Gut Microbial Dysbiosis in the Pathogenesis of Gastrointestinal Dysmotility and Metabolic Disorders

Of all microorganisms in the human body, the largest and most complex population resides in the gastrointestinal (GI) tract. The gut microbiota continuously adapts to the host environment and serves multiple critical functions for their hosts, including regulating host immunity, procuring energy from food, and preventing the colonization of pathogens. Mounting evidence has suggested gut microbial imbalance (dysbiosis) as a core pathophysiology in the development of GI motility and metabolic disorders, such as irritable bowel syndrome and diabetes. Current research has focused on discovering associations between these disorders and gut microbial dysbiosis; however, whether these associations are a consequence or cause is still mostly unexplored. State-of-the-art studies have investigated how gut microbes communicate with our body systems through microbiota-derived metabolites and how they are able to modulate host physiology. There is now mounting evidence that alterations in the composition of small intestinal microbes have an association with GI dysmotility and metabolic disorders. Although treatment options for gut microbial dysbiosis are currently limited, antibiotics, fecal microbiota transplantation, probiotics, and dietary interventions are currently the best options. However, treatment with broad-spectrum antibiotics has been viewed with skepticism due to the risk of developing antibiotic resistant bacteria. Studies are warranted to elucidate the cellular and molecular pathways underlying gut microbiota-host crosstalk and for the development of a powerful platform for future therapeutic approaches. Here, we review recent literature on gut microbial alterations and/or interactions involved in the pathophysiology of GI dysmotility and metabolic disorders.

A case of oligoasthenoteratozoospermia with AZFc deletion and persistent oxidative stress.

Y-chromosomal microdeletions are associated with severe oligozoospermia or azoospermia. AZFc microdeletions have been always associated with severe oligozoospermia or azoospermia with a rare occurrence in individuals with other infertility phenotypes. We report here a rare case of an infertile man carrying AZFc deletion, whose semen picture is oligoasthenoteratozoospermia complexed with seminal oxidative stress. Anti-oxidant therapy could make no change in either oxidative stress biomarker levels of semen, seminal parameters or serum hormone levels. Therefore, oligoasthenoteratozoospermia in the present case correlates with AZFc deletion, and high content of abnormal sperm eventually might be responsible for persistently elevated reactive oxygen species levels. Understanding the function of genes in AZFc region could help decipher the exact cause of the phenotype in such cases.

R659X mutation in the MLH1 gene in hereditary non-polyposis colorectal cancer (HNPCC) in an Indian extended family.

Background & objective: Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome), is a genetically heterogeneous disorder that is believed to account for 2–10 per cent of all the colorectal cancer cases. The disease follows autosomal dominant inheritance pattern with high penetrance (85%) and younger age of onset when compared to patients with sporadic tumours. HNPCC is associated with germ-line mutations in the DNA mismatch repair (MMR) genes namely MLH1, MSH2, MSH6, and PMS2. The present study was aimed at analyzing mismatch repair gene(s) in an extended Indian family satisfying the Amsterdam criteria, and extending the analysis to general population to estimate frequency of the mutations/polymorphisms observed. Methods: A total 12 members of the HNPCC family were studied for genetic investigation. Ethnically matched 250 normal individuals were also included as controls to study the observed mutations/ polymorphisms at population level. Results: The analysis resulted in identification of a 1975C>T mutation in exon 17, resulting in substitution of arginine residue with stop codon at codon 659. 655A>G substitution was also observed, resulting in replacement of isoleucine with valine at codon 219. Similar analysis on 250 ethnically matched control subjects revealed complete absence of R659X mutation, while I219V variant was found in 9.8 per cent of the controls. Interpretation & conclusion: R659X mutation correlates with disease phenotype, and 655A>G locus is highly polymorphic. Our study suggested that R659X substitution was prime cause for the disease phenotype in this family. I219V substitution is a polymorphism having no association with the disease onset or segregation. The family members harbouring this mutation were advised to be under regular medical surveillance.

Androgen insensitivity syndrome: do trinucleotide repeats in androgen receptor gene have any role? / 亚洲男科学杂志(英文版)

<p><b>AIM</b>To investigate the role of CAG and GGN repeats as genetic background affecting androgen insensitivity syndrome (AIS) phenotype.</p><p><b>METHODS</b>We analyzed lengths of androgen receptor (AR)-CAG and GGN repeats in 69 AIS cases, along with 136 unrelated normal male individuals. The lengths of repeats were analyzed using polymerase chain reaction (PCR) amplification followed by allelic genotyping to determine allele length.</p><p><b>RESULTS</b>Our study revealed significantly shorter mean lengths of CAG repeats in patients (mean 18.25 repeats, range 14-26 repeats) in comparison to the controls (mean 22.57 repeats, range 12-39 repeats) (two-tailed P < 0.0001). GGN repeats, however, did not differ significantly between patients (mean 21.48 repeats) and controls (mean 21.21 repeats) (two-tailed P = 0.474). Among patients' groups, the mean number of CAG repeats in partial androgen insensitivity cases (mean 15.83 repeats) was significantly less than in complete androgen insensitivity cases (mean 19.46 repeats) (two-tailed P < 0.0001).</p><p><b>CONCLUSION</b>The findings suggest that shorter lengths of repeats in the AR gene might act as low penetrance genetic background in varying manifestation of androgen insensitivity.</p>

Phenotypic heterogeneity of mutations in androgen receptor gene / 亚洲男科学杂志(英文版)

Androgen receptor (AR) gene has been extensively studied in diverse clinical conditions. In addition to the point mutations, trinucleotide repeat (CAG and GGN) length polymorphisms have been an additional subject of interest and controversy among geneticists. The polymorphic variations in triplet repeats have been associated with a number of disorders, but at the same time contradictory findings have also been reported. Further, studies on the same disorder in different populations have generated different results. Therefore, combined analysis or review of the published studies has been of much value to extract information on the significance of variations in the gene in various clinical conditions. AR genetics has been reviewed extensively but until now review articles have focused on individual clinical categories such as androgen insensitivity, male infertility, prostate cancer, and so on. We have made the first effort to review most the aspects of AR genetics. The impact of androgens in various disorders and polymorphic variations in the AR gene is the main focus of this review. Additionally, the correlations observed in various studies have been discussed in the light of in vitro evidences available for the effect of AR gene variations on the action of androgens.

Indocyanine green enhanced maculorhexis in macular hole surgery.

PURPOSE: To demonstrate the usefulness of staining the internal limiting membrane (ILM) with a solution of indocyanine green (ICG) to facilitate the removal of ILM in eyes with idiopathic macular hole. METHODS: Eighteen patients underwent vitrectomy with the removal of posterior cortical vitreous, induction of posterior vitreous detachment (PVD), ICG-enhanced removal of the macular ILM, and fluid-gas exchange, followed by facedown positioning. RESULTS: Fifteen (83.33%) of the macular holes were closed at 3 months postoperatively. The visual outcome was relatively better in holes smaller than 400 microns in diameter, as compared to bigger macular holes (more than 400 microns in diameter). Of the 18 eyes, 9 (50%) recorded visual improvement of 2 or more lines over the preoperative level. CONCLUSION: Our results show the safety and usefulness of this technique in visualization of the ILM during macular hole surgery, thereby leading to successful removal of optimal amount of ILM, with minimum damage to the retina.

Marker assisted detection of gene (1Dx5) and translocation (1B/1R) in wheat genotypes.

Detection of 1Dx5 gene and presence of 1B/1R wheat rye translocation were studied in nineteen elite Indian wheat genotypes using AS-PCR and STS markers, respectively. Fifteen genotypes had 1B/1R translocation whereas ten showed presence of 1Dx5 gene. More than 50 per cent of the genotypes tested were found positive for both 1Dx5 and 1B/1R translocation. The results are in conformity with HMW glutenin SDS-PAGE profile for 1Dx5 and cytological observations for 1B/1R translocation.