Transferable Immunoglobulin A-Coated Odoribacter splanchnicus in Responders to Fecal Microbiota Transplantation for Ulcerative Colitis Limits Colonic Inflammation.

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is an emerging treatment modality for ulcerative colitis (UC). Several randomized controlled trials have shown efficacy for FMT in the treatment of UC, but a better understanding of the transferable microbiota and their immune impact is needed to develop more efficient microbiome-based therapies for UC. METHODS: Metagenomic analysis and strain tracking was performed on 60 donor and recipient samples receiving FMT for active UC. Sorting and sequencing of immunoglobulin (Ig) A-coated microbiota (called IgA-seq) was used to define immune-reactive microbiota. Colonization of germ-free or genetically engineered mice with patient-derived strains was performed to determine the mechanism of microbial impact on intestinal immunity. RESULTS: Metagenomic analysis defined a core set of donor-derived transferable bacterial strains in UC subjects achieving clinical response, which predicted response in an independent trial of FMT for UC. IgA-seq of FMT recipient samples and gnotobiotic mice colonized with donor microbiota identified Odoribacter splanchnicus as a transferable strain shaping mucosal immunity, which correlated with clinical response and the induction of mucosal regulatory T cells. Colonization of mice with O splanchnicus led to an increase in Foxp3+/RORγt+ regulatory T cells, induction of interleukin (IL) 10, and production of short chain fatty acids, all of which were required for O splanchnicus to limit colitis in mouse models. CONCLUSIONS: This work provides the first evidence of transferable, donor-derived strains that correlate with clinical response to FMT in UC and reveals O splanchnicus as a key component promoting both metabolic and immune cell protection from colitis. These mechanistic features will help enable strategies to enhance the efficacy of microbial therapy for UC. Clinicaltrials.gov ID NCT02516384.

A Rectal Sunflower Seed Bezoar Causing Fecal Impaction in a Healthy Young Woman.

Bezoars, characterized by undigested or partially digested foreign bodies in the gastrointestinal (GI) tract, are a rare condition associated with significant complications. We present a case of a 31-year-old woman who sought medical attention due to weight loss, diarrhea, and anorectal pain. Upon investigation, she was diagnosed with fecal impaction caused by a rectal sunflower seed bezoar. The patient had a history of regular sunflower seed consumption, suggesting a potential association with the development of the bezoar. Fecal impaction resulting from the bezoar led to chronic constipation, contributing to the patient's weight loss and anorectal discomfort. Imaging studies, including abdominal X-rays or computed tomography (CT) scans, played a crucial role in confirming the diagnosis by identifying the presence of the bezoar within the rectum. Management involved a multidisciplinary approach, with gastroenterologists and colorectal surgeons. A flexible endoscope was utilized to visualize and remove the sunflower seed bezoar under direct vision, providing immediate relief from the symptoms. This case emphasizes the importance of considering bezoars as a potential cause of GI symptoms, even in young and otherwise healthy individuals. Although rectal bezoars are relatively rare, they can lead to significant morbidity. Therefore, it is essential to include them in the differential diagnosis of patients presenting with fecal impaction, anorectal pain, and associated symptoms. Prompt diagnosis, appropriate imaging, and early intervention are crucial for the successful management and prevention of potential complications and the improvement of patient outcomes.

Hospital Utilization for Patients With Cirrhosis and Severe Ascites in a Model of Outpatient Paracentesis by Interventional Radiology.

BACKGROUND:  Paracentesis is currently performed by interventional radiologists (IR) rather than gastroenterologists/hepatologists or internists. In this model of care, there is usually no evaluation of patients' renal function or adjustment of their medications at the time of paracentesis. The objectives of this study were to analyze hospital utilization and cirrhosis complications within six months of index outpatient paracentesis by IR and to identify potential areas of improvement in care. METHODS: This is a retrospective study of patients with cirrhosis and ascites who underwent outpatient paracentesis by IR between October 15, 2015, and October 15, 2018, at a tertiary academic medical center. We collected demographics, data on cirrhosis etiology/complications, laboratory tests, provider notes, outpatient paracentesis dates, emergency department (ED) visits, hospitalizations, and ICU admissions within the following six months post index paracentesis. Associations between categorical predictors and clinical outcomes were analyzed using the chi-square test. Associations between quantitative predictors and clinical outcomes were analyzed using the Wilcoxon rank sum test. RESULTS: Our study included 69 unique patients who had at least one outpatient encounter for paracentesis by IR in the study period. Most patients were men (71%), had alcohol-related cirrhosis as primary etiology (53.6%), an average age of 60 years, and an average Model for End-Stage Liver Disease-sodium (MELDNa) score at baseline of 16. Within six months from index paracentesis, 44 patients (64.7%) underwent repeat IR outpatient paracentesis (total 187 paracenteses, 4.25 paracenteses/patient), 43 patients (62.3%) had ER visits (total 118 ER visits, 2.8/patient), 41 patients (59.4%) had hospital admissions (total 88 admissions, 2.2/patient), and 11 patients required ICU admission. Complications of cirrhosis noted during follow-up included hepatic encephalopathy (40.5%), acute kidney injury (38.2%), upper gastrointestinal (UGI) bleeding (16%), and spontaneous bacterial peritonitis (SBP) in 15%. The mortality rate at six months was 20%. On multivariate analysis, the predictive factors for mortality were older age (p = 0.03) and MELDNa score (p = 0.02). Baseline MELDNa was predictive of acute kidney injury (p = 0.02), UGI bleed (p < 0.01), and ICU admission (p < 0.01), but not of SBP, encephalopathy, ED visit, or hospital admissions. Among patients with more than one paracentesis (64%),six patients underwent transjugular portosystemic shunt (TIPS), but there was no documentation of TIPS consideration in 31 patients (70.4%). A total of 20 patients (29%) were waitlisted for liver transplantation. CONCLUSION: In this contemporary cohort of patients with cirrhosis undergoing outpatient IR paracentesis, we found a high rate of short-term cirrhosis complications and hospital utilization, while TIPS consideration was very low. Further data are needed to identify specific gaps in care, but IR paracentesis should be integrated within a multidisciplinary management model, with emphasis on early TIPS in eligible patients, as recommended by the current practice guidelines.

Immune-bacteriophage interactions in inflammatory bowel diseases.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are influenced by the bacterial and fungal organisms found within the intestine. However, the intestine is also home to a vast number of viral particles, with most of them being viruses that infect prokaryotes, called bacteriophages. While use of bacteriophages to specifically target pathogenic bacterial species involved in IBD is currently under investigation, recent studies have also highlighted that these viral particles can impact the mammalian immune system. IBD is a chronic multi-factorial inflammatory condition with unknown etiology. This review will highlight the current investigations that have revealed that bacteriophage-mammalian immune cell interactions can influence disease processes beyond their known role for infecting bacteria, which might identify novel ways to treat or diagnose IBD.

Intestinal Dysbiosis and Markers of Systemic Inflammation in Viscerally and Generally Obese Persons Living With HIV.

BACKGROUND: The intestinal microbiota contributes to the pathogenesis of obesity and metabolic disorders. People living with HIV (PLWH) have a higher risk for the development of visceral adiposity with accompanying worsened cardiovascular risk. SETTING: Convenience sample from an HIV clinic and research unit. METHODS: To understand the relationship between adiposity and intestinal dysbiosis, we compared the gut microbiota and inflammatory markers in a cross-sectional study of viscerally obese, generally obese, and lean PLWH. Fecal intestinal microbiota was characterized by 16S ribosomal DNA sequencing. Abdominal CTs quantified subcutaneous adipose tissue and visceral adipose tissue (SAT; VAT). Serum high sensitivity C-reactive protein, adiponectin, leptin, IL-6, MCP-1, and sCD14 were assayed. RESULTS: We studied 15, 9, and 11 participants with visceral obesity, general obesity, and lean body type, respectively. The generally obese group were all women and 2/3 African American, whereas the visceral obesity and lean groups were predominantly white and men who have sex with men. Markers of systemic inflammation and sCD14 were higher in general obesity compared with lean. sCD14 was positively correlated with VAT, but not SAT. Bacterial diversity was significantly reduced in participants with visceral and general obesity and composition of intestinal microbiota was significantly different from lean body types. Bacterial alpha diversity was negatively correlated with VAT area, waist/hip ratio, and sCD14, but not with SAT area. CONCLUSIONS: In this exploratory study, obesity in general was associated with dysbiotic intestinal microbiota. The relationships of VAT to bacterial diversity and sCD14 suggest that dysbiosis in viscerally obese PLWH could be associated with heightened inflammatory state.

Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis.

Bacteriophages are the most abundant members of the microbiota and have the potential to shape gut bacterial communities. Changes to bacteriophage composition are associated with disease, but how phages impact mammalian health remains unclear. We noted an induction of host immunity when experimentally treating bacterially driven cancer, leading us to test whether bacteriophages alter immune responses. Treating germ-free mice with bacteriophages leads to immune cell expansion in the gut. Lactobacillus, Escherichia, and Bacteroides bacteriophages and phage DNA stimulated IFN-γ via the nucleotide-sensing receptor TLR9. The resultant immune responses were both phage and bacteria specific. Additionally, increasing bacteriophage levels exacerbated colitis via TLR9 and IFN-γ. Similarly, ulcerative colitis (UC) patients responsive to fecal microbiota transplantation (FMT) have reduced phages compared to non-responders, and mucosal IFN-γ positively correlates with bacteriophage levels. Bacteriophages from active UC patients induced more IFN-γ compared to healthy individuals. Collectively, these results indicate that bacteriophages can alter mucosal immunity to impact mammalian health.

A member of the gut mycobiota modulates host purine metabolism exacerbating colitis in mice.

The commensal microbiota has an important impact on host health, which is only beginning to be elucidated. Despite the presence of fungal, archaeal, and viral members, most studies have focused solely on the bacterial microbiota. Antibodies against the yeast Saccharomyces cerevisiae are found in some patients with Crohn's disease (CD), suggesting that the mycobiota may contribute to disease severity. We report that S. cerevisiae exacerbated intestinal disease in a mouse model of colitis and increased gut barrier permeability. Transcriptome analysis of colon tissue from germ-free mice inoculated with S. cerevisiae or another fungus, Rhodotorula aurantiaca, revealed that S. cerevisiae colonization affected the intestinal barrier and host metabolism. A fecal metabolomics screen of germ-free animals demonstrated that S. cerevisiae colonization enhanced host purine metabolism, leading to an increase in uric acid production. Treatment with uric acid alone worsened disease and increased gut permeability. Allopurinol, a clinical drug used to reduce uric acid, ameliorated colitis induced by S. cerevisiae in mice. In addition, we found a positive correlation between elevated uric acid and anti-yeast antibodies in human sera. Thus, yeast in the gut may be able to potentiate metabolite production that negatively affects the course of inflammatory bowel disease.

MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection.

The presentation of protein antigens on the cell surface by major histocompatibility complex (MHC) molecules coordinates vertebrate adaptive immune responses, thereby mediating susceptibility to a variety of autoimmune and infectious diseases. The composition of symbiotic microbial communities (the microbiota) is influenced by host immunity and can have a profound impact on host physiology. Here we use an MHC congenic mouse model to test the hypothesis that genetic variation at MHC genes among individuals mediates susceptibility to disease by controlling microbiota composition. We find that MHC genotype significantly influences antibody responses against commensals in the gut, and that these responses are correlated with the establishment of unique microbial communities. Transplantation experiments in germfree mice indicate that MHC-mediated differences in microbiota composition are sufficient to explain susceptibility to enteric infection. Our findings indicate that MHC polymorphisms contribute to defining an individual's unique microbial fingerprint that influences health.

The tip of the tail needle affects the rate of DNA delivery by bacteriophage P22.

The P22-like bacteriophages have short tails. Their virions bind to their polysaccharide receptors through six trimeric tailspike proteins that surround the tail tip. These short tails also have a trimeric needle protein that extends beyond the tailspikes from the center of the tail tip, in a position that suggests that it should make first contact with the host's outer membrane during the infection process. The base of the needle serves as a plug that keeps the DNA in the virion, but role of the needle during adsorption and DNA injection is not well understood. Among the P22-like phages are needle types with two completely different C-terminal distal tip domains. In the phage Sf6-type needle, unlike the other P22-type needle, the distal tip folds into a "knob" with a TNF-like fold, similar to the fiber knobs of bacteriophage PRD1 and Adenovirus. The phage HS1 knob is very similar to that of Sf6, and we report here its crystal structure which, like the Sf6 knob, contains three bound L-glutamate molecules. A chimeric P22 phage with a tail needle that contains the HS1 terminal knob efficiently infects the P22 host, Salmonella enterica, suggesting the knob does not confer host specificity. Likewise, mutations that should abrogate the binding of L-glutamate to the needle do not appear to affect virion function, but several different other genetic changes to the tip of the needle slow down potassium release from the host during infection. These findings suggest that the needle plays a role in phage P22 DNA delivery by controlling the kinetics of DNA ejection into the host.

Phage therapy in clinical practice: treatment of human infections.

Phage therapy is the application of bacteria-specific viruses with the goal of reducing or eliminating pathogenic or nuisance bacteria. While phage therapy has become a broadly relevant technology, including veterinary, agricultural, and food microbiology applications, it is for the treatment or prevention of human infections that phage therapy first caught the world's imagination--see, especially, Arrowsmith by Sinclair Lewis (1925)--and which today is the primary motivator of the field. Nonetheless, though the first human phage therapy took place in the 1920s, by the 1940s the field, was in steep decline despite early promise. The causes were at least three-fold: insufficient understanding among researchers of basic phage biology; over exuberance, which led, along with ignorance, to carelessness; and the advent of antibiotics, an easier to handle as well as highly powerful category of antibacterials. The decline in phage therapy was neither uniform nor complete, especially in the former Soviet Republic of Georgia, where phage therapy traditions and practice continue to this day. In this review we strive toward three goals: 1. To provide an overview of the potential of phage therapy as a means of treating or preventing human diseases; 2. To explore the phage therapy state of the art as currently practiced by physicians in various pockets of phage therapy activity around the world, including in terms of potential commercialization; and 3. To avert a recapitulation of phage therapy's early decline by outlining good practices in phage therapy practice, experimentation, and, ultimately, commercialization.