Original Article
Identification of the Uncultured Bacillus of Whipple's Disease
N Engl J Med 1992; 327:293-301July 30, 1992
- Abstract
- Abstract
Background.
Whipple's disease is a systemic disorder known for 85 years to be associated with an uncultured, and therefore unidentified, bacillus.
Methods.
We used a molecular genetic approach to identify this organism. The bacterial 16S ribosomal RNA (rRNA) sequence was amplified directly from tissues of five unrelated patients with Whipple's disease by means of the polymerase chain reaction, first with broad-range primers and then with specific primers. We determined and analyzed the nucleotide sequence of the amplification products.
Results.
A unique 1321-base bacterial 16S rRNA sequence was amplified from duodenal tissue of one patient. This sequence indicated the presence of a previously uncharacterized organism. We then detected this sequence in tissues from all 5 patients with Whipple's disease, but in none of those from 10 patients without the disorder. According to phylogenetic analysis, this bacterium is a gram-positive actinomycete that is not closely related to any known genus.
Conclusions.
We have identified the uncultured bacillus associated with Whipple's disease. The phylogenetic relations of this bacterium, its distinct morphologic characteristics, and the unusual features of the disease are sufficient grounds for naming this bacillus Tropheryma whippelii gen. nov. sp. nov. Our findings also provide a basis for a specific diagnostic test for this organism. (N Engl J Med 1992;327:293–301.)
Article Activity
- Article
IN 1907, George Whipple reported a "hitherto undescribed disease" in a 36-year-old medical missionary with migratory polyarthritis, cough, diarrhea, malabsorption, weight loss, and mesenteric lymphadenopathy.1 He named this disease "intestinal lipodystrophy." We now refer to it as Whipple's disease, a systemic illness, predominantly of middle-aged white men, characterized by arthralgias, diarrhea, abdominal pain, and weight loss.2 Other common findings include lymphadenopathy, fever, and increased skin pigmentation.3 The disease usually involves the gastrointestinal tract, mesentery, heart, and central nervous system; however, it can affect nearly every other organ system. The diagnosis is established when microscopical examination of the small intestine shows infiltration of the lamina propria by large macrophages that contain diastase-resistant inclusions that are positive on periodic acidSchiff (PAS) staining. Similar PAS-positive macrophages may be found in other involved tissues.
In his original report Whipple noted "great numbers of a rod-shaped organism (?)" in silver-stained sections of a lymph node and speculated that this organism might be the causative agent of the disease.1 It was not until 1961 that the rod-shaped structures were identified by electron microscopy as bacilli.4 , 5 Subsequent studies have demonstrated that these bacilli have a unique cell-wall structure and are found in extracellular locations as well as within macrophages, where they appear to have undergone various degrees of degradation.6 , 7 These bacteria and the remnants of their walls correspond to the PAS-positive material in stained tissues.4 , 5 Their unusual and uniform appearance suggests that the disease is caused by a single organism.2
No one, including Whipple, has reproducibly grown the bacillus associated with this disease, despite numerous attempts. The identity of this unusual organism remains one of the most persistent mysteries of microbiology. We have developed a technique for the identification of bacterial pathogens that does not rely on their cultivation, and have used it to identify the agent of bacillary angiomatosis.8 This technique is based on the amplification of the bacterial (formerly eubacterial9) 16S ribosomal RNA (rRNA) sequence directly from infected tissue.
The gene that encodes the rRNA small subunit (16S, or 16S-like) accumulates random mutations over time. Because of structural constraints, the 16S rRNA sequence mutates at a rate that makes it useful as an evolutionary clock.10 For example, the evolutionary distance from one organism to another can be calculated from the number of nucleotide differences between their respective 16S rRNA sequences. Because portions of all 16S rRNA genes are highly conserved, these genes can be amplified from uncharacterized organisms with broad-range primers used in the polymerase chain reaction (PCR). From the sequence of the amplified products phylogenetic relations can be established. This approach was applied to Whipple's disease in a preliminary study11 that described a partial (<50 percent) bacterial 16S rRNA sequence in one specimen from a single patient with the disorder.
In this study we determined approximately 90 percent of the 16S rRNA gene sequence of the bacillus associated with Whipple's disease. We designed PCR primers that are specific for this novel organism, and used them to detect the bacillus in all of five unrelated patients with the disease.
Methods
Further details of each of the following methods are available from the National Auxiliary Publications Service.*
Tissues from Patients
Tissues were obtained from five patients with Whipple's disease, each of whom lived in a different geographical region of the United States and had no known contact with the others.
Patient 1 was a 36-year-old white man with a history of abdominal bloating, diarrhea, episodic fever, pleuritic chest pain, and weight loss. Initially, he was believed to have sarcoidosis because noncaseating granulomas were found in numerous tissues. Subsequently, Whipple's disease was diagnosed by histologic and electron-micrographic examination of duodenal and lymph-node tissues. Duodenal tissue obtained by endoscopy was frozen for PCR analysis.
Patient 2 was a 51-year-old white man with skin hyperpigmentation, weight loss, and diarrhea (Case 4 of Feldman and Price12). Endoscopic biopsy of the duodenum and biopsy of an enlarged supraclavicular lymph node revealed characteristic findings of Whipple's disease. Fixed, embedded lymph-node tissue was used for PCR analysis.
Patient 3 was a 50-year-old man with a history of night sweats, anemia, and enlarged retroperitoneal lymph nodes. Histologic examination of the nodes revealed numerous foamy macrophages containing granular PAS-positive, diastase-resistant material. Fixed, embedded tissue was used for PCR analysis.
Patient 4 was a 52-year-old white man in whom arthralgias, arthritis, and mesenteric and mediastinal lymphadenopathy developed. The lymph nodes contained numerous macrophages with sickle-shaped, PAS-positive, diastase-resistant inclusions. Endoscopic biopsy of the duodenum confirmed the diagnosis of Whipple's disease. Fixed, embedded lymph-node tissue was used for PCR analysis.
Patient 5 was a 48-year-old white man with a history of diarrhea, back pain, arthralgias, uveitis, abdominal pain, and weight loss. Endoscopic biopsy of the duodenum revealed a massive accumulation of macrophages containing PAS-positive material in the lamina propria (Fig. 1Figure 1
Histologic Evidence of Whipple's Disease in the Duodenum of Patient 5.A and 1B). Acid-fast stains were negative. Electron microscopy confirmed the presence of extracellular and intracellular bacilli, the latter in various stages of degeneration within macrophages (Fig. 1C). These findings were diagnostic of Whipple's disease. Duodenal mucosa was frozen for PCR analysis.Tissues from Controls
Tissues from 10 patients without Whipple's disease (14 control specimens) (Table 1Table 1
Source of Tissues from the Controls.) were processed and tested in parallel withthose from the 5 patients described above. The specimens from Controls 1 and 2 and the biopsy specimens from Patients 1 and 5 were obtained in the same endoscopy suite.*See NAPS document no. 04954 for 12 pages of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513. Grand Central Station, New York, NY 10163–3513. Remit in advance (In U.S. funds only) $7.75 for photocopies or $4 for microfiche. Outside the U.S. and Canada, add postage of $4.50 ($1.75 for microfiche postage). There is a $15 invoicing charge for all orders filled before payment.
DNA Extraction
Ten-micrometer sections of formalin-fixed, paraffin-embedded tissues were extracted and digested in 100-μl volumes overnight at 55°C and otherwise according to previously described methods.8 Approximately 20 mg of frozen tissue was digested under the same conditions. Approximately 10 mg of each of several lyophilized bacterial cultures was separately digested under the same conditions as those for frozen tissues. Tissues from the controls were always interspersed with those from the patients and processed in parallel.
Oligonucleotide Primers
Oligonucleotide primers (Table 2Table 2
Oligonucleotide Primers Used to Amplify the 16S rRNA Sequence.) were synthesized at the Digestive Disease Center Core Laboratory, Stanford University, and the Department of Microbiology, Miami University, Oxford, Ohio.PCR Amplification
One to 10 percent of the supernatant fluid obtained by tissue digestion (extract) was added to the preparation for amplification reaction, which also contained 200 nmol of each primer, 200 μmol of each deoxyribonucleoside triphosphate, and 2 mmol of magnesium chloride per liter. The tissue extracts were first tested for amplification of a 268-bp (base pair) human β-globin gene sequence with primers PC04 and GH20 (Perkin-Elmer, Norwalk, Conn.).14 If this β-globin gene product could not be amplified from extracts of a given tissue, no further PCR assays of the tissue were performed. After an initial four minutes of denaturation at 95°C, 40 cycles of amplification were carried out in a DNA Thermal Cycler 480 (Perkin-Elmer); each cycle consisted of one minute of denaturation at 94°C, one minute of annealing at 55°C, and two minutes of extension at 72°C. Reactions with primers pW3FE and pW2RB were conducted with each annealing step at 60°C. Every set of amplification reactions with each set of primers included reactions without added tissue extract and reactions with extract from control tissues (Table 1). Products were detected by electrophoresis of 10 percent of the reaction volume in a 1.5 percent agarose gel containing ethidium bromide.
Determination of DNA Sequence of Amplified Products
All detection and manipulation of PCR products were performed in a laboratory other than that used for tissue extraction and PCR amplification. Products from reactions with tissue extracts from Patients 1, 2, and 3 and Control 1 (Table 1) were purified, cloned, and sequenced according to a procedure described previously.8 Products from reactions with tissue extracts from Patients 4 and 5 were sequenced directly with a commercial kit (Taq DyeDeoxy Terminator Cycle Sequencing Kit [Applied Biosystems, Foster City, Calif.]) and an automated sequencing system (Applied Biosystems Model 373A DNA Sequencing System15).
Results
Amplification of the 16S rRNA Gene
Tissue from Patient 1
PCR reactions with the bacterial (formerly eubacterial9) broad-range 16S rRNA pair of primers p515FPL—p13B (Fig. 2Figure 2
PCR-Amplified 16S rDNA Fragments from Tissue DNA Extracts.A) reproducibly generated a DNA product of the expected size (approximately 904 bp, on the basis of the Escherichia coli 16S rRNA sequence) with an extract of duodenal tissue from Patient 1 (Fig. 2B, lane 2). Reactions without added tissue extract were negative (data not shown). The DNA product from the tissue of Patient 1 was cloned, and three clones were sequenced. These 838-bp 16S rRNA sequences of Patient 1 differed at four positions and corresponded to the sequence of an uncharacterized bacterium.When an extract of gastric tissue from Control 1 (Table 1) was tested in multiple reactions run in parallel, all reactions were positive (Fig. 2B, lane 3). The partial sequence of one clone of this tissue was 99.0 percent similar to the 16S rRNA sequence of Helicobacter pylori — a result consistent with the pathological features of the tissue.
To confirm the presence of a single dominant 16S rRNA gene in the tissue extract from Patient 1, two other sets of bacterial broad-range PCR primers were used. Amplification reactions with this tissue extract and each of the pairs p8FPL-p806R and p91E-p13B (Fig. 2A) yielded products of the expected size (Fig. 2B, lanes 1 and 4). The pair p91E-p13B also occasionally generated several smaller, nonspecific products. All the full-sized PCR products were cloned, and two clones of each were sequenced. One 439-bp sequence from the reaction with p91E—p13B was identical to the corresponding portion of the previously obtained 838-bp bacterial sequence; the other clone differed at two positions. The two 736-bp sequences from the reaction with p8FPL—p806R were identical to the 253-bp overlap region with the 838-bp sequence obtained with p515FPL—p13B (Fig. 2A), and differed from each other at one position. These sequences generated from the tissue extract of Patient 1 were combined to form a 1321-bp sequence, representing approximately 90 percent of the 16S rRNA gene of a single uncharacterized bacterium. This sequence has been deposited in the GenBank data base (accession number, M87484).
Tissue from Patients 2, 3, 4, and 5
Previous studies had suggested that bacterial contamination and damage to DNA impede PCR amplification of pathogen-specific 16S rRNA genes from extracts of formalin-fixed, paraffin-embedded tissues.8 To avoid these two problems with such tissue, we designed PCR primers pW3FE and pW2RB (Fig. 2A), believing that they would be specific for the 16S rRNA sequence associated with Whipple's disease and would prime the synthesis of a relatively small (284-bp) product. As a further measure to avoid bacterial contamination, we selected formalin-fixed, paraffin-embedded tissues from patients with extraintestinal Whipple's disease — Patients 2, 3, 4, and 5. Reactions with the specific primers generated a product of the expected size from extracts of fixed, embedded lymph nodes from Patients 2, 3, and 4 (Fig. 2B, lanes 6 through 8; the band in lane 7 is faint), as well as from the extracts of frozen duodenal tissue from Patients 1 and 5 (Fig. 2B, lanes 5 and 9). All these reactions gave the same results at least twice.
The PCR products specific for Whipple's disease from all five patients were sequenced. One clone from Patient 1 was sequenced; its sequence was identical to the corresponding 230-base region of the original 1321-base 16S rRNA sequence described above. One clone from Patient 2 was sequenced; its sequence differed from the original sequence at one position. The sequence of one of two clones from Patient 3 differed from the original sequence at one position, and that of the other clone differed at two positions. The PCR products from Patients 4 and 5 were sequenced directly, without cloning. Both sequences were identical to the original sequence (that for Patient 4 could not be evaluated at one position). This extremely low degree of sequence variation among these different samples suggested that the same bacterium was present in all five patients with Whipple's disease.
Evaluation of PCR Primers Specific for the Whipple's Disease Bacillus
We tested the specificity of the pair pW3FE—pW2RB to confirm the association of the 16S rRNA sequence with Whipple's disease. The extracts used were from fresh-frozen tissues and formalin-fixed, paraffin-embedded tissues from patients without Whipple's disease (Table 1). The specific primers failed to amplify a visible product with any of these extracts on numerous attempts, although β-globin primers had elicited positive reactions from all of them. Occasionally, reactions with greater amounts of tissue extract generated faint bands of an inappropriately large size. Some of these results are shown in Figure 2B (lanes 10 through 14). One of the negative tissues was a duodenal biopsy sample with normal histologic features from Control 2 (Table 1) that had been obtained in the same endoscopy suite as the samples from Patients 1 and 5.
These primers were also tested with chromosomal DNA from the human lymphoid cell line K562, as well as with extracts from lyophilized cultures of Dermatophilus congolensis (ATCC 14637), Arthrobacter globiformis (ATCC 8010), Rhodococcus equi (strain 90–568, a gift from Dr. Dwight Hirsh, University of California, Davis), and Corynebacterium bovis (ATCC 7715). All these samples did not react with pW3FE—pW2RB but reacted with control primers (β-globin for human tissues, or p8FPL—p806R for bacterial cultures; data not shown). The first three organisms were selected because phylogenetic analysis of the 16S rRNA sequence that we detected suggested that they were related to the Whipple bacillus (see below). C. bovis had been isolated from a patient with Whipple's disease,21 and its phylogeny was unclear. The negative results of PCR testing of all four organisms helped to demonstrate the specificity of the primers and serve as evidence that C. bovis is not the Whipple's disease bacillus. In addition, primers pW3FE and pW2RB failed to generate PCR product from various tissues of the patients without Whipple's disease, strengthening the specific association of the 16S rRNA sequence with this disorder.
Phylogeny of the Whipple's Disease Bacillus
Analysis of the 1321-base 16S rRNA sequence associated with Whipple's disease suggested that the responsible bacillus was an uncharacterized organism that belongs to the subdivision of gram-positive bacteria with DNA rich in guanine and cytosine,10 also known as actinomycetes.22 Analysis of the sequence at positions 906, 955, 998, 1116, 1167, 1198, and 1229 (E. coli numbering10) confirmed the assignment to this subdivision. Figure 3Figure 3
Phylogenetic Tree Indicating Relations among Selected Gram-Positive Bacteria and the Whipple's Disease Bacillus, Tropheryma whippelii. shows the evolutionary relations of the bacillus as a phylogenetic tree, consistent with previously established relations among the actinomycetes.22 23 24 25 To determine its reproducibility, 100 new trees were created by random reassortment of the 16S rRNA sequence of the bacillus (bootstrap analysis19). The bacillus was associated with the actinobacteria suprageneric group in 67 of these trees and with the streptomycetes group in 6 trees; it was not associated with any particular suprageneric group in 27 trees. In no tree was it associated with the nocardioform group (e.g., R. equi), as previously suggested.11 The bacteria that are most closely related to the bacillus associated with Whipple's disease are all actinobacteria: D. congolensis (similarity to the 16S rRNA sequence after weighting, 92.5 percent), A. globiformis (92.3 percent), Terrabacter tumescens (92.2 percent), and Micrococcus luteus (92.1 percent). However, none of these organisms are significantly more closely related to the bacillus than any other. The Whipple's disease bacillus is not closely related to any organism whose 16S rRNA sequence has been determined.
Discussion
The Whipple's disease bacillus is one example of a group of organisms that either infect or cause disease in humans but cannot be cultured in vitro. The direct amplification of a 16S rRNA sequence from a microbial pathogen in tissue provides one approach to identifying such organisms, as demonstrated by the identification of the agent of bacillary angiomatosis.8 In the present study, the amplification of a 16S rRNA sequence nearly identical to that of H. pylori from a patient with chronic gastritis (Control 1) is a further demonstration of this technique. When we applied this approach to Whipple's disease, we found that the bacillus associated with the disorder was an uncharacterized actinomycete.
Several lines of evidence support our contention that the 16S rRNA sequence described here corresponds to that of the bacillus seen in tissues from patients with Whipple's disease. First, in independent experiments with tissue from Patient 1, three pairs of bacterial (formerly eubacterial9) broad-range 16S rRNA primers generated DNA products with identical, overlapping sequences. Multiple clones shared nearly identical sequences. Second, with the use of specific PCR primers, a highly divergent portion of the same bacterial 16S rRNA sequence was detected in all five unrelated patients with Whipple's disease. Lymph-node (nonmucosal) tissue was chosen for testing (Patients 2, 3, and 4) so that a positive result would more probably reflect the presence of a pathogen than contamination with an organism from the intestinal lumen. Third, the specific primers failed to generate a PCR product from 14 control tissues (Table 1). Several of these tissues were presumed to harbor normal human flora (tissues from Controls 1, 2, 3, 5, and 7) or known specific bacterial pathogens (Controls 1, 4, 5, and 6), including a known actinomycete (M. avium complex). These results strengthen the specificity of the association between the 16S rRNA sequence we identified and the Whipple's disease bacillus. Finally, Wilson et al. recently described the amplification of a partial 16S rRNA sequence from a single patient with Whipple's disease.11 Among the 525 nucleotide positions where this sequence can be compared with ours, there are only two discrepancies.
The observation of heterogeneity of the 16S rRNA sequence within a single tissue sample and between various samples suggests several possible explanations. These include amplification of different, variable copies of the rRNA operon from a single organism, Taq polymerase errors that might be more common with formalin-damaged DNA, and the presence of multiple, genetically distinct microbial populations. Among the various 16S rRNA sequences of the frozen tissue of Patient 1, we observed a total of seven discrepancies in 4864 nucleotide positions (0.14 percent); among the sequences of formalin-fixed tissues, we observed four discrepancies in 790 positions (0.51 percent). The positions where the discrepancies occurred were distributed throughout the 16S rRNA molecule, and no two discrepancies occurred at the same position. No two nucleotide substitutions represented changes in paired complementary bases in regions of known secondary structure. We believe that this heterogeneity is best explained by the first two factors listed above (amplification of different copies of the same rRNA operon, and Taq polymerase errors due to formalin damage to DNA). Our results support earlier findings8 that fresh-frozen tissue is preferable to fixed tissue for this kind of study. Since the former was not available from a normally sterile anatomical site, we relied initially on the disproportionate representation of the Whipple's disease bacillus in the duodenalbiopsy tissue from Patient 1.
Wilson et al.11 reported a 16S rRNA sequence that they amplified from the duodenal tissue of one patient with Whipple's disease. They determined 645 nucleotide positions (less than 50 percent of the gene) and concluded that the Whipple's disease bacillus was an uncharacterized gram-positive bacterium with high levels of guanine and cytosine, most closely related to the nocardioform R. equi. Our investigation included tissues from 5 unrelated patients with Whipple's disease and 10 controls. The 1321-base 16S rRNA sequence described here was sufficient to place the associated bacillus in an evolutionary tree. This tree demonstrates that the Whipple's disease bacillus shares an ancestor with the actinobacteria that is more recent than the one it shares with the nocardioforms. We have also proposed and tested PCR primers that may be used in a specific diagnostic test for the bacillus.
The traditional criteria classifying organisms have included phenotypes that reflect biochemical, physiologic, or morphologic properties.26 The assessment of many of these properties depends on cultivation of the organism in vitro or in vivo. Analysis of the 16S rRNA sequence does not require microbial cultivation. Although such analysis may fail to distinguish among closely related species,27 it has proved reliable in defining members of the same genus.10 The Whipple's disease bacillus is a distinct organism with unique morphologic features that has defied efforts at cultivation for 85 years.2 No single bacterium has been reproducibly isolated from patients with Whipple's disease, nor has any specific genotype or phenotype emerged that might allow the causative agent to be identified.2 We believe that our data, together with the distinct features of this organism and the disease with which it is associated, provide definitive phylogenetic information about this bacterium and a basis for specific detection. Each of the bacteria most closely related to the bacillus belongs to a separate genus, yet the evolutionary distance between the bacillus and any of these bacteria is no less than that between any two within this group. For these reasons, we propose a genus and a species name for the bacillus: Tropheryma whippelii gen. nov. sp. nov. (from the Greek trophe, nourishment, and eryma, barrier, because it causes malabsorption, and from the name of George Whipple).
Are the phylogenetic relations of T. whippelii shown in Figure 3 consistent with what has been known about this organism? The actinomycetes are a diverse group of bacteria whose suprageneric classification is undergoing revision.22 Most of them are aerobic soil organisms that form branching filaments or hyphae. The wall structure of T. whippelii does not exactly resemble that of any previously studied bacterium; however, like many actinomycetes, it is gram-positive and PAS-positive. All but one of the PAS-positive organisms in one study were actinomycetes.28 Although T. whippelii does not appear to form branching filaments or hyphae in human tissue, the preferred conditions for the growth of this organism are unknown. The morphologic features of the actinomycetes may vary according to growth conditions.29 , 30 Knowledge of the phylogenetic relations of T. whippelii may lead to the determination of the conditions for culturing this organism in vitro. Our findings disprove previous claims that the bacillus associated with Whipple's disease is Streptococcus dysgalactiae 31 or C. bovis.21
Whipple remarked on the similarity of this disease to a gastrointestinal mycobacteriosis.1 Although T. whippelii is not one of the nocardioforms, it is distantly related to them. In this regard, it is interesting that the nocardioforms M. paratuberculosis, M. avium complex, and R. equi 22 have all been associated with an illness resembling Whipple's disease that has been seen in animals or in patients infected with the human immunodeficiency virus.2 , 32 33 34 35 36 The unusual nature of their cell walls may be a common pathogenic feature of these organisms in certain immunodeficient hosts.
It is unclear whether T. whippelii is a rare member of the normal human microbial flora and whether it might be associated with other human diseases. The occasional similarity of Whipple's disease and sarcoidosis37 38 39 (as in our Patient 1) suggests that T. whippelii could be one cause of sarcoidosis. Differences in the immune response to this organism may explain the differences in clinical manifestations among hosts. The availability of PCR primers and oligonucleotide probes specific for T. whippelii may make it possible to make an early diagnosis of Whipple's disease and to address some of these questions for the first time.
Supported in part by a grant from the Lucille P. Markey Charitable Trust (to Dr. Relman, a Lucille P. Markey Scholar), by grants (Digestive Disease Center grants DK-38707 [Dr. Relman] and DK-21474 [Dr. MacDermott]) from the National Institute of Diabetes and Digestive and Kidney Diseases, and a grant (AI-26195 [Dr. Falkow]) from the National Institute of Allergy and Infectious Diseases.
We are indebted to Dr. Harry B. Greenberg (Division of Gastroenterology, Stanford University) for intellectual contributions and support; to Dr. Mark Feldman (Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas) for providing tissue from Patient 2; to Drs. Donald Regula and Ronald F. Dorfman (Department of Pathology, Stanford University) for invaluable assistance with embedded tissue samples and for providing tissue from Patient 3; to Dr. William O. Dobbins III (Veterans Affairs Hospital, Ann Arbor, Mich.) for intellectual contributions and assistance with the selection of a bacterial name, and to Dr. Jack E. Finger (Saginaw Medical Center, Saginaw, Mich.) for providing tissue from Patient 4; to Ms. Nafisa Ghori and Dr. Christopher Contag (Department of Microbiology and Immunology, Stanford University) for assistance with electron-microscopical examination of tissue from Patient 5 and with automated DNA-sequence determination, respectively; to Drs. B.J. Paster and F.E. Dewhirst (Forsyth Dental Center, Boston) for providing the H. pylori 16S rRNA sequence; to Ms. Catherine Greer and Dr. M. Michele Manos (Cetus Corp., Emeryville, Calif.) for their advice and gracious provision of reagents; and to Prof. Thomas O. MacAdoo (Virginia Polytechnic Institute, Blacksburg, Va.) for assistance with bacterial nomenclature.
Source Information
From the Departments of Medicine and of Microbiology and Immunology, and the Digestive Disease Center, Stanford University, Stanford, Calif. (D.A.R., S.F.); the Department of Microbiology, Miami University, Oxford, Ohio (T.M.S.); and the Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia (R.P.M.). Address reprint requests to Dr. Relman at the Palo Alto Department of Veterans Affairs Medical Center, 154T, 3801 Miranda Ave., Palo Alto, CA 94304.
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