Search

Dysbiosis within microbiomes has been increasingly implicated in many systemic illnesses, such as cardiovascular disease, metabolic syndrome, respiratory infections, and Alzheimer disease (Ad). The correlation between Ad and microbial dysbiosis has been repeatedly shown, yet the etiologic cause of microbial dysbiosis remains elusive. From a neuropathology perspective, abnormal (often age-related) changes in the brain, associated structures, and bodily lumens tend toward an accumulation of oxygen-depleted pathologic structures, which are anaerobically selective niches. These anaerobic environments may promote progressive change in the microbial community proximal to the brain and thus deserve further investigation. In this review, we identify and explore what is known about the anaerobic niche near or associated with the brain and the anaerobes that it is harbors. We identify the anaerobe stakeholders within microbiome communities and the impacts on the neurodegenerative processes associated with Ad. Chronic oral dysbiosis in anaerobic dental pockets and the composition of the gut microbiota from fecal stool are the 2 largest anaerobic niche sources of bacterial transference to the brain. At the blood-brain barrier, cerebral atherosclerotic plaques are predominated by anaerobic species intimately associated with the brain vasculature. Focal cerebritis/brain abscess and corpora amylacea may also establish chronic anaerobic niches in direct proximity to brain parenchyma. In exploring the anaerobic niche proximal to the brain, we identify research opportunities to explore potential sources of microbial dysbiosis associated with Ad., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Among the Gram-positive anaerobic bacteria associated with clinical infections, the Gram-positive anaerobic cocci (GPAC) are the most prominent and account for approximately 25-30% of all isolated anaerobic bacteria from clinical specimens. Still, routine culture and identification of these slowly growing anaerobes to the species level has been limited in the diagnostic laboratory, mainly due to the requirement of prolonged incubation times and time-consuming phenotypic identification. In addition, GPAC are mostly isolated from polymicrobial infections with known pathogens and therefore their relevance has often been overlooked. However, through improvements in diagnostic and in particular molecular techniques, the isolation and identification of individual genera and species of GPAC associated with specific infections have been enhanced. Furthermore, the taxonomy of GPAC has undergone considerable changes over the years, mainly due to the development of molecular identification methods. Existing species have been renamed and novel species have been added, resulting in changes of the nomenclature. As the abundance and significance of GPAC in clinical infections grow, knowledge of virulence factors and antibiotic resistance patterns of different species becomes more important. The present review describes recent advances of GPAC and what is known of the biology and pathogenic effects of Anaerococcus, Finegoldia, Parvimonas, Peptoniphilus and Peptostreptococcus, the most important GPAC genera isolated from human infections., (© 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

Fifty-three beta-lactamase-producing strains of oral bacteria isolated from patients with refractory periodontitis in Norway and USA were screened for the presence of the bla(TEM), bla(SHV), bla(OXA), bla(ampC), bla(cfxA), and bla(cepA/cblA) genes by the polymerase chain reaction (PCR). The PCR products were characterized by direct sequencing of the amplified DNA. Thirty-four of the 53 enzyme-producing strains (64%) were positive in one of the PCR assays. All beta-lactamase-producing Prevotella and Capnocytophaga spp. were CfxA positive. TEM-type beta-lactamases were identified in one strain each of Escherichia coli and Neisseria sp., and one strain of Citrobacter freundii possessed an AmpC-type beta-lactamase. Screening for gene cassettes and genes known to be associated with integrons did not reveal the presence of integrons in these oral bacteria. Sequence analyses showed that most CfxA positive Prevotella and Capnocytophaga isolates from patients with refractory periodontitis harboured variants of the CfxA2 and CfxA3 enzyme. The present study also showed that many different genetic determinants of beta-lactamase production are found in bacteria isolated from refractory periodontitis, many of which remain to be characterized.

This study compared the in vitro activities of ertapenem, ceftriaxone, co-amoxiclav, ciprofloxacin and piperacillin-tazobactam against 314 aerobic bacteria and of ertapenem, piperacillin-tazobactam, cefoxitin, ceftriaxone, chloramphenicol, ticarcillin-clavulanate, ampicillin-sulbactam, clindamycin and metronidazole against 500 anaerobic bacteria from 212 patients with acute pelvic infection. Antimicrobial susceptibilities were determined by broth microdilution (aerobes) or agar dilution (anaerobes), following NCCLS guidelines. The most common isolates were Enterobacteriaceae and Peptostreptococcus spp. Ertapenem was the most active drug tested against Enterobacteriaceae (100% susceptible) and anaerobes (99.8% susceptible); the least active agents were co-amoxiclav (79% of Enterobacteriaceae susceptible) and ceftriaxone (85.9% of anaerobes susceptible). All agents tested had excellent activity against beta-haemolytic streptococci and methicillin-susceptible Staphylococcus aureus.

Deficiency of the innate, humoral immune component mannose-binding lectin (MBL) predisposes individuals to a variety of infections, but the importance of MBL in infection by anaerobes has not been addressed. The attachment of MBL to a wide range of anaerobic bacteria associated with human disease and colonization was surveyed. The results suggest that for the species we examined, resistance to MBL binding may be associated with organisms that are more commonly pathogenic and that MBL binding to some bacteria may be phase variable.

Bacterial vaginosis (BV) is a common disorder characterized by increased levels of anaerobic bacteria in the genital tract. BV has been associated with an increased rate of sexual transmission of human immunodeficiency virus (HIV). The effects of BV-associated anaerobic bacteria on HIV expression in monocytoid cells and T cells were examined. Peptostreptococcus asaccharolyticus and Prevotella bivia stimulated HIV expression in monocytoid cells, whereas Bacteroides ureolyticus, Peptostreptococcus anaerobius, and Lactobacillus acidophilus did not enhance HIV expression. P. asaccharolyticus also enhanced HIV expression in T cells and activated HIV long-terminal-repeat transcription in U38 cells. This report suggests a mechanism by which disturbances in vaginal flora could lead to a higher rate of sexual transmission of HIV. Furthermore, this study supports the idea that treatment of BV might serve as a preventive measure to reduce the risk of HIV transmission.

Streptococci that colonize the mouth and upper respiratory tract tend to be considered harmless commensals. In 45 cases of acute pneumonia and/or pulmonary abscess and 25 cases of thoracic empyema, the predominant species recovered were anaerobic bacteria and the Streptococcus milleri group, which encompasses the oral species Streptococcus anginosus, Streptococcus constellatus, and Streptococcus intermedius. The isolation of most S. milleri organisms along with oral anaerobes indicated synergy between these groups. Studies in a mouse model of pneumonia demonstrated this synergy; mortality was higher, histopathologic abnormalities were more marked (reflecting acute pneumonia followed by pulmonary abscess or empyema), and viable bacteria were more numerous in the lungs of mice with mixed infections caused by the S. milleri group and anaerobes than in the lungs of those with monomicrobial infection. In vitro studies elucidated a possible mechanism of this synergistic effect: anaerobes may enhance the growth of the S. milleri group and/or inhibit the bactericidal activity of the host. We conclude that the S. milleri group is more important in pulmonary infections than has previously been recognized.

Chronic and recurrent upper respiratory tract infections represent a significant clinical challenge. The causative organisms tend to be heterogeneous, involving both aerobes and gram-positive and gram-negative anaerobes. There is evidence that these mixed groups of bacteria interact synergistically, enhancing and prolonging the overall virulence of infection. The role of anaerobic bacteria, in particular their proposed ability to protect susceptible organisms by the production of beta-lactamases, has been the subject of intense speculation. The evidence of a significant role for anaerobic bacteria in recurrent episodes of tonsillitis and sinusitis is reviewed and the most appropriate antimicrobial strategies and possible future developments in diagnosis and therapy are discussed.

Among the broad spectrum of species of anaerobic bacteria in the normal flora of humans, a few exhibit marked pathogenic potential and are responsible for the majority of infections. The factors that determine the virulence of particular species are varied and probably interrelated. Just as most anaerobic infections are polymicrobial and depend on interactions of a combination of species, the virulence of a species probably depends on a combination of properties, including surface structures, metabolic functions, ability to avoid the host's defenses, and capacity to damage tissues. Thus, the production of each virulence factor--adhesins that attach to epithelial and red blood cells and to other bacteria, producing metabolically interdependent ecosystems; capsules that protect against phagocytosis and induce abscess formation; lipopolysaccharide; proteases, including those that degrade immunoglobulins and complement components; and other hydrolytic enzymes--represents only a component of virulence, but a consideration of these factors in combination begins to clarify the mechanisms by which anaerobes cause disease.

It has been one hundred years since the appearance of the first clinical paper on infection involving anaerobic bacteria, an article that also detailed recovery of and description of the organisms responsible for the infection. We pay tribute to the author of that landmark paper, André Veillon, in celebration of the centennial of this important occasion.

Before the early 1970s, a large proportion of samples collected from sites of postoperative wound infections yielded no pathogens upon routine culture yet did contain pleomorphic forms visible upon gram staining. The inability to recover pathogens often led to incorrect choices of antibiotics for empirical therapy and thus to clinical failures of therapy. It is now known that many of these infections were due to the various endogenous anaerobic constituents of the normal human microflora. Because of advances in the techniques used for anaerobic specimen collection and culture, anaerobic bacteria are now routinely recovered from a variety of intraabdominal and postoperative soft-tissue infections. In all but clean operative procedures, the causative organisms often reflect the normal aerobic and anaerobic flora of the resected organ. Before colonic surgery, counts of both aerobes and anaerobes must be reduced by appropriate mechanical cleansing and antibiotic administration. Successful treatment of surgical infections includes both the implementation of careful operative technique and the choice of appropriate antibiotics.

Gram-negative anaerobic bacteria belonging to the genera Bacteroides, Prevotella, and Porphyromonas represent the most common cause of endogenous, usually mixed, infections occurring after abdominal or gynecologic surgery. Anaerobes are important pathogens in oral-cavity infections as well as in systemic infections that originate from the mouth. Clinical interest in these organisms is linked to the therapeutic problems usually encountered in treating mixed infections. Despite their clinical relevance, very little is known about the pathogenetic mechanism of anaerobic infections. In Bacteroides species, the capsule has been thought to be important, and initially it was considered unique to Bacteroides fragilis, the most common pathogen. It has been claimed that the capsule is involved in adhesion, abscess formation, and impaired phagocytosis. However, other structures such as pili and extracellular substances, including metabolic by-products (e.g., short-chain fatty acids), have to be considered as potentially relevant pathogenetic mechanisms in anaerobic infections. Several extracellular enzymes have been investigated, but no clear evidence is available for establishing their relevance in disease mechanisms. Special attention should be devoted to enzymes able to digest IgA (IgA proteases), a first-line defense mechanism that is active in the mucosal membranes.

The effect of encapsulation on the virulence, survival, and protection of anaerobic bacteria from phagocytosis is reviewed. Support for the importance of encapsulated Gram-negative anaerobic rods (Bacteroides sp., Prevotella sp. and Porphyromonas sp.), anaerobic and facultative Gram-positive cocci (AFGPC) was provided by their higher recovery rate in oropharyngeal infections, abscesses and blood, compared to their number in the normal flora. The pathogenicity of Bacteroides, Fusobacterium, Clostridium, and AFGPC was studied by inoculating them into mice and observing their ability to induce subcutaneous abscesses. Encapsulated Bacteroides, Fusobacteria, and AFGPC generally induced abscesses, whereas non-encapsulated organisms did not. However, many of the strains that had only a minimal number of encapsulated organisms (< 1%) survived in the abscesses, and they became heavily encapsulated when inoculated with other viable or non-viable encapsulated bacteria. Thereafter, these strains were able to induce abscesses when injected alone. Encapsulated Gram-negative anaerobic rods and AFGPC-induced bacteraemia and translocation, and increased the mortality of the infected animals more often than did the non-encapsulated form of the same strains. As determined by using selective antimicrobial therapy and quantitative cultures of abscesses induced in mice, possession of a capsule generally made Gram-negative anaerobic rods more important than their aerobic counterparts. Synergistic potentials were seen between encapsulated Gram-negative anaerobic rods and all tested aerobic bacteria and most AFGPC, and also between most AFGPC and Pseudomonas aeruginosa or Staphylococcus aureus. These studies demonstrated the importance of encapsulated anaerobes in mixed infections.

Identification of anaerobic bacteria in specimens from sites of infection due to mixed organisms can be time-consuming and expensive. Laboratories should limit anaerobic workups by testing only those specimens that have been properly collected and transported to the laboratory. Use of selective and differential media for initial processing can provide rapid and relevant information to the clinician. Anaerobes isolated from normally sterile sites and sites of serious infection should always be completely identified. Group- or genus-level identifications may suffice in other instances. The Bacteroides fragilis group of organisms should always be identified because of their virulence and resistance to many antimicrobial agents. Some of the other organisms that warrant identification include Clostridium septicum (associated with gastrointestinal malignancy); Clostridium ramosum, Clostridium innocuum, and Clostridium clostridioforme (which are resistant to antibiotics); Clostridium perfringens (a cause of potentially serious infection); anaerobic cocci (which may be resistant to metronidazole and clindamycin); and fusobacteria (which may be virulent and resistant to clindamycin and penicillin).

Anaerobic bacteria include the most pathogenic of microorganisms. Their primary function, however, is hardly to cause illness. They rarely are involved in epidemics or in clinically significant infections. Some organisms, e.g. lactobacilli, control the normal vaginal ecosystem, and the intestinal anaerobes probably are instrumental in restraining the growth of Clostridium difficile in human carriers. The main role of anaerobes appears to be the provision of catabolic enzymes for organic compounds that cannot be digested by enzymes of eukaryotic origin. They are needed for the catabolism of cholesterol, bile acids, and steroid hormones; they hydrolyze a number of flavonoid glycosides to anticarcinogens; and they detoxify certain carcinogens. Anaerobic enzymes are used industrially in the production of cheese; the conversion of starch to sweeteners; and the transformation of sawdust, wood chips, and waste paper to fuel. Indeed, the anaerobes may well be the gene bank on which future generations of eukaryotic organisms will rely to adapt successfully to an ever-changing world.

It has been a hundred years since the role of anaerobic bacteria and, especially, non-spore-forming anaerobes in infections began to be appreciated. Accordingly, it is of interest to review the history of anaerobes and anaerobic infections. The waxing and waning of interest on the part of clinicians and microbiologists over this period is noteworthy and suggests that we need to avoid complacence lest we lose much of what has been gained over the years. In this review I discuss a number of milestones marking our progress in this field and consider some areas of concern.

In 193 reviewed cases of pleuropulmonary infections involving anaerobic bacteria, the predominant clinical syndromes were aspiration pneumonia, lung abscess, and empyema. Most patients had an indolent infection with tissue necrosis (abscess or bronchopulmonary fistula) at initial presentation. Nevertheless, many had a more fulminant disease course resembling that of pneumococcal pneumonia. Transtracheal aspiration was the procedure most commonly used to obtain uncontaminated specimens for anaerobic culture; since this procedure now is seldom employed, pulmonary infections due to anaerobes rarely have an etiologic diagnosis at present. The dominant pathogens are Peptostreptococcus, Bacteroides, Prevotella, and Fusobacterium species. Although clindamycin is widely considered to be the antibiotic of choice, proper therapeutic trials would probably prove many antibiotics to be effective for the treatment of anaerobic pleuropulmonary infections.

A retrospective bacteriologic study of anaerobic pleuropulmonary infections diagnosed at the Wadsworth Veterans Affairs Medical Center between 1976 and 1991 was performed. There were 116 specimens from 110 patients. Available strains were reexamined using the latest tests and taxonomic schemes. Pleural fluid was believed to provide the most reliable specimen; cultures yielded an average of 3.0 anaerobes and 0.6 nonanaerobes per specimen. The most commonly encountered anaerobes were pigmented Prevotella species, nonpigmented Prevotella species, Fusobacterium nucleatum, Peptostreptococcus species, and Bacteroides species. Thirty percent of the anaerobic gram-negative rods were beta-lactamase producers.

Microbial populations colonizing the teeth are a major source of pathogens responsible for oral and dental infections, including periodontal diseases, gingivitis, pericoronitis, endodontitis, peri-implantitis, and postextraction infections. Each entity has distinct clinical and microbial features. Bacterial species associated with oral infections include Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Bacteroides forsythus, Campylobacter rectus, Eubacterium species, Fusobacterium nucleatum, Eikenella corrodens, and Peptostreptococcus micros. Treponema pallidum-related spirochetes have been associated with acute necrotizing ulcerative gingivitis. Porphyromonas endodontalis appears to be specifically related to endodontic infections. Oral infections in medically compromised patients, including those with AIDS, are associated with similar species and are usually complicated by superinfection with enteric and Candida species. Isolation of species causing oral infections requires the collection of appropriate samples and the use of strictly anaerobic techniques. Rapid selective culture, immunofluorescence, and DNA probe methods have been developed for the identification of these oral species. The varied measures required in the management of oral and dental infections may include antimicrobial therapy. Accurate microbiological diagnosis, including antibiotic susceptibility testing, is indicated for cases that do not respond to therapy.

Anaerobic bacteria are frequent isolates from the mixed bacterial flora of surgical infections. Recent studies have defined an important role for these microorganisms in determining the overall virulence of these infections. One mechanism underlying this effect is the ability of anaerobes to interact with leukocytes, resulting in impairment of host defense mechanisms. This review will address two such mechanisms. First, short-chain fatty acids generated by Bacteroides species during the stationary phase of culture have been shown to cause global impairment of the microbicidal activity of neutrophils. The observation that inhibition was maximal at low extracellular pH led to the finding that the fatty acids mediated this effect by shuttling protons from the extracellular to cytoplasmic space, thereby causing intracellular acidification with resultant cell dysfunction. Second, local fibrin deposition at the site of infection appears to impair bacterial clearance. Interaction between Bacteroides species and peritoneal macrophages has been shown to induce cell-associated procoagulant activity. This may represent another potential mechanism by which anaerobes impair leukocyte function and predispose to abscess formation.

The potential for synergy between aerobic, facultative, and anaerobic bacteria was studied by subcutaneous inoculation of mixtures of these organisms into mice and observation of subsequent mortality and abscess formation. The anaerobic bacteria tested included 12 strains of gram-positive cocci and two strains each of Bacteroides species, Clostridium species, and Fusobacterium species. The facultative and aerobic bacteria included one strain each of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. Mortality increased significantly when each aerobic organism was inoculated along with either of the Bacteroides species. A similar increase occurred when the anaerobic gram-positive cocci were inoculated along with P. aeruginosa (four of six combinations) or S. aureus (four of six). The rate of abscess induction increased significantly when 10 of the 12 strains of anaerobic gram-positive cocci were injected along with B. fragilis and when nine of these strains were inoculated along with Bacteroides asaccharolyticus . The results demonstrate synergistic potential between Bacteroides species and all aerobic bacteria tested, between Bacteroides species and most anaerobic gram-positive cocci, and between most anaerobic gram-positive cocci and P. aeruginosa or S. aureus.