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Microbiome therapeutic PMC101 inhibits the translocation of carbapenem-resistant Klebsiella while enhancing eubiosis in antibiotic-induced dysbiosis mice.

Carbapenem-resistant Enterobacteriaceae (CRE), known for their extensive antibiotic resistance, pose a severe global medical threat. Therefore, developing novel therapeutics beyond conventional antibiotics is urgently needed, and the importance of microbiome therapeutics is increasingly being recognized. This study explores the expanded systemic efficacy of PMC101, a microbiome therapeutic, beyond intestinal CRE infections and investigates its mechanism of action from a microbiome perspective. First, the genetic characteristics of the novel strain were identified through whole-genome analysis, and a scalable cultivation process was established as part of the overall development of this microbiome therapeutic. PMC101 increased the survival rate to 100%, significantly reduced disease severity scores, and prevented weight loss in CRE-infected mice treated with antibiotics. These effects are attributed to the inhibition of CRE growth in stool and the reduced detection of CRE in the lungs and kidneys, indicating suppression of systemic translocation. Metagenomic analysis revealed that PMC101 prevented the reduction in microbial population caused by antibiotics and CRE infection, restored species diversity indices, and mitigated dysbiosis while promoting eubiosis. This CRE translocation suppression was closely associated with increased CRE translocation-microbiome index, defined as the ratio of Bacteroidetes to Proteobacteria. This relationship was further confirmed through simulations using a human intestinal microbial ecosystem model. Additionally, increases in short-chain fatty acids, reductions in excessive inflammatory responses, and decreases in tissue damage were observed, all of which contribute to preventing CRE translocation. Finally, pathogen inhibition effects and safety tests were conducted, confirming the prophylactic potential of PMC101 as a microbiome therapeutic. These findings strongly support PMC101 as a promising candidate for future microbiome-based therapies against CRE infections.

Animals

[Treatment of neonatal infections: the place of cephalosporins].

The most commonly used antibiotic combination as a first-line treatment in neonates is ampicillin and an aminoglycoside. The increasing resistance of E. coli to ampicillin requires another choice. Good activity against group B Streptococci and E. coli, good CSF penetration and fewer side-effects are in favour of third generation cephalosporins as part of the antibiotic therapy. If a Listeria infection has not been excluded at the beginning of treatment, a triple combination may be given: ampicillin + third generation cephalosporin + aminoglycoside during the first 48 hours. The prognosis of enterobacterial meningitis has improved with third generation cephalosporins. As the other beta-lactam antibiotics, they modify the intestinal microbial ecosystem.

Bacterial Infections

Role of human microflora in health and disease.

The human host and its microbial flora constitute a complex ecosystem whose equilibrium serves as a remarkable example of reciprocal adaptation. Intestinal bacteria play an important role in the development of the immune system. The normal intestinal flora is responsible for resistance to colonization by exogenous pathogenic microorganisms. Nevertheless, it also constitutes a reservoir of potentially pathogenic bacteria in close contact with the host. These bacteria are responsible for opportunistic infections in immunocompromised hosts. The equilibrium of the flora can be upset by antibiotics, leading to infections as a result of proliferation of antibiotic-resistant pathogenic bacteria.

Animals

Bacterial overgrowth.

Small bowel bacterial overgrowth is a syndrome manifested by malabsorption, weight loss, and diarrhea. Human intestinal flora is part of a complex ecosystem regulated by host mechanisms, environmental factors, and bacterial interactions. Numerous conditions can tilt this balance to favor bacterial contamination of the gut. Knowledge of intestinal microbial control enables the clinician to better understand the pathophysiology and the clinical features of this disorder. Current strategies in diagnosis and therapy are discussed.

Bacteria

Microbially controlled drug delivery to the colon.

The human gastrointestinal tract consists of a highly complex ecosystem of aerobic and anaerobic microorganisms that plays a significant role in the metabolism of nutrients as well as drugs. In the colon, bacteria ferment various types of substrates that are not susceptible to digestion in the small intestine. This arouses interest in specific drugs, drug delivery systems, and prodrugs that escape small bowel digestion, arrive intact, and are absorbed or degraded in the large bowel. For the past forty years, experience has been gained with the azo prodrug of 5-amino salicylic acid, salazopyrine, which is cleaved by colonic bacteria to its parent drug. Some laxative drugs were also reported to degrade into active metabolites in the colon. Lately equally interesting and more sophisticated microbial controlled delivery systems, have been developed based on similar principles.

Animals

The role of mobile genetic elements in adaptation of the microbiota to the dynamic human gut ecosystem.

The human intestinal microbiota is a dynamic ecosystem shaped by extensive horizontal gene transfer, particularly in individuals from industrialized populations. In this review, we discuss recent advances in our understanding of how mobile genetic elements (MGEs) contribute to microbial ecology and evolution in this diverse community, focusing on MGEs carrying fitness-conferring genes. Bacteroidales species can colonize individuals for decades and serve as major hubs for MGE exchange. Most MGEs are highly variable across individuals and geographies. Occasionally, conserved MGEs can spread across geography and lifestyles. Functional characterizations of MGEs reveal their roles in antibiotic resistance, interbacterial antagonism, biofilm formation, immune evasion, and nutrient acquisition, among others. Substantive progress in our understanding of MGEs in the gut microbiome offers promising avenues for therapeutic microbiome interventions. However, major challenges remain in functional prediction, host-MGE linkage, and experimental characterization.

Humans

[Effects of nifuroxazide on fecal flora in healthy subjects].

Effect of nifuroxazide on fecal flora was studied in 12 healthy volunteers receiving, in hazardous order and double-blind procedure, three six-days courses of treatment separated by eight-days spaces of time: the conventional dosage of 400 mg twice a day, a dosage of 1200 mg once a day, and placebo. Among six settled bacteriological index (wealth of the fecal flora, percentage of gram-negative bacteria, numbers of E. coli, Enterococcus, Clostridium and Bacteroides), no significant variation was found by means of statistical study between D0, D2 and D7, nor between the three courses of treatment. Therefore nifuroxazide, even in high dosage, does not injure integrity of microbial intestinal ecosystem under so defined experimental conditions, similar with clinical conditions.

Adult

Escherichia coli serotypes throughout the gastrointestinal tract of patients with intestinal disorders.

The O and H serotypes of Escherichia coli that were present along the entire length of the gastrointestinal tract of patients with small intestinal bacterial overgrowth were studied. Multiple sero- and biotypes were represented, although usually a single serotype predominated in each patient. In a number of cases the different O:H serotypes were antigenically related indicating that antigenic degradation was occurring. The serotypes isolated from the stomach and small intestine were represented in the faeces. In general, within the limitations of this study, there appears to be a stable ecosystem in each patient and it may require specific oral antibiotics to alter it.

Adult

Lactic acid bacteria in the gut in normal and disordered states.

The human gut flora is a complex and finely balanced ecosystem which plays an important protective role in humans. Although relatively stable, its composition may be altered in various disease states and by the administration of antimicrobial agents. Preparations containing viable lactic acid bacteria of human origin appear to have value in restoring normal microbial function and alleviating symptoms in some patients with gastrointestinal infection and other conditions.

Animals

[Bacterial ecology of the digestive tract and defense of the body].

The indigenous microflora of the upper digestive tract is poorly developed and consists of microorganisms in transit, originating in the oro-pharynx. Aerobic bacteria, mainly streptococci, predominate. In the normohydrochloric stomach, the mean fasting bacterial concentration is 10(3)-10(4)/ml gastric juice. In the small intestine, levels of up to 10(5) bacteria/ml contents are reached. The essential mechanism which maintains this relative sterility of the upper digestive tract is the gastro-intestinal transit and in particular the interdigestive migrating motor complex. In the terminal ileum, a zone subject to relative stasis, the intraluminal bacterial population rises to 10(8)/ml in one third of subjects, with the appearance of enterobacter and strict anaerobes. In the colon, a zone of physiological stasis, the number of microorganisms per ml of contents is 10(8)-10(9) on the right side and 10(10)-10(12) on the left side. The dominant flora is strictly anaerobic and the subdominant flora optionally aero-anaerobic, consist mainly of Enterobacter, Streptococci and Lactobacilli. The balance between the species of microorganisms in the colonic ecosystem and its stability results primarily from microbial antagonisms. The barrier flora, consisting of groups of anaerobes, either prevent the implantation of exogenous microorganisms (drastic barrier) or limit it to the subdominant flora (permissive barrier). The repression of the subdominant flora by the dominant flora prevents the subdominant flora from spreading to the mesenteric ganglia and then the whole body. Rupture of the barrier flora by a wide-spectrum antibiotic may permit the local multiplication of a pathogenic organism (C. difficile, Salmonella), or the spread of an opportunist organism (Klebsiella pneumoniae).

Animals

[Gastrointestinal flora and health in man and animal].

A balanced and stable gastro-intestinal microflora is of vital importance for the optimum function of the gastro-intestinal tract and consequently for the health of man and animals. The gastro-intestinal microflora is a very complex ecosystem, the current knowledge of which is still very limited. It is obvious that the intestinal flora has a protective function (prevention of infection). In addition it has a positive effect on nutrition (digestion, effects on physiology, production of vitamins). Changes in diet, stress, the use of antibiotics and excessive hygiene all bring about changes in the micro-biological ecosystem and consequently changes in health conditions. Knowledge about the microbial ecology of the intestine is also of importance in the prevention of zoonoses. Recently, increasing attention is being paid to the development of methods to influence the composition of the gastro-intestinal microflora in man and animals by probiotics (dried cells or fermented food). These concepts will be dealt with in the present paper and, in addition some of the possible uses will be discussed.

Animal Nutritional Physiological Phenomena

Clinical use of selective decontamination: the concept.

Infections can be classified according to: (1) the type of offending microorganism (virus, bacteria, fungi, parasites), (2) according to the clearance by the defence system (T cell dependent/independent) and (3) in case bacteria are the causative agents in Gram-positive and Gram-negative infections. The latter classification in Gram-positive and Gram-negative infections has appeared to have a practical consequence. Gram-negative bacteria, often involved in major infections and yeasts, appear to play practically no role in the intestinal ecological system. Consequently, it is nowadays increasingly attempted to eliminate Gram-negative bacteria and yeasts selectively from the digestive tract with antimicrobial agents. Selective suppression of Gram-positive bacteria may severely affect the ecosystem of the digestive tract. This selective suppression of Gram-negatives must be continued as long as patients are immunocompromised (locally or systemically) and is called selective decontamination of the digestive tract.

Anti-Bacterial Agents

Arthritis and enteritis--an interface of protean manifestations.

We live in tenuous proximity to a vast array of microbial agents that inhabit the balanced ecosystem of the gut. When an alteration in that balance occurs our immune system can be challenged abruptly with pathogens expressing microbial antigens that may form immune complexes or that may induce autoimmunity by cross-reactivity with host endogenous antigens. Toxins and proteolytic enzymes, normally limited to bowel lumen, may evade local mucosal defences and effect systemic inflammatory responses. Understanding the pathogenic events behind arthritis related to GI pathology will provide insight not only into this important group of diseases but also into fundamental mechanisms underlying other forms of inflammatory joint disease which remain of unknown origin.

Arthritis

Surgical pathology of the infected gut.

In the normal digestive tract, interaction of the mucosa with a large and varied microbial flora is inevitable. In fact, the "normal" state of the digestive tract reflects the impact of the resident flora to a significant degree. The pathogenesis of various infectious conditions encountered by the surgical pathologist in the gut is understood more readily when the gastrointestinal tract is viewed as a complex ecosystem. Significant disease may result from perturbation of the normal flora, as well as from exogenous infection, and susceptibility of the host may vary with disturbances of the digestive ecosystem. An ecologic perspective is essential in the consideration not only of the "infected" gut, but of conditions as diverse as ischemia or even carcinogenesis in the gastrointestinal mucosa.

Animals

Role of motility, chemotaxis, and adhesion in microbial ecology.

This review emphasized the implications of recent data pertaining to the role that motility, chemotaxis, and adhesion play in microbial ecology. Some of these processes appear to promote colonization by allowing certain organisms to selectively "seek out" nutrients or sites of colonization. For example, chemotaxis to NO3- and NO2- may provide pseudomonads with such a strong competitive mechanism that it allows this group of bacteria to outcompete other members of the soil microbiota for these chemicals. Likewise, chemotaxis also allows other bacteria to enter and colonize the mucus gel lining the intestinal epithelium and thereby resist physical removal from the gut. On the other hand, the understanding of such mechanisms offers important new possibilities for the deliberate control of microorganisms for the benefit of man. To that end, much remains to be done before a thorough understanding of the ecology of the microflora of any ecosystem can be accomplished. It is hoped that this review will stimulate further work in this area, as well as to lead to collaboration between engineers and microbiologists, which should lead to fruitful and exciting research in the future.

Animals