Pathophysiology of diverticular disease.

INTRODUCTION: Inflammation of diverticula, or outpouchings of the colonic mucosa and submucosa through the muscularis layer, leads to diverticulitis. The development of diverticular disease, encompassing both diverticulosis and diverticulitis, is a result of genetic predisposition, lifestyle, and environmental factors, including the microbiome. Areas covered: Previous reports implicated genetic predisposition, environmental factors, and colonic dysmotility in diverticular disease. Recent studies have associated specific host immune responses and the microbiome as contributors to diverticulitis. To review pertinent literature describing pathophysiological factors associated with diverticulosis or diverticulitis, we searched the PubMed database (March 2018) for articles considering the role of colonic architecture, genetic predisposition, environment, colonic motility, immune response, and the microbiome. Expert commentary: In the recent years, research into the molecular underpinnings of diverticular disease has enhanced our understanding of diverticular disease pathogenesis. Although acute uncomplicated diverticulitis is treated with broad spectrum antibiotics, evaluation of the microbiome has been limited and requires further comprehensive studies. Evidence suggests that a deregulation of the host immune response is associated with both diverticulosis and diverticulitis. Further examining these pathways may reveal proteins that can be therapeutic targets or aid in identifying biological determinants of clinical or surgical decision making.

An Aberrant Microbiota is not Strongly Associated with Incidental Colonic Diverticulosis.

Colonic diverticula are protrusions of the mucosa through weak areas of the colonic musculature. The etiology of diverticulosis is poorly understood, but could be related to gut bacteria. Using mucosal biopsies from the sigmoid colon of 226 subjects with and 309 subjects without diverticula during first-time screening colonoscopy, we assessed whether individuals with incidental colonic diverticulosis have alternations in the adherent bacterial communities in the sigmoid colon. We found little evidence of substantial associations between the microbial community and diverticulosis among cases and controls. Comparisons of bacterial abundances across all taxonomic levels showed differences for phylum Proteobacteria (p = 0.038) and family Comamonadaceae (p = 0.035). The r-squared values measuring the strength of these associations were very weak, however, with values ~2%. There was a similarly small association between the abundance of each taxa and total diverticula counts. Cases with proximal only diverticula and distal only diverticula likewise showed little difference in overall microbiota profiles. This large study suggests little association between diverticula and the mucosal microbiota overall, or by diverticula number and location. We conclude that the mucosal adherent microbiota community composition is unlikely to play a substantial role in development of diverticulosis.

Gut microbiota, metabolome and immune signatures in patients with uncomplicated diverticular disease.

OBJECTIVE: The engagement of the gut microbiota in the development of symptoms and complications of diverticular disease has been frequently hypothesised. Our aim was to explore colonic immunocytes, gut microbiota and the metabolome in patients with diverticular disease in a descriptive, cross-sectional, pilot study. DESIGN: Following colonoscopy with biopsy and questionnaire phenotyping, patients were classified into diverticulosis or symptomatic uncomplicated diverticular disease; asymptomatic subjects served as controls. Mucosal immunocytes, in the diverticular region and in unaffected sites, were quantified with immunohistochemistry. Mucosa and faecal microbiota were analysed by the phylogenetic platform high taxonomic fingerprint (HTF)-Microbi.Array, while the metabolome was assessed by 1H nuclear magnetic resonance. RESULTS: Compared with controls, patients with diverticula, regardless of symptoms, had a >70% increase in colonic macrophages. Their faecal microbiota showed depletion of Clostridium cluster IV. Clostridium cluster IX, Fusobacterium and Lactobacillaceae were reduced in symptomatic versus asymptomatic patients. A negative correlation was found between macrophages and mucosal Clostridium cluster IV and Akkermansia. Urinary and faecal metabolome changes in diverticular disease involved the hippurate and kynurenine pathways. Six urinary molecules allowed to discriminate diverticular disease and control groups with >95% accuracy. CONCLUSIONS: Patients with colonic diverticular disease show depletion of microbiota members with anti-inflammatory activity associated with mucosal macrophage infiltration. Metabolome profiles were linked to inflammatory pathways and gut neuromotor dysfunction and showed the ability to discriminate diverticular subgroups and controls. These data pave the way for further large-scale studies specifically aimed at identifying microbiota signatures with a potential diagnostic value in patients with diverticular disease.

Probiotics for the Treatment of Symptomatic Uncomplicated Diverticular Disease: Rationale and Current Evidence.

Changes in the colonic microbiota are critical to the pathogenesis of diverticular complications such as diverticulitis and peridiverticular abscesses. However, more subtle changes in microbiota composition may well be important to the more chronic manifestations of diverticulosis. Some studies have shown the presence of bacterial overgrowth in subgroups of patients with diverticular disease and recent studies, using molecular biology techniques, found an increase of proteobacteria and actinobacteria in patients with symptomatic uncomplicated diverticular disease (SUDD), compared with healthy controls. The use of probiotics to modulate intestinal microecology in SUDD appears therefore rational. Although several investigations evaluating the clinical efficacy of probiotics have been performed, no definitive results have yet been achieved, mainly due to the heterogeneity of the available studies. Most of the studies used probiotics in combination with poorly absorbed antimicrobials or anti-inflammatory drugs. In only 4 studies, there was a harm using probiotics alone, but only 1 was a placebo-controlled, double-blind trial. The analysis of the available evidence reveals a poor quality of the published studies, whose design was heterogeneous, with only 2 out of 11 trials being double-blind and randomized. Therefore, available data can only suggest a benefit of probiotics in SUDD, but do not allow any evidence-based definite conclusion. As a consequence, current guidelines state that there is insufficient evidence to recommend probiotics for symptom relief in patients with diverticular disease.

Assessment of Fecal Microbiota and Fecal Metabolome in Symptomatic Uncomplicated Diverticular Disease of the Colon.

GOAL: The aim of this study was to assess fecal microbiota and metabolome in a population with symptomatic uncomplicated diverticular disease (SUDD). BACKGROUND: Whether intestinal microbiota and metabolic profiling may be altered in patients with SUDD is unknown. PATIENTS AND METHODS: Stool samples from 44 consecutive women [15 patients with SUDD, 13 with asymptomatic diverticulosis (AD), and 16 healthy controls (HCs)] were analyzed. Real-time polymerase chain reaction was used to quantify targeted microorganisms. High-resolution proton nuclear magnetic resonance spectroscopy associated with multivariate analysis with partial least-square discriminant analysis (PLS-DA) was applied on the metabolite data set. RESULTS: The overall bacterial quantity did not differ among the 3 groups (P=0.449), with no difference in Bacteroides/Prevotella, Clostridium coccoides, Bifidobacterium, Lactobacillus, and Escherichia coli subgroups. The amount of Akkermansia muciniphila species was significantly different between HC, AD, and SUDD subjects (P=0.017). PLS-DA analysis of nuclear magnetic resonance -based metabolomics associated with microbiological data showed significant discrimination between HCs and AD patients (R=0.733; Q=0.383; P<0.05, LV=2). PLS analysis showed lower N-acetyl compound and isovalerate levels in AD, associated with higher levels of A. municiphila, as compared with the HC group. PLS-DA applied on AD and SUDD samples showed a good discrimination between these 2 groups (R=0.69; Q=0.35; LV=2). SUDD patients were characterized by low levels of valerate, butyrate, and choline and by high levels of N-acetyl derivatives and U1. CONCLUSIONS: SUDD and AD do not show colonic bacterial overgrowth, but a significant difference in the levels of fecal A. muciniphila was observed. Moreover, increasing expression of some metabolites as expression of different AD and SUDD metabolic activity was found.

Changing views on diverticular disease: impact of aging, obesity, diet, and microbiota.

The development of colonic diverticulosis is a common aging change in industrialized nations. While most patients have asymptomatic diverticulosis, around one in five develops symptomatic diverticular disease. This is characterized by recurrent abdominal pain and disturbed bowel habit. Some of the pain episodes are prolonged and are due to acute diverticulitis, which itself may be complicated by abscess, perforation, fistulation, or stricture formation. Risk factors favouring the development of symptomatic diverticular disease include obesity, smoking and diets low in fiber but high in red meat and animal fat. What determines the transition from asymptomatic diverticulosis to symptomatic diverticular disease is unclear but neuromuscular changes following acute diverticulitis may be responsible in some cases. The severity of symptoms generated depends on cerebral pain processing which is influenced by psychosocial factors. These are important considerations in deciding optimal patient management. Prior theories of the cause of diverticulosis suggested that constipation was an important cause, but new data challenge this and has provoked new ideas. Underlying mechanisms causing diverticulosis include weakening of the colonic wall and/or degenerative changes in the enteric nerves. Dietary induced changes in microbiota and the host inflammatory response may underlie the subsequent development of acute/chronic diverticulitis and its sequela.

Prospective evaluation of peritoneal fluid contamination following transabdominal vs. transanal specimen extraction in laparoscopic left-sided colorectal resections.

BACKGROUND: Natural orifice specimen extraction (NOSE) in colorectal surgery prevents the need for an enlarged port site or minilaparotomy to extract the surgical specimen. The downside of this technique may be an increased risk of bacterial contamination of the peritoneal cavity from the external milieu. The aim of this study was to prospectively analyze the peritoneal bacterial contamination in NOSE and non-NOSE laparoscopic colorectal procedures. METHODS: Consecutive patients operated for sigmoid diverticulitis with laparoscopic approach and transanal extraction of the specimen from January to December 2010 at our university hospital were enrolled. Patients who underwent a laparoscopic sigmoidectomy in the same study period with conventional specimen extraction were used as reference. Peritoneal fluid samples were collected under sterile conditions at the end of the procedure and sent for gram stain as well as anaerobic, aerobic, and fungal cultures. RESULTS: Twenty-nine patients underwent laparoscopic sigmoidectomy for diverticulitis with transanal NOSE, while 9 patients underwent laparoscopic sigmoidectomy with conventional specimen extraction during the same period. The two groups were successfully matched 1:2 (17 NOSE and 9 non-NOSE) according age, sex, ASA, and Charlson comorbidity score. The contamination rate of peritoneal fluid was 100% vs. 88.9% in NOSE and non-NOSE procedures, respectively (P = 0.23). Overall and major complications rates were 27.6% vs. 11.10% (P = 0.41) and 5.08% vs. 11.1% (P = 1) in NOSE vs. non-NOSE procedures, respectively. In the NOSE group there was a statistically significant lower consumption of oral paracetamol (P = 0.007) and of oral tramadol (P = 0.02). CONCLUSIONS: Although a higher peritoneal contamination was found in the NOSE procedures, there were no significant differences in clinical outcomes relative to standard approach. Avoiding a minilaparotomy to extract the specimen resulted in a significantly lower postoperative analgesic requirement in the NOSE group.

Accelerated recovery from Candida peritonitis of enteric origin by early surgical drainage in a peritoneal dialysis patient.

A 62-year-old man on continuous ambulatory peritoneal dialysis was transferred to our hospital with recurrent abdominal pain and a cloudy peritoneal effluent. Three weeks before the transfer, his symptoms were successfully treated with broad-spectrum antibiotics. However, their effectiveness was lost for his recurrent symptoms. Fungal peritonitis was diagnosed because of an increased white blood cell count in the peritoneal fluid on admission and isolation of Candida albicans from a peritoneal fluid culture. Intravenous fos-fluconazole was immediately started, although it was ineffective for his deteriorating symptoms. The concomitant isolation of Candida albicans in a stool culture suggested that fungal peritonitis had an enteric origin. An emergency laparotomy revealed multiple diverticulosis and sigmoid colon diverticulitis. A surgical drainage was performed in addition to peritoneal catheter removal. Postoperatively, the patient's symptoms improved rapidly and there were no signs of recurrence with continuous administration of fos-fluconazole. Surgical drainage accelerated the recovery from fungal peritonitis. This patient is the first case showing the usefulness of stool culture in the diagnosis of fungal peritonitis secondary to prior bacterial peritonitis. This case also demonstrated the importance of laparotomy to confirm the enteric origin of the fungus, and the efficacy of early surgical drainage for the treatment.

[Evaluation of alpha-normiks (rifaximin) efficacy in the treatment of patients with diverticular disease associated with medium and severe intestinal dysbacteriosis].

THE PURPOSE OF THE STUDY: to evaluate the efficacy of using rifaksimin drug within complex therapy of patients with the disease and diverticular intestinal dysbacteriosis. MATERIALS AND METHODS: 57 patients participated with a moderate exacerbation of the disease, they were divided equally on the composition of the group--two control and one under study. Patients in the control groups were composed of complex treatment of oral antibacterial drugs, or bacteriophage, the investigated group of patients--rifaksimin. We evaluated the dynamics of clinical symptoms, analysis of stool for dysbacteriosis and biochemical parameters. RESULTS: detected superior effectiveness of the Alpha-normiks drug in the treatment of patients with colon pathologies investigated in comparison with the use of oral antibacterial drugs, or bacteriophages. Proved the high safety of treatment with using of rifaksimin. CONCLUSIONS: The preparation of Alpha-normiks may be appointed with great success at patients with diverticular disease, and with intestinal dysbacteriosis.

Molecular characterization of the bacteria adherent to human colorectal mucosa.

AIMS: To study large intestinal mucosal bacterial communities by Denaturing Gradient Gel Electrophoresis (DGGE) profiling and sequencing of 16S rRNA gene polymerase chain reaction (PCR) products amplified from DNA extracted from colorectal biopsies taken from healthy individuals. The specific aims were to determine how similar the mucosa-associated bacterial communities are within and between individuals and also to characterize the phylogenetic origin of isolated DGGE bands. METHODS AND RESULTS: Human colorectal biopsies were taken at routine colonoscopy from 33 patients with normal looking mucosa. The DNA was extracted directly from single biopsies and the bacterial 16S rDNA PCR amplified. The PCR products were profiled using DGGE to generate a fingerprint of the dominant members of the bacterial community associated with the biopsy. The reproducibility of this method was high (>98%). Washed and unwashed biopsies gave similar DGGE banding patterns (Median Similarity Coefficient - MSC 96%, InterQuartile Range - IQR 3.0%, n = 5). Adjacent biopsies sampled from the same patient using different forceps gave similar DGGE profiles (MSC 94%, n = 2). Two colorectal biopsies sampled at locations 2-5 cm apart, from each of 18 patients, resulted in very similar profiles (MSC 100%, IQR 2.8%). Biopsies sampled from different locations within the large intestine of the same patient also gave similar DGGE profiles (MSC 98% IQR 3.3%n = 6). Although all patients (n = 33) gave different DGGE profiles, some similarity (c. 34%) was observed between profiles obtained from 15 patients arbitrarily selected. 35 DGGE bands were excised and sequenced. Many were found to be most closely related to uncultured bacterial sequence entries in the Genbank database. Others belonged to typical gut bacterial genera including Bacteroides, Ruminococcus, Faecalibacterium and Clostridium. CONCLUSIONS: Bacterial communities adherent to colorectal mucosa within a normal patient show little variation; in contrast, mucosal bacterial communities sampled from different patients with normal colorectal mucosa show a high degree of variation. SIGNIFICANCE AND IMPACT OF THE STUDY: This research demonstrates that DGGE profiling of 16S rRNA gene PCR products amplified from DNA extracted directly from mucosal samples offers fresh insight into the bacterial communities that are adherent to colorectal mucosa. These findings are important with respect to further studies on the gastrointestinal tract in health and disease.