on stroke outcome.
We have identified a bidirectional communication along the brain-gut microbiota-immune axis and show that the gut microbiota is a central regulator of immune homeostasis. Acute brain lesions induced dysbiosis of the microbiome and, in turn, changes in the gut microbiota affected neuroinflammatory and functional outcome after brain injury. The microbiota impact on immunity and stroke outcome was transmissible by microbiota transplantation. Our findings support an emerging concept in which the gut microbiota is a key regulator in priming the neuroinflammatory response to brain injury. These findings highlight the key role of microbiota as a potential therapeutic target to protect brain function after injury.
Gut microbial communities protect the host against a variety of major human gastrointestinal pathogens. Bacteriophages (phages) are ubiquitous in nature and frequently ingested via food and drinking ...water. Moreover, they are an attractive tool for microbiome engineering due to the lack of known serious adverse effects on the host. However, the functional role of phages within the gastrointestinal microbiome remain poorly understood. Here, we investigated the effects of microbiota-directed phages on infection with the human enteric pathogen
Salmonella enterica
serovar Typhimurium (
S
. Tm), using a gnotobiotic mouse model (OMM
14
) for colonization resistance (CR). We show, that phage cocktails targeting
Escherichia coli
and
Enterococcus faecalis
acted in a strain-specific manner. They transiently reduced the population density of their respective target before establishing coexistence for up to 9 days. Infection susceptibility to
S
. Tm was markedly increased at an early time point after challenge with both phage cocktails. Surprisingly, OMM
14
mice were also susceptible 7 days after a single phage inoculation, when the targeted bacterial populations were back to pre-phage administration density. Concluding, our work shows that phages that dynamically modulate the density of protective members of the gut microbiota can provide opportunities for invasion of bacterial pathogens, in particular at early time points after phage application. This suggests, that phages targeting protective members of the microbiota may increase the risk for
Salmonella
infection.
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