Microbiota composition and mucosal immunity in patients with asymptomatic diverticulosis and controls.

INTRODUCTION: The etiology of diverticulosis is still poorly understood. However, in patients with diverticulitis, markers of mucosal inflammation and microbiota alterations have been found. The aim of this study was to evaluate potential differences of the gut microbiota composition and mucosal immunity between patients with asymptomatic diverticulosis and controls. METHODS: We performed a prospective study on patients who underwent routine colonoscopy for causes not related to diverticular disease or inflammatory bowel disease. Participants were grouped based on the presence or absence of diverticula. Mucosal biopsies were obtained from the sigmoid and transverse colon. Microbiota composition was analyzed with IS-pro, a 16S-23S based bacterial profiling technique. To predict if patients belonged to the asymptomatic diverticulosis or control group a partial least squares discriminant analysis (PLS-DA) regression model was used. Inflammation was assessed by neutrophil and lymphocyte counts within the taken biopsies. RESULTS: Forty-three patients were enrolled. Intestinal microbiota profiles were highly similar within individuals for all phyla. Between individuals, microbiota profiles differed substantially but regardless of the presence (n = 19) of absence (n = 24) of diverticula. Microbiota diversity in both sigmoid and transverse colon was similar in all participants. We were not able to differentiate between diverticulosis patients and controls with a PLS-DA model. Mucosal lymphocyte counts were comparable among both groups; no neutrophils were detected in any of the studied biopsies. CONCLUSIONS: Microbiota composition and inflammatory markers were comparable among asymptomatic diverticulosis patients and controls. This suggests that the gut microbiota and mucosal inflammation do not play a major role in the pathogenesis of diverticula formation.

Genetic variants of tissue inhibitors of matrix metalloproteinase 1 (rs4898) and 2 (rs8179090) in diverticulosis.

INTRODUCTION: Diverticulosis affects approximately 60% of population after 60th year of age. Diverticular disease is symptomatic diverticulosis characterized by abdominal pain, flatulence and bloating, and bowel habits change. Age and lifestyle are risk factors for diverticulosis, additionally genetic predisposition is postulated. The aim of the study was to assess whether tissue inhibitors of matrix metalloproteinase (TIMP) 1 rs4898 and TIMP2 rs8179090 genetic variants are related to colonic diverticulosis. METHODS: The study included 220 patients, 100 with colon diverticulosis diagnosed on colonoscopy and 120 controls. TIMP1 rs4898 and TIMP2 rs8179090 variants were examined using PCR-restriction fragments length polymorphism from a blood sample. RESULTS: Allele T of TIMP1 rs4898 was more frequent in male patients with diverticulosis than in controls (P < 0.01), whereas in women there were no differences in its distribution, both in heterozygotes and homozygotes or in homozygotes separately, proving a recessive effect. TIMP2 s8179090 allele G frequency was 0.95 in cases and controls, there were no CC homozygotes identified, and no associations with diverticulosis showed. CONCLUSION: TIMP1 rs4898 allele T may be a genetic determinant of the risk of diverticulosis in men.

Hypothalamic hamartomas and inner ear diverticula with X-linked stapes gusher syndrome - new associations?

X-linked stapes gusher syndrome is a genetic form of deafness with distinct radiographic features on temporal bone CT. Hypothalamic hamartoma is a congenital glioneuronal anomaly of the hypothalamus. We report a potential association between these two rare anomalies that, to our knowledge, has not been reported. Two brothers presented with sensorineural hearing loss and almost identical inner ear and hypothalamic abnormalities, consistent with a diagnosis of X-linked stapes gusher syndrome and hypothalamic hamartoma. Genetic testing revealed identical mutations in the POU3F4 gene associated with X-linked stapes gusher syndrome. Furthermore, multiple vestibular diverticula were seen in both brothers, which have also not been reported with X-linked stapes gusher syndrome. This case suggests that POU3F4 mediated X-linked stapes gusher syndrome may also lead to multiple vestibular diverticula and hypothalamic hamartoma and, therefore, brain magnetic resonance imaging (MRI) could be considered in patients presenting with these inner ear findings.

Pathogenesis of Diverticulosis and Diverticular Disease.

In this session different problems regarding the pathogenesis of diverticular disease were considered, including "Genetics", "Neuromuscular function abnormalities", "Patterns of mucosa inflammation", and "Impact of lifestyle". The patients affected by diverticular disease have clear genetic pattern, that might predispose to the occurrence of the disease as well as to its complications. Neuromuscular abnormalities may be recognized already at the stage of diverticulosis, and inflammation may explain symptoms occurrence in symptomatic uncomplicated diverticular disease (SUDD) or symptoms persistence after an episode of acute diverticulitis. Finally, lifestyle might also have an impact on symptoms' occurrence. Specifically smoking, but also obesity seem to play an important role, while the role of low-fiber diet and constipation is now under debate.

Uncomplicated diverticular disease: innate and adaptive immunity in human gut mucosa before and after rifaximin.

BACKGROUND/AIM: Uncomplicated diverticular disease (UDD) is a frequent condition in adults. The pathogenesis of symptoms remains unknown. Bacteria are able to interact with Toll-like receptors (TLRs) and to induce inflammation through both innate immunity and T-cell recruitment. We investigated the pattern of TLRs 2 and 4 and the intestinal homing in patients with UDD before and after a course of Rifaximin. METHODS: Forty consecutive patients with UDD and 20 healthy asymptomatic subjects were enrolled. Among UDD patients, 20 were assigned to a 2-month course of treatment with Rifaximin 1.2 g/day for 15 days/month and 20 received placebo. Blood sample and colonic biopsies were obtained from patients and controls. The samples were collected and analyzed at baseline and at the end of treatment. Flow cytometry was performed using monoclonal antibodies (CD3, CD4, CD8, CD103, TCR-gamma/delta, CD14, TLR2, and TLR4). RESULTS: In UDD, TLR2 and TLR4 expression on immune cell subpopulations from blood and mucosa of the affected colon are altered as compared with controls. Rifaximin treatment induced significant modifications of altered conditions. CONCLUSIONS: Our data show the role of TLRs in the development of inflammation in UDD. TLRs distribution is altered in UDD and these alterations are reversed after antibiotic treatment. This trial is registered with ClinicalTrials.gov: NCT02068482.

Long segmental hyperplasia of interstitial cells of Cajal with giant diverticulum formation.

Sporadic gastrointestinal stromal tumors (GISTs) usually form a well-circumscribed mass. In contrast, diffuse interstitial cell of Cajal (ICC) hyperplasia along the Auerbach plexus without a discrete mass may occur in patients with germline mutations in the NF1, c-KIT or PDGFRA genes. However, sporadic, diffuse ICC hyperplasia without c-KIT or PDGFRA mutations has not been reported. We describe herein one such case, forming a giant diverticulum. A 63-year-old woman with no features of Neurofibromatosis 1 (NF1) presented with increasing abdominal pain for more than 30 years. A large, diverticulum-like mass in the ileum was resected. Microscopically, a diffuse proliferation of bland spindle cells was seen extending for 12 cm, replacing the muscularis propria and lined by intact mucosa. The spindle cells were CD117+/CD34+/DOG1+/SMA+/Desmin-/S100-. Mutation analyses did not reveal any mutations in c-KIT or PDGFRA. The lesion had two silent mutations in the NF1 gene. It is rare of the diffuse form of sporadic ICC hyperplasia showing diffuse longitudinal microscopic growth completely replacing the muscularis propria, mimicking diffuse ICC hyperplasia in hereditary GIST syndromes, but without solid components and no c-KIT or PDGFRA gene mutations. This peculiar form of sporadic ICC hyperplasia may be related to intestinal dysmotility in this ileal segment and giant diverticulum formation.

Heritability and familial aggregation of diverticular disease: a population-based study of twins and siblings.

BACKGROUND & AIMS: Little is known about the role of heritable factors in diverticular disease. We evaluated the contribution of heritable factors to the development of diverticular disease diagnosed at a hospitalization or outpatient visit. METHODS: Using nationwide patient registries, we identified 142,123 incident cases of diverticular disease diagnosed at a hospitalization (1977-2011) or an outpatient hospital visit (1995-2011) in Denmark, including cases in 10,420 index siblings and 923 twins. We calculated standardized incidence ratios for siblings versus the general population and concordance rates for monozygotic versus dizygotic twin pairs as measures of relative risk (RR). RESULTS: The RR for diverticular disease in siblings of index cases was 2.92 (95% confidence interval [CI], 2.50-3.39) compared with the general population. The RRs were similar irrespective of the sex of the sibling or index case and were particularly strong in siblings of hospitalized cases and cases that underwent surgery. The proband-wise concordance rate for monozygotic twins was double that of dizygotic twins (0.16 [95% CI, 0.11-0.22] vs 0.07 [95% CI, 0.05-0.11], respectively). The RR of diverticular disease in one twin when the other had diverticular disease was 14.5 (95% CI, 8.9-23) for monozygotic twins compared with 5.5 (95% CI, 3.3-8.6) for dizygotic twins. Associations were stronger in female monozygotic twins compared with male twins (tetrachoric correlation, 0.60 [95% CI, 0.49-0.70] vs 0.33 [95% CI, 0.13-0.51]; P = .03 in an analysis stratified by sex and zygosity). We estimate that 53% (95% CI, 45%-61%) of susceptibility to diverticular disease results from genetic factors. CONCLUSIONS: Based on a population-based study in Denmark, genetic factors appear to contribute to development of diverticular disease.

The genetic influence on diverticular disease--a twin study.

BACKGROUND: The contribution of hereditary factors to the development of diverticular disease (DD) of the colon is unknown. Prevalence and location of diverticula differ in Western world compared to in Asia and several case reports describing families with DD have been published. AIM: To assess the heritability of DD in a large population-based sample of twins. METHODS: The Swedish Twin Registry was cross-linked to the Swedish Inpatient Registry. All twins, born between 1886 and 1980 and not dead before 1969, with a discharge diagnosis of DD were identified. Twins with diagnoses of colon cancer, coeliac disease or non-infectious colitis were excluded to decrease bias. Co-twin odds ratio (OR), concordance rates and tetrachoric correlations were calculated for monozygotic (MZ) and same gender-dizygotic (SS-DZ) twins. Mx-analyses were used to estimate the relative contributions of genetic effects and environmental factors to susceptibility for DD. Calculations were based on both primary and secondary discharge diagnoses to provide estimates reflecting impact of severity of the disease. RESULTS: A total of 104,452 twins met the inclusion criteria. Of these, 2296 had a diagnosis of DD. The OR of developing the disease given one's co-twin was affected was 7.15 (95% CI: 4.82-10.61) for MZ and 3.20 (95% CI: 2.21-4.63) for SS-DZ twins. Similarly, concordance rates and tetrachoric correlations were higher in MZ than those in SS-DZ twins. The heritability was estimated to 40% and the non shared environmental effects to 60%. CONCLUSION: Genetic susceptibility is an important component, along with individual specific environmental factors, for the development of diverticular disease of the colon.

Transforming growth factor ß receptor type 1 is essential for female reproductive tract integrity and function.

The transforming growth factor ß (TGFß) superfamily proteins are principle regulators of numerous biological functions. Although recent studies have gained tremendous insights into this growth factor family in female reproduction, the functions of the receptors in vivo remain poorly defined. TGFß type 1 receptor (TGFBR1), also known as activin receptor-like kinase 5, is the major type 1 receptor for TGFß ligands. Tgfbr1 null mice die embryonically, precluding functional characterization of TGFBR1 postnatally. To study TGFBR1-mediated signaling in female reproduction, we generated a mouse model with conditional knockout (cKO) of Tgfbr1 in the female reproductive tract using anti-Müllerian hormone receptor type 2 promoter-driven Cre recombinase. We found that Tgfbr1 cKO females are sterile. However, unlike its role in growth differentiation factor 9 (GDF9) signaling in vitro, TGFBR1 seems to be dispensable for GDF9 signaling in vivo. Strikingly, we discovered that the Tgfbr1 cKO females develop oviductal diverticula, which impair embryo development and transit of embryos to the uterus. Molecular analysis further demonstrated the dysregulation of several cell differentiation and migration genes (e.g., Krt12, Ace2, and MyoR) that are potentially associated with female reproductive tract development. Moreover, defective smooth muscle development was also revealed in the uteri of the Tgfbr1 cKO mice. Thus, TGFBR1 is required for female reproductive tract integrity and function, and disruption of TGFBR1-mediated signaling leads to catastrophic structural and functional consequences in the oviduct and uterus.

Cervical aortic arch and Kommerell's diverticulum associated with the anomalous subaortic left brachiocephalic vein in a patient with chromosome 22q11.2 deletion.

We report the surgical case of an eight-year-old girl who had a very rare combination of ventricular septal defect and abnormal aortic arch anatomy: right cervical aortic arch, left descending aorta and Kommerell's diverticulum from which the left subclavian artery arose with anomalous subaortic left brachiocephalic vein. She was confirmed the chromosomal 22q11.2 deletion.

The outcome of diverticulosis in kidney recipients with polycystic kidney disease.

INTRODUCTION: Diverticulosis is a common finding in autosomal-dominant polycystic kidney disease (ADPKD). To avoid the serious complications of diverticulosis after kidney transplantation, some policies have recommended aggressive actions, such as elective colectomy. These policies are not widely agreed upon. This controversy led us to investigate the serious complications and the outcome of diverticulosis in ADPKD kidney recipients to see whether such therapies are justified. MATERIALS AND METHODS: From 2002 to 2006, we followed 18 ADPKD kidney recipient patients with barium enema-documented diverticulosis. All subjects were asymptomatic for diverticulosis at the time of transplantation. The mean value +/- SD of follow-up duration was 25.4 +/- 28.5 months. We documented demographic data, familial history of ADPKD, barium enema findings, and complications as well as graft and patient survivals. RESULTS: Hepatic flexure was the most prevalent site for diverticula. The mean (SD) of diverticular count was 6 +/- 5.1. Patients with a familial history of ADPKD showed a higher number of diverticular (P=.01). Diverticulitis occurred in three patients, all of whom died. CONCLUSION: Diverticulitis is a fatal and not rare complication in ADPKD patients. The rate of complications in our study was similar to previous findings, but we observed serious complications even among patients asymptomatic at the time of transplantation. The decision to take aggressive action such as elective colectomy is still a matter of debate that needs further evaluation.

Extensive jejunal diverticulosis in a family, a matter of inheritance?

Diverticulosis of the jejunum is a rare finding (0.06 to 1.3%). Possible complications are bacterial overgrowth, malabsorption, bleeding, mechanical obstruction, volvulus and perforation. At present only one case report on familial jejunal diverticulosis has been published. We describe three patients with jejunal diverticulosis within one family, which might suggest inheritance.

Smoothelin-a is essential for functional intestinal smooth muscle contractility in mice.

BACKGROUND & AIMS: In patients with chronic intestinal pseudo-obstruction, intestinal motility is disturbed by either nervous or myogenic aberrations. The cause of the myogenic form is unknown, but it is likely to originate in the contractile apparatus of the smooth muscle cells. Smoothelins are actin-binding proteins that are expressed abundantly in visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Experimental data indicate a role for smoothelins in smooth muscle contraction. A smoothelin-deficient mouse model may help to establish the role of smoothelin-A in intestinal contraction and provide a model for myogenic chronic intestinal pseudo-obstruction. METHODS: We used gene targeting to investigate the function of smoothelin-A in intestinal tissues. By deletion of exons 18, 19, and 20 from the smoothelin gene, the expression of both smoothelin isoforms was disrupted. The effects of the deficiency were evaluated by pathologic and physiologic analyses. RESULTS: In smoothelin-A/B knockout mice, the intestine was fragile and less flexible compared with wild-type littermates. The circular and longitudinal muscle layers of the intestine were hypertrophic. Deficiency of smoothelin-A led to irregular slow wave patterns and impaired contraction of intestinal smooth muscle, leading to hampered transport in vivo. This caused obstructions that provoked intestinal diverticulosis and occasionally intestinal rupture. CONCLUSIONS: Smoothelin-A is essential for functional contractility of intestinal smooth muscle. Hampered intestinal transit in smoothelin-A/B knockout mice causes obstruction, starvation, and, ultimately, premature death. The pathology of mice lacking smoothelin-A is reminiscent of that seen in patients with chronic intestinal pseudo-obstruction.

Autosomal dominant occipital cephalocele.

The authors report the clinical and radiographic characteristics of a non-consanguineous Vietnamese kindred with an autosomal dominant form of occipital cephalocele. Affected family members all presented with occipital subscalp bulges at birth. Except for the proband, all individuals were developmentally normal with otherwise normal neurologic examinations. Unaffected family members, including obligate carriers, share no clinical characteristics, demonstrating incomplete penetrance.

Hypoparathyroidism associated with aneurysm of the left subclavian artery (Kommerell's diverticulum) in an adult patient with a chromosome 22q11.2 deletion.

Hypoparathyroidism may either be acquired or of congenital origin. From the latter group, which represents a minority of cases, agenesis or hypoplasia of the parathyroid glands resulting in symptomatic hypocalcemia in the newborn or infant frequently is caused by a microdeletion of chromosome 22q11.2. We describe a man in whom hypoparathyroidism was first diagnosed at the age of 59 years. The endocrine disorder was found to be associated with this chromosome imbalance and also with an aneurysm of the left subclavian artery (Kommerell's diverticulum) compressing the esophagus and trachea. Given the potential implication for genetic counseling, a 22q11.2 deletion should be considered in the differential diagnosis of adult patients with hypoparathyroidism of unknown origin and should be searched for by appropriate molecular cytogenetic technique.