Lama Nazzal - Academia.edu (original) (raw)

Papers by Lama Nazzal

Research paper thumbnail of End Point Considerations for Clinical Trials in Enteric Hyperoxaluria

Clinical Journal of The American Society of Nephrology, Jun 21, 2023

Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion ... more Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion due to increased gastrointestinal oxalate absorption. Causative features include fat malabsorption and/or increased intestinal permeability to oxalate. Enteric hyperoxaluria has long been known to cause nephrolithiasis and nephrocalcinosis, and, more recently, an association with CKD and kidney failure has been shown. Currently, there are no US Food and Drug Administration–approved therapies for enteric hyperoxaluria, and it is unclear what end points should be used to evaluate the efficacy of new drugs and biologics for this condition. This study represents work of a multidisciplinary group convened by the Kidney Health Initiative to review the evidence supporting potential end points for clinical trials in enteric hyperoxaluria. A potential clinical outcome is symptomatic kidney stone events. Potential surrogate end points include (1) an irreversible loss of kidney function as a surrogate for progression to kidney failure, (2) asymptomatic kidney stone growth/new stone formation observed on imaging as a surrogate for symptomatic kidney stone events, (3) urinary oxalate and urinary calcium oxalate supersaturation as surrogates for the development of symptomatic kidney stone events, and (4) plasma oxalate as a surrogate for the development of the clinical manifestations of systemic oxalosis. Unfortunately, because of gaps in the data, this Kidney Health Initiative workgroup was unable to provide definitive recommendations. Work is underway to obtain robust information that can be used to inform trial design and medical product development in this space.

Research paper thumbnail of Oxalate homeostasis

Nature Reviews Nephrology

Research paper thumbnail of The Microbiome and Uremic Solutes

Toxins, Mar 30, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Author response: Microbial genetic and transcriptional contributions to oxalate degradation by the gut microbiota in health and disease

Research paper thumbnail of Additional file 15: of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

R functions that were used in Additional files 13 and 14. (R 2 kb)

Research paper thumbnail of Additional file 14: of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

R script for network analysis. (R 9 kb)

Research paper thumbnail of Additional file 12: of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

Statistical details of the phylogenetic tree in Additional file 2: Figure S2A. (FASTA 424 bytes)

Research paper thumbnail of Additional file 9: of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

Alignment results of 16S rRNA gene V4 region sequence of 13 O. formigenes strains, 3 O. formigene... more Alignment results of 16S rRNA gene V4 region sequence of 13 O. formigenes strains, 3 O. formigenes-associated OTUs, and O. vicrioformis. (TXT 14 kb)

Research paper thumbnail of Additional file 8: Figure S7. of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

β-Diversity of 824 samples based on Bray–Curtis dissimilarities, by number of O. formigenes OTUs ... more β-Diversity of 824 samples based on Bray–Curtis dissimilarities, by number of O. formigenes OTUs detected. Panels A–D. Visualization of β-diversity ordination through PCoA of all 824 samples meeting the inclusion criteria (Additional file 5: Table S2) (A), 604 US samples (B), 144 UK or Ireland samples (C), the rest of the 70 samples (D). Samples with 0, 1, or 2 O. formigenes OTUs are represented in blue, green, and red dots. Ellipses were drawn with ggplot2 stat_ellipse function using multivariate t-distribution. By Adonis test, *p value <0.05. Panels E–H. Bar plots (mean ± S.E.M) of intra- and intergroup pairwise sample distance by Bray–Curtis dissimilarities for all (E), 604 US (F), and 144 UK or Ireland (G) samples or for the remaining 70 samples (H). By Bonferroni-corrected t tests, *p

Research paper thumbnail of Additional file 6: Figure S5. of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

Correlation between diet and O. formigenes relative abundance in 197 subjects. Panels focus on ox... more Correlation between diet and O. formigenes relative abundance in 197 subjects. Panels focus on oxalate (left), calcium (middle), or oxalate/calcium (right). Dietary intake over the 90Â days preceding sample collection was estimated through the Vioscreen questionnaire. *p value <0.05, by Spearman rank correlation. (PDF 96 kb)

Research paper thumbnail of Additional file 4: Figure S4. of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

Number of study subjects, by the number of samples provided. (PDF 25 kb)

Research paper thumbnail of Effect of Vancomycin on the Gut Microbiome and Plasma Concentrations of Gut-Derived Uremic Solutes

Kidney International Reports, 2021

Introduction Declining renal function results in the accumulation of solutes normally excreted by... more Introduction Declining renal function results in the accumulation of solutes normally excreted by healthy kidneys. Data suggest that some of the protein-bound solutes mediate accelerated cardiovascular disease. Many of the poorly dialyzable protein-bound uremic retention solutes are products of gut bacterial metabolism. Methods We performed a blinded-randomized controlled trial comparing the changes in plasma concentrations of a panel of protein-bound solutes and microbiome structure in response to the once-weekly oral administration of 250 mg of vancomycin or placebo over a period of 12 weeks in a cohort of stable patients with end-stage kidney disease. We also examined the pattern of recovery of the solutes and gut microbiome over 12 weeks of placebo administration following vancomycin. Results We enrolled 15 subjects. Ten subjects provided sufficient plasma and stool samples to permit us to examine the effect of vancomycin on plasma solute levels. We showed that a weekly dose of vancomycin resulted in a reduction in the plasma concentration of 7 colon-derived solutes. We described a significant effect of vancomycin on the microbiome structure with a decrease in alpha diversity and change in beta diversity. Multiple taxa decreased with vancomycin including genera Clostridium and Bacteroides. We demonstrated microbiome recovery after stopping vancomycin. However, recovery in the solutes was highly variable between subjects. Conclusions We demonstrated that microbiome suppression using vancomycin resulted in changes in multiple gut-derived uremic solutes. Future studies are needed to address whether reduction in those uremic solutes results in improvement of cardiovascular outcomes in ESKD patients.

Research paper thumbnail of Microbial genetic and transcriptional contributions to oxalate degradation by the gut microbiota in health and disease

eLife, 2021

Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans l... more Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbes can degrade oxalate using multiple ODPs and protect against its absorption. The exact oxalate-degrading taxa in the human microbiota and their ODP have not been described. We leverage multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota primarily uses the type II ODP, rather than type I. Furthermore, among the diverse ODP-encoding microbes, an oxalate autotroph, Oxalobacter formigenes, dominates this function transcriptionally. Patients with inflammatory bowel disease (IBD) frequently suffer from disrupted oxalate homeostasis and calcium oxalate nephrolithiasis. We show that the enteric oxalate level is elevated in IBD patients, with highest levels in Crohn’s disease (CD) patients with both ileal and colonic involvement consistent with known nephrolithiasis risk. We show tha...

Research paper thumbnail of Forty Years of Oxalobacter formigenes, a Gutsy Oxalate-Degrading Specialist

Applied and Environmental Microbiology, 2021

Oxalobacter formigenes , a unique anaerobic bacterium that relies solely on oxalate for growth, i... more Oxalobacter formigenes , a unique anaerobic bacterium that relies solely on oxalate for growth, is a key oxalate-degrading bacterium in the mammalian intestinal tract. Degradation of oxalate in the gut by O. formigenes plays a critical role in preventing renal toxicity in animals that feed on oxalate-rich plants.

Research paper thumbnail of Enteric Hyperoxaluria and Kidney Stone Management in Inflammatory Bowel Disease

Current Treatment Options in Gastroenterology, 2020

Purpose of review Enteric hyperoxaluria is frequently seen in patients with inflammatory bowel di... more Purpose of review Enteric hyperoxaluria is frequently seen in patients with inflammatory bowel disease (IBD). IBD patients are therefore at higher risk of nephrolithiasis, particularly calcium oxalate stones. We reviewed the recent medical literature to elucidate the mechanisms and risk factors behind nephrolithiasis in IBD patients, as well as therapies to treat and prevent the formation of kidney stones. Recent findings At present, there are no specific guidelines for screening and monitoring the progression of nephrolithiasis in the IBD population. Yet, recent epidemiologic data suggests that the prevalence of nephrolithiasis in the adult IBD patients is as high as 28%. Enteric oxalate levels of IBD patients are significantly elevated compared with non-IBD patients, and recent studies have shown that the gut microbiota largely mediates this process. In particular, intestinal disruption and malabsorption in IBD patients lead to the decolonization of Oxalobacter formigenes which normally metabolizes oxalate in the gut lumen. As such, future studies are needed to clarify the role of O. formigenes in IBD patients with the goal of devising new therapeutic approaches for nephrolithiasis treatment and risk reduction. Summary Enteric hyperoxaluria plays a large role in nephrolithiasis, a serious extra-intestinal manifestation of IBD that may progress to chronic kidney disease. The gut microbiota offers a promising approach to treating and preventing hyperoxaluria in the IBD population.

Research paper thumbnail of Microbial contributions to oxalate metabolism in health and disease

Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans l... more Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbiota can degrade oxalate and protect against its absorption. However, the particular microbes that actively degrade oxalate in vivo are ill-defined, which restricts our ability to disentangle the underlying taxonomic contributions. Here we leverage large-scale multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota in health harbors diverse ODP-encoding microbial species, but an oxalate autotroph-Oxalobacter formigenes- dominates this function transcriptionally. Patients with Inflammatory Bowel Disease (IBD) are at significantly increased risk for disrupted oxalate homeostasis and calcium-oxalate nephrolithiasis. Here, by analyzing multi-omics data from the iHMP-IBD study, we demonstrate that the oxalate degradation function conferred by the intestinal microbiota is severely impai...

Research paper thumbnail of OUP accepted manuscript

The Journal of Infectious Diseases, 2019

Background Oxalobacter formigenes are bacteria that colonize the human gut and degrade oxalate, a... more Background Oxalobacter formigenes are bacteria that colonize the human gut and degrade oxalate, a component of most kidney stones. Clinical and epidemiological studies suggest that O. formigenes colonization reduces the risk for kidney stones. We sought to develop murine models to allow investigating O. formigenes in the context of its native human microbiome. For humanization, we transplanted pooled feces from healthy, non-colonized human donors supplemented with a human O. formigenes strain into recipient mice. We compared transplanting microbiota into mice that were either treated with broad-spectrum antibiotics to suppress their native microbiome, or were germ-free, or received humanization without pre-treatment or received a sham gavage (controls). Results All humanized mice were stably colonized with O. formigenes through 8 weeks post-gavage, whereas mice receiving sham gavage remained uncolonized (p<0.001). Humanization significantly changed the murine intestinal microbial...

Research paper thumbnail of Enteric hyperoxaluria

Current Opinion in Nephrology and Hypertension, 2019

PURPOSE OF REVIEW Enteric hyperoxaluria is commonly observed in malabsorptive conditions includin... more PURPOSE OF REVIEW Enteric hyperoxaluria is commonly observed in malabsorptive conditions including Roux en Y gastric bypass (RYGB) and inflammatory bowel diseases (IBD). Its incidence is increasing secondary to an increased prevalence of both disorders. In this review, we summarize the evidence linking the gut microbiota to the risk of enteric hyperoxaluria. RECENT FINDINGS In enteric hyperoxaluria, fat malabsorption leads to increased binding of calcium to free fatty acids resulting in more soluble oxalate in the intestinal lumen. Bile acids and free fatty acids in the lumen also cause increased gut permeability allowing more passive absorption of oxalate. In recent years, there is more interest in the role of the gut microbiota in modulating urinary oxalate excretion in enteric hyperoxaluria, stemming from our knowledge that microbiota in the intestines can degrade oxalate. Oxalobacter formigenes reduced urinary oxalate in animal models of RYGB. The contribution of other oxalate-degrading organisms and the microbiota community to the pathophysiology of enteric hyperoxaluria are also currently under investigation. SUMMARY Gut microbiota might play a role in modulating the risk of enteric hyperoxaluria through oxalate degradation and bile acid metabolism. O. formigenes is a promising therapeutic target in this population; however, further studies in humans are needed to test its effectiveness.

Research paper thumbnail of Comparative prevalence of Oxalobacter formigenes in three human populations

Scientific Reports, 2019

There has been increasing interest in the human anaerobic colonic bacterium Oxalobacter formigene... more There has been increasing interest in the human anaerobic colonic bacterium Oxalobacter formigenes because of its ability to metabolize oxalate, and its potential contribution to protection from calcium oxalate kidney stones. Prior studies examining the prevalence of this organism have focused on subjects in developed countries and on adults. Now using O. formigenes-specific PCR, we have compared the prevalence of these organisms among subjects in two remote areas in which modern medical practices have hardly been present with a USA group of mothers and their infants for the first three years of life. Among the Amerindians of the Yanomami-Sanema and Yekwana ethnic groups in Venezuela and the Hadza in Tanzania, O. formigenes was detected in 60–80% of the adult subjects, higher than found in adults from USA in this and prior studies. In young children, the prevalence was much lower in USA than in either tribal village. These data extend our understanding of the epidemiology of O. form...

Research paper thumbnail of MesoTIPS: Combined approach for the treatment of portal hypertension secondary to portal vein thrombosis – A brief report

The Arab Journal of Interventional Radiology, 2017

Introduction: We describe a technique we call "Meso-transjugular intrahepatic portosystemic shunt... more Introduction: We describe a technique we call "Meso-transjugular intrahepatic portosystemic shunt (MTIPS)" for relief of portal hypertension secondary to portal vein thrombosis (PVT) using combined surgical and endovascular technique. Materials and Methods: Nine adult patients with PVT underwent transjugular intrahepatic portosystemic shunt through a combined transjugular and mesenteric approach (MTIPS), in which a peripheral mesenteric vein was exposed through a minilaparotomy approach. The right hepatic vein was accessed through a transjugular approach. Mechanical thrombectomy, thrombolysis, and angioplasty were performed when feasible to clear PVT. Results: All patients had technically successful procedures. Patients were followed up for a mean time of 13.3 months (range: 8 days to 3 years). All patients are still alive and asymptomatic. Conclusion: We conclude that MTIPS is effective for the relief of portal hypertension secondary to PVT.

Research paper thumbnail of End Point Considerations for Clinical Trials in Enteric Hyperoxaluria

Clinical Journal of The American Society of Nephrology, Jun 21, 2023

Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion ... more Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion due to increased gastrointestinal oxalate absorption. Causative features include fat malabsorption and/or increased intestinal permeability to oxalate. Enteric hyperoxaluria has long been known to cause nephrolithiasis and nephrocalcinosis, and, more recently, an association with CKD and kidney failure has been shown. Currently, there are no US Food and Drug Administration–approved therapies for enteric hyperoxaluria, and it is unclear what end points should be used to evaluate the efficacy of new drugs and biologics for this condition. This study represents work of a multidisciplinary group convened by the Kidney Health Initiative to review the evidence supporting potential end points for clinical trials in enteric hyperoxaluria. A potential clinical outcome is symptomatic kidney stone events. Potential surrogate end points include (1) an irreversible loss of kidney function as a surrogate for progression to kidney failure, (2) asymptomatic kidney stone growth/new stone formation observed on imaging as a surrogate for symptomatic kidney stone events, (3) urinary oxalate and urinary calcium oxalate supersaturation as surrogates for the development of symptomatic kidney stone events, and (4) plasma oxalate as a surrogate for the development of the clinical manifestations of systemic oxalosis. Unfortunately, because of gaps in the data, this Kidney Health Initiative workgroup was unable to provide definitive recommendations. Work is underway to obtain robust information that can be used to inform trial design and medical product development in this space.

Research paper thumbnail of Oxalate homeostasis

Nature Reviews Nephrology

Research paper thumbnail of The Microbiome and Uremic Solutes

Toxins, Mar 30, 2022

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Author response: Microbial genetic and transcriptional contributions to oxalate degradation by the gut microbiota in health and disease

Research paper thumbnail of Additional file 15: of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

R functions that were used in Additional files 13 and 14. (R 2 kb)

Research paper thumbnail of Additional file 14: of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

R script for network analysis. (R 9 kb)

Research paper thumbnail of Additional file 12: of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

Statistical details of the phylogenetic tree in Additional file 2: Figure S2A. (FASTA 424 bytes)

Research paper thumbnail of Additional file 9: of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

Alignment results of 16S rRNA gene V4 region sequence of 13 O. formigenes strains, 3 O. formigene... more Alignment results of 16S rRNA gene V4 region sequence of 13 O. formigenes strains, 3 O. formigenes-associated OTUs, and O. vicrioformis. (TXT 14 kb)

Research paper thumbnail of Additional file 8: Figure S7. of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

β-Diversity of 824 samples based on Bray–Curtis dissimilarities, by number of O. formigenes OTUs ... more β-Diversity of 824 samples based on Bray–Curtis dissimilarities, by number of O. formigenes OTUs detected. Panels A–D. Visualization of β-diversity ordination through PCoA of all 824 samples meeting the inclusion criteria (Additional file 5: Table S2) (A), 604 US samples (B), 144 UK or Ireland samples (C), the rest of the 70 samples (D). Samples with 0, 1, or 2 O. formigenes OTUs are represented in blue, green, and red dots. Ellipses were drawn with ggplot2 stat_ellipse function using multivariate t-distribution. By Adonis test, *p value <0.05. Panels E–H. Bar plots (mean ± S.E.M) of intra- and intergroup pairwise sample distance by Bray–Curtis dissimilarities for all (E), 604 US (F), and 144 UK or Ireland (G) samples or for the remaining 70 samples (H). By Bonferroni-corrected t tests, *p

Research paper thumbnail of Additional file 6: Figure S5. of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

Correlation between diet and O. formigenes relative abundance in 197 subjects. Panels focus on ox... more Correlation between diet and O. formigenes relative abundance in 197 subjects. Panels focus on oxalate (left), calcium (middle), or oxalate/calcium (right). Dietary intake over the 90Â days preceding sample collection was estimated through the Vioscreen questionnaire. *p value <0.05, by Spearman rank correlation. (PDF 96 kb)

Research paper thumbnail of Additional file 4: Figure S4. of Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project

Number of study subjects, by the number of samples provided. (PDF 25 kb)

Research paper thumbnail of Effect of Vancomycin on the Gut Microbiome and Plasma Concentrations of Gut-Derived Uremic Solutes

Kidney International Reports, 2021

Introduction Declining renal function results in the accumulation of solutes normally excreted by... more Introduction Declining renal function results in the accumulation of solutes normally excreted by healthy kidneys. Data suggest that some of the protein-bound solutes mediate accelerated cardiovascular disease. Many of the poorly dialyzable protein-bound uremic retention solutes are products of gut bacterial metabolism. Methods We performed a blinded-randomized controlled trial comparing the changes in plasma concentrations of a panel of protein-bound solutes and microbiome structure in response to the once-weekly oral administration of 250 mg of vancomycin or placebo over a period of 12 weeks in a cohort of stable patients with end-stage kidney disease. We also examined the pattern of recovery of the solutes and gut microbiome over 12 weeks of placebo administration following vancomycin. Results We enrolled 15 subjects. Ten subjects provided sufficient plasma and stool samples to permit us to examine the effect of vancomycin on plasma solute levels. We showed that a weekly dose of vancomycin resulted in a reduction in the plasma concentration of 7 colon-derived solutes. We described a significant effect of vancomycin on the microbiome structure with a decrease in alpha diversity and change in beta diversity. Multiple taxa decreased with vancomycin including genera Clostridium and Bacteroides. We demonstrated microbiome recovery after stopping vancomycin. However, recovery in the solutes was highly variable between subjects. Conclusions We demonstrated that microbiome suppression using vancomycin resulted in changes in multiple gut-derived uremic solutes. Future studies are needed to address whether reduction in those uremic solutes results in improvement of cardiovascular outcomes in ESKD patients.

Research paper thumbnail of Microbial genetic and transcriptional contributions to oxalate degradation by the gut microbiota in health and disease

eLife, 2021

Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans l... more Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbes can degrade oxalate using multiple ODPs and protect against its absorption. The exact oxalate-degrading taxa in the human microbiota and their ODP have not been described. We leverage multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota primarily uses the type II ODP, rather than type I. Furthermore, among the diverse ODP-encoding microbes, an oxalate autotroph, Oxalobacter formigenes, dominates this function transcriptionally. Patients with inflammatory bowel disease (IBD) frequently suffer from disrupted oxalate homeostasis and calcium oxalate nephrolithiasis. We show that the enteric oxalate level is elevated in IBD patients, with highest levels in Crohn’s disease (CD) patients with both ileal and colonic involvement consistent with known nephrolithiasis risk. We show tha...

Research paper thumbnail of Forty Years of Oxalobacter formigenes, a Gutsy Oxalate-Degrading Specialist

Applied and Environmental Microbiology, 2021

Oxalobacter formigenes , a unique anaerobic bacterium that relies solely on oxalate for growth, i... more Oxalobacter formigenes , a unique anaerobic bacterium that relies solely on oxalate for growth, is a key oxalate-degrading bacterium in the mammalian intestinal tract. Degradation of oxalate in the gut by O. formigenes plays a critical role in preventing renal toxicity in animals that feed on oxalate-rich plants.

Research paper thumbnail of Enteric Hyperoxaluria and Kidney Stone Management in Inflammatory Bowel Disease

Current Treatment Options in Gastroenterology, 2020

Purpose of review Enteric hyperoxaluria is frequently seen in patients with inflammatory bowel di... more Purpose of review Enteric hyperoxaluria is frequently seen in patients with inflammatory bowel disease (IBD). IBD patients are therefore at higher risk of nephrolithiasis, particularly calcium oxalate stones. We reviewed the recent medical literature to elucidate the mechanisms and risk factors behind nephrolithiasis in IBD patients, as well as therapies to treat and prevent the formation of kidney stones. Recent findings At present, there are no specific guidelines for screening and monitoring the progression of nephrolithiasis in the IBD population. Yet, recent epidemiologic data suggests that the prevalence of nephrolithiasis in the adult IBD patients is as high as 28%. Enteric oxalate levels of IBD patients are significantly elevated compared with non-IBD patients, and recent studies have shown that the gut microbiota largely mediates this process. In particular, intestinal disruption and malabsorption in IBD patients lead to the decolonization of Oxalobacter formigenes which normally metabolizes oxalate in the gut lumen. As such, future studies are needed to clarify the role of O. formigenes in IBD patients with the goal of devising new therapeutic approaches for nephrolithiasis treatment and risk reduction. Summary Enteric hyperoxaluria plays a large role in nephrolithiasis, a serious extra-intestinal manifestation of IBD that may progress to chronic kidney disease. The gut microbiota offers a promising approach to treating and preventing hyperoxaluria in the IBD population.

Research paper thumbnail of Microbial contributions to oxalate metabolism in health and disease

Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans l... more Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbiota can degrade oxalate and protect against its absorption. However, the particular microbes that actively degrade oxalate in vivo are ill-defined, which restricts our ability to disentangle the underlying taxonomic contributions. Here we leverage large-scale multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota in health harbors diverse ODP-encoding microbial species, but an oxalate autotroph-Oxalobacter formigenes- dominates this function transcriptionally. Patients with Inflammatory Bowel Disease (IBD) are at significantly increased risk for disrupted oxalate homeostasis and calcium-oxalate nephrolithiasis. Here, by analyzing multi-omics data from the iHMP-IBD study, we demonstrate that the oxalate degradation function conferred by the intestinal microbiota is severely impai...

Research paper thumbnail of OUP accepted manuscript

The Journal of Infectious Diseases, 2019

Background Oxalobacter formigenes are bacteria that colonize the human gut and degrade oxalate, a... more Background Oxalobacter formigenes are bacteria that colonize the human gut and degrade oxalate, a component of most kidney stones. Clinical and epidemiological studies suggest that O. formigenes colonization reduces the risk for kidney stones. We sought to develop murine models to allow investigating O. formigenes in the context of its native human microbiome. For humanization, we transplanted pooled feces from healthy, non-colonized human donors supplemented with a human O. formigenes strain into recipient mice. We compared transplanting microbiota into mice that were either treated with broad-spectrum antibiotics to suppress their native microbiome, or were germ-free, or received humanization without pre-treatment or received a sham gavage (controls). Results All humanized mice were stably colonized with O. formigenes through 8 weeks post-gavage, whereas mice receiving sham gavage remained uncolonized (p<0.001). Humanization significantly changed the murine intestinal microbial...

Research paper thumbnail of Enteric hyperoxaluria

Current Opinion in Nephrology and Hypertension, 2019

PURPOSE OF REVIEW Enteric hyperoxaluria is commonly observed in malabsorptive conditions includin... more PURPOSE OF REVIEW Enteric hyperoxaluria is commonly observed in malabsorptive conditions including Roux en Y gastric bypass (RYGB) and inflammatory bowel diseases (IBD). Its incidence is increasing secondary to an increased prevalence of both disorders. In this review, we summarize the evidence linking the gut microbiota to the risk of enteric hyperoxaluria. RECENT FINDINGS In enteric hyperoxaluria, fat malabsorption leads to increased binding of calcium to free fatty acids resulting in more soluble oxalate in the intestinal lumen. Bile acids and free fatty acids in the lumen also cause increased gut permeability allowing more passive absorption of oxalate. In recent years, there is more interest in the role of the gut microbiota in modulating urinary oxalate excretion in enteric hyperoxaluria, stemming from our knowledge that microbiota in the intestines can degrade oxalate. Oxalobacter formigenes reduced urinary oxalate in animal models of RYGB. The contribution of other oxalate-degrading organisms and the microbiota community to the pathophysiology of enteric hyperoxaluria are also currently under investigation. SUMMARY Gut microbiota might play a role in modulating the risk of enteric hyperoxaluria through oxalate degradation and bile acid metabolism. O. formigenes is a promising therapeutic target in this population; however, further studies in humans are needed to test its effectiveness.

Research paper thumbnail of Comparative prevalence of Oxalobacter formigenes in three human populations

Scientific Reports, 2019

There has been increasing interest in the human anaerobic colonic bacterium Oxalobacter formigene... more There has been increasing interest in the human anaerobic colonic bacterium Oxalobacter formigenes because of its ability to metabolize oxalate, and its potential contribution to protection from calcium oxalate kidney stones. Prior studies examining the prevalence of this organism have focused on subjects in developed countries and on adults. Now using O. formigenes-specific PCR, we have compared the prevalence of these organisms among subjects in two remote areas in which modern medical practices have hardly been present with a USA group of mothers and their infants for the first three years of life. Among the Amerindians of the Yanomami-Sanema and Yekwana ethnic groups in Venezuela and the Hadza in Tanzania, O. formigenes was detected in 60–80% of the adult subjects, higher than found in adults from USA in this and prior studies. In young children, the prevalence was much lower in USA than in either tribal village. These data extend our understanding of the epidemiology of O. form...

Research paper thumbnail of MesoTIPS: Combined approach for the treatment of portal hypertension secondary to portal vein thrombosis – A brief report

The Arab Journal of Interventional Radiology, 2017

Introduction: We describe a technique we call "Meso-transjugular intrahepatic portosystemic shunt... more Introduction: We describe a technique we call "Meso-transjugular intrahepatic portosystemic shunt (MTIPS)" for relief of portal hypertension secondary to portal vein thrombosis (PVT) using combined surgical and endovascular technique. Materials and Methods: Nine adult patients with PVT underwent transjugular intrahepatic portosystemic shunt through a combined transjugular and mesenteric approach (MTIPS), in which a peripheral mesenteric vein was exposed through a minilaparotomy approach. The right hepatic vein was accessed through a transjugular approach. Mechanical thrombectomy, thrombolysis, and angioplasty were performed when feasible to clear PVT. Results: All patients had technically successful procedures. Patients were followed up for a mean time of 13.3 months (range: 8 days to 3 years). All patients are still alive and asymptomatic. Conclusion: We conclude that MTIPS is effective for the relief of portal hypertension secondary to PVT.