Richard L. Guerrant

Education

  • MD, Department of Medicine, University of Virginia
  • BS, Davidson College, Davidson, NC

Primary Appointment

  • Professor, Medicine- Infectious Diseases and International Health

Contact

Research Interest(s)

Recognition, Diagnosis, Pathogenesis, Impact, Treatment and Prevention of Enteric Infections; Global Health and Tropical Infectious Diseases

Research Description



Building on a background of work defining the unique, prolonged activation of adenylate cyclase by cholera toxin and E. coli LT (1971-1972), the development of the CHO cell assay for cholera toxin and E. coli LT (1974-1976), and the discovery that particulate guanylate cyclase is activated by E. coli ST (1978-1981) and on field work defining the magnitude of diarrheal diseases and their nutritional impact in rural and urban communities in Northeast Brazil (1978-present), Guerrant's laboratory is focused on the recognition, diagnosis, pathogenesis, impact, treatment and prevention of enteric infections. This work includes active studies of the roles of host and microbial genetics, ApoE4 (protection), enteric cytokines and neutrophils and the neutrophil marker lactoferrin in pathogenesis and diagnosis as well as of zinc and glutamine derivatives in the repair of disrupted intestinal barrier function. Guerrant's research with Drs. Cirle Warren and Laurie Archbald-Pannone on the leading cause of hospital-acquired diarrhea, Clostridium difficile, shows a key role for PLA2, PAF and COX-2 in the secretory and inflammatory effects of C. difficile toxin A, and of adenosine A2a-agonitt, A2b antagonists, PPAR-?, ApoE-peptides, zinc and alanyl-glutamine in preventing inflammation or secretion in animal models of enteric infections. Current work involves animal model, tissue culture, and clinical studies of the roles of these mediators in inflammatory, parasitic (Cryptosporidium) and microbial adhesion or toxin-induced (ex. enteroaggregative E. coli, C. difficile, cholera) diarrheas. Work with colleagues at the Federal University of Ceara in Fortaleza, Brazil, supported by a current NIH International Collaboration for Infectious Diseases Research (ICIDR) award in its 21st year, shows new and emerging pathogens to be leading causes of persistent diarrhea: enteroaggregative E. coli, Cryptosporidium and perhaps Giardia. In addition, Cryptosporidium and other persistent diarrheas disrupt intestinal barrier function (as determined by lactulose:mannitol permeability) and lead to substantial increased diarrhea burdens for extended periods thereafter in young children. Having recently shown an apparent role for leukocytes (with fecal lactoferrin) in cryptosporidial and enteroaggregative E. coli persistent diarrheas, current work includes studies of the roles of cytokines in intestinal barrier disruption and secretion in bacterial and parasitic diarrheas. Most important, with colleagues in Brazil, Guerrant has shown that early childhood diarrhea and enteric infections have a lasting impact on growth and cognitive development, more than doubling the global diarrhea DALYs (disability-adjusted life years lost). Current work involves in-vitro, animal model and field studies of mechanisms, genetics (including APOE polymorphisms) and micronutrient interventions to ameliorate these effects. Having also recently demonstrated in collaborative studies that glutamine (the major bowel enterocyte energy source) and its new stable derivatives enhance intestinal sodium absorption at least as well if not better than glucose, current studies are addressing the roles of these compounds and micronutrients in speeding the repair of intestinal barrier functions oral rehydration and repair therapy (ORRT) and hence improving child development and also absorption of antiretroviral drugs in collaborative studies at Virginia, Haiti, South Africa and in Brazil. This work also involves collaborations with Drs. Glynis Kolling, Martin Wu and Michael Timko to examine normal and probiotic flora and to engineer Arg-Gln derivatives into edible plants or probiotic bacteria.

Selected Publications

  • Azevedo O, Bolick D, Roche J, Pinkerton R, Lima A, Vitek M, Warren C, Oriá R, Guerrant R. Apolipoprotein E Plays a Key Role against Cryptosporidial Infection in Transgenic Undernourished Mice. PloS one. 2014;9(2): e89562. PMID: 24586873
  • Bartelt L, Guerrant R. Antibiotics help control rotavirus infections and enhance anti-rotaviral immunity: Are you serious? The Journal of infectious diseases. 2014. PMID: 24625806
  • Boone J, Archbald-Pannone L, Wickham K, Carman R, Guerrant R, Franck C, Lyerly D. Ribotype 027 Clostridium difficile infections with measurable stool toxin have increased lactoferrin and are associated with a higher mortality. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2014. PMID: 24449345
  • Lima A, Anstead G, Zhang Q, Figueiredo I, Soares A, Mota R, Lima N, Guerrant R, Oriá R. Effects of glutamine alone or in combination with zinc and vitamin A on growth, intestinal barrier function, stress and satiety-related hormones in Brazilian shantytown children. Clinics (São Paulo, Brazil). 2014;69(4): 225-33. PMID: 24714829
  • Mathers A, Guerrant R. Dissecting the evolutionary stealth of our flora against antibiotics. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2014;108(3): 121-2. PMID: 24535149
  • Richard S, Black R, Gilman R, Guerrant R, Kang G, Lanata C, Mølbak K, Rasmussen Z, Sack R, Valentiner-Branth P, Checkley W. Catch-Up Growth Occurs after Diarrhea in Early Childhood. The Journal of nutrition. 2014. PMID: 24699805
  • Bartelt L, Lima A, Kosek M, Peñataro Yori P, Lee G, Guerrant R. "Barriers" to child development and human potential: the case for including the "neglected enteric protozoa" (NEP) and other enteropathy-associated pathogens in the NTDs. PLoS neglected tropical diseases. 2013;7(4): e2125. PMID: 23593514 | PMCID: PMC3623703
  • Bartelt L, Roche J, Kolling G, Bolick D, Noronha F, Naylor C, Hoffman P, Warren C, Singer S, Guerrant R. Persistent G. lamblia impairs growth in a murine malnutrition model. The Journal of clinical investigation. 2013;123(6): 2672-84. PMID: 23728173 | PMCID: PMC3668820
  • Bartelt L, Sevilleja J, Barrett L, Warren C, Guerrant R, Bessong P, Dillingham R, Samie A. High anti-Cryptosporidium parvum IgG seroprevalence in HIV-infected adults in Limpopo, South Africa. The American journal of tropical medicine and hygiene. 2013;89(3): 531-4. PMID: 23836569 | PMCID: PMC3771295
  • Bolick D, Roche J, Hontecillas R, Bassaganya-Riera J, Nataro J, Guerrant R. Enteroaggregative Escherichia coli strain in a novel weaned mouse model: exacerbation by malnutrition, biofilm as a virulence factor and treatment by nitazoxanide. Journal of medical microbiology. 2013;62 896-905. PMID: 23475903 | PMCID: PMC3709553
  • DeBoer M, Chen D, Burt D, Ramirez-Zea M, Guerrant R, Stein A, Martorell R, Luna M. Early childhood diarrhea and cardiometabolic risk factors in adulthood: the Institute of Nutrition of Central America and Panama Nutritional Supplementation Longitudinal Study. Annals of epidemiology. 2013;23(6): 314-20. PMID: 23608305
  • Keusch G, Rosenberg I, Denno D, Duggan C, Guerrant R, Lavery J, Tarr P, Ward H, Black R, Nataro J, Ryan E, Bhutta Z, Coovadia H, Lima A, Ramakrishna B, Zaidi A, Burgess D, Brewer T. Implications of acquired environmental enteric dysfunction for growth and stunting in infants and children living in low- and middle-income countries. Food and nutrition bulletin. 2013;34(3): 357-64. PMID: 24167916
  • Khan O, Guerrant R, Sanders J, Carpenter C, Spottswood M, Jones D, O'Callahan C, Brewer T, Markuns J, Gillam S, O'Neill J, Nathanson N, Wright S. Global health education in U.S. medical schools. BMC medical education. 2013;13 3. PMID: 23331630 | PMCID: PMC3637494
  • Leite R, Lima N, Leite C, Farhat C, Guerrant R, Lima A. Improvement of intestinal permeability with alanyl-glutamine in HIV patients: a randomized, double blinded, placebo-controlled clinical trial. Arquivos de gastroenterologia. 2013;50(1): 56-63. PMID: 23657308
  • Lima A, Kvalsund M, Souza P, Figueiredo Í, Soares A, Mota R, Lima N, Pinkerton R, Patrick P, Guerrant R, Oriá R. Zinc, vitamin A, and glutamine supplementation in Brazilian shantytown children at risk for diarrhea results in sex-specific improvements in verbal learning. Clinics (São Paulo, Brazil). 2013;68(3): 351-8. PMID: 23644855 | PMCID: PMC3611743
  • Lima I, Boisen N, Quetz J, Havt A, de Carvalho E, Soares A, Lima N, Mota R, Nataro J, Guerrant R, Lima A. Prevalence of enteroaggregative Escherichia coli and its virulence-related genes in a case-control study among children from north-eastern Brazil. Journal of medical microbiology. 2013;62 683-93. PMID: 23429698 | PMCID: PMC3709657
  • Medeiros P, Bolick D, Roche J, Noronha F, Pinheiro C, Kolling G, Lima A, Guerrant R. The micronutrient zinc inhibits EAEC strain 042 adherence, biofilm formation, virulence gene expression, and epithelial cytokine responses benefiting the infected host. Virulence. 2013;4(7): 624-33. PMID: 23958904
  • Philipson C, Bassaganya-Riera J, Viladomiu M, Pedragosa M, Guerrant R, Roche J, Hontecillas R. The role of peroxisome proliferator-activated receptor γ in immune responses to enteroaggregative Escherichia coli infection. PloS one. 2013;8(2): e57812. PMID: 23469071 | PMCID: PMC3585146
  • Richard S, Black R, Gilman R, Guerrant R, Kang G, Lanata C, Mølbak K, Rasmussen Z, Sack R, Valentiner-Branth P, Checkley W. Diarrhea in early childhood: short-term association with weight and long-term association with length. American journal of epidemiology. 2013;178(7): 1129-38. PMID: 23966558 | PMCID: PMC3783094
  • Rodrigues R, Oliveira R, Li Y, Zaja-Milatovic S, Costa L, Braga Neto M, Kolling G, Lima A, Guerrant R, Warren C. Intestinal epithelial restitution after TcdB challenge and recovery from Clostridium difficile infection in mice with alanyl-glutamine treatment. The Journal of infectious diseases. 2013;207(10): 1505-15. PMID: 23359592 | PMCID: PMC3627196
  • Sanders M, Guarner F, Guerrant R, Holt P, Quigley E, Sartor R, Sherman P, Mayer E. An update on the use and investigation of probiotics in health and disease. Gut. 2013;62(5): 787-96. PMID: 23474420
  • Santos A, Braga-Neto M, Oliveira M, Freire R, Barros E, Santiago T, Rebelo L, Mermelstein C, Warren C, Guerrant R, Brito G. Glutamine and alanyl-glutamine increase RhoA expression and reduce Clostridium difficile toxin-a-induced intestinal epithelial cell damage. BioMed research international. 2013;2013 152052. PMID: 23484083 | PMCID: PMC3591182
  • Su Y, Tsegaye M, Varhue W, Liao K, Abebe L, Smith J, Guerrant R, Swami N. Quantitative dielectrophoretic tracking for characterization and separation of persistent subpopulations of Cryptosporidium parvum. The Analyst. 2013;139(1): 66-73. PMID: 24225592
  • Wazny K, Zipursky A, Black R, Curtis V, Duggan C, Guerrant R, Levine M, Petri W, Santosham M, Scharf R, Sherman P, Simpson E, Young M, Bhutta Z. Setting research priorities to reduce mortality and morbidity of childhood diarrhoeal disease in the next 15 years. PLoS medicine. 2013;10(5): e1001446. PMID: 23690756 | PMCID: PMC3653794
  • Braga-Neto M, Oliveira B, Rodrigues R, Noronha F, Leitao R, Brito G, Lima A, Guerrant R, Warren C. Protective effects of alanyl-glutamine supplementation against nelfinavir-induced epithelial impairment in IEC-6 cells and in mouse intestinal mucosa. Cancer biology & therapy. 2012;13(14): 1482-90. PMID: 22986234 | PMCID: PMC3542240
  • Costa L, Noronha F, Roche J, Sevilleja J, Warren C, Oriá R, Lima A, Guerrant R. Novel in vitro and in vivo models and potential new therapeutics to break the vicious cycle of Cryptosporidium infection and malnutrition. The Journal of infectious diseases. 2012;205(9): 1464-71. PMID: 22454464 | PMCID: PMC3324401
  • DeBoer M, Lima A, Oría R, Scharf R, Moore S, Luna M, Guerrant R. Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome? Nutrition reviews. 2012;70(11): 642-53. PMID: 23110643 | PMCID: PMC3493112
  • Fischer Walker C, Lamberti L, Adair L, Guerrant R, Lescano A, Martorell R, Pinkerton R, Black R. Does childhood diarrhea influence cognition beyond the diarrhea-stunting pathway? PloS one. 2012;7(10): e47908. PMID: 23118906 | PMCID: PMC3485308
  • Guerrant R, Bartelt L, Scharf R. Thinking deeper about important mass treatment trials. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2012;54(11): 1674-5. PMID: 22431805 | PMCID: PMC3404721
  • Guerrant R, DeBoer M, Moore S, Scharf R, Lima A. The impoverished gut--a triple burden of diarrhoea, stunting and chronic disease. Nature reviews. Gastroenterology & hepatology. 2012;10(4): 220-9. PMID: 23229327 | PMCID: PMC3617052
  • Kolling G, Wu M, Guerrant R. Enteric pathogens through life stages. Frontiers in cellular and infection microbiology. 2012;2 114. PMID: 22937528 | PMCID: PMC3427492
  • Kolling G, Wu M, Warren C, Durmaz E, Klaenhammer T, Timko M, Guerrant R. Lactic acid production by Streptococcus thermophilus alters Clostridium difficile infection and in vitro Toxin A production. Gut microbes. 2012;3(6): 523-9. PMID: 22895082 | PMCID: PMC3495789
  • Kosek M, Haque R, Lima A, Babji S, Shrestha S, Qureshi S, Amidou S, Mduma E, Lee G, Yori P, Guerrant R, Bhutta Z, Mason C, Kang G, Kabir M, Amour C, Bessong P, Turab A, Seidman J, Olortegui M, Quetz J, Lang D, Gratz J, Miller M, Gottlieb M. Fecal markers of intestinal inflammation and permeability associated with the subsequent acquisition of linear growth deficits in infants. The American journal of tropical medicine and hygiene. 2012;88(2): 390-6. PMID: 23185075 | PMCID: PMC3583335
  • Li Y, Figler R, Kolling G, Bracken T, Rieger J, Stevenson R, Linden J, Guerrant R, Warren C. Adenosine A2A receptor activation reduces recurrence and mortality from Clostridium difficile infection in mice following vancomycin treatment. BMC infectious diseases. 2012;12 342. PMID: 23217055 | PMCID: PMC3523970
  • Lima I, Quetz J, Guerrant R, Nataro J, Houpt E, Lima A, Havt A. Enteroaggregative Escherichia coli quantification in children stool samples using quantitative PCR. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2012;121(7): 643-51. PMID: 23216208 | PMCID: PMC3604144
  • Mitter S, Oriá R, Kvalsund M, Pamplona P, Joventino E, Mota R, Gonçalves D, Patrick P, Guerrant R, Lima A. Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil. Clinics (São Paulo, Brazil). 2012;67(1): 11-8. PMID: 22249475 | PMCID: PMC3248595
  • Preidis G, Saulnier D, Blutt S, Mistretta T, Riehle K, Major A, Venable S, Barrish J, Finegold M, Petrosino J, Guerrant R, Conner M, Versalovic J. Host response to probiotics determined by nutritional status of rotavirus-infected neonatal mice. Journal of pediatric gastroenterology and nutrition. 2012;55(3): 299-307. PMID: 22343914
  • Queiroz D, Silva C, Goncalves M, Braga-Neto M, Fialho A, Fialho A, Rocha G, Rocha A, Batista S, Guerrant R, Lima A, Braga L. Higher frequency of cagA EPIYA-C phosphorylation sites in H. pylori strains from first-degree relatives of gastric cancer patients. BMC gastroenterology. 2012;12 107. PMID: 22891666 | PMCID: PMC3462145
  • Richard S, Black R, Gilman R, Guerrant R, Kang G, Lanata C, Mølbak K, Rasmussen Z, Sack R, Valentiner-Branth P, Checkley W. Wasting is associated with stunting in early childhood. The Journal of nutrition. 2012;142(7): 1291-6. PMID: 22623393 | PMCID: PMC3374667
  • Roche J, Rojo A, Costa L, Smeltz R, Manque P, Woehlbier U, Bartelt L, Galen J, Buck G, Guerrant R. Intranasal vaccination in mice with an attenuated Salmonella enterica Serovar 908htr A expressing Cp15 of Cryptosporidium: impact of malnutrition with preservation of cytokine secretion. Vaccine. 2012;31(6): 912-8. PMID: 23246541 | PMCID: PMC3563240
  • Viladomiu M, Hontecillas R, Pedragosa M, Carbo A, Hoops S, Michalak P, Michalak K, Guerrant R, Roche J, Warren C, Bassaganya-Riera J. Modeling the role of peroxisome proliferator-activated receptor γ and microRNA-146 in mucosal immune responses to Clostridium difficile. PloS one. 2012;7(10): e47525. PMID: 23071818 | PMCID: PMC3469550
  • Warren C, Calabrese G, Li Y, Pawlowski S, Figler R, Rieger J, Ernst P, Linden J, Guerrant R. Effects of adenosine A₂A receptor activation and alanyl-glutamine in Clostridium difficile toxin-induced ileitis in rabbits and cecitis in mice. BMC infectious diseases. 2012;12 13. PMID: 22264229 | PMCID: PMC3323464
  • Warren C, Li Y, Calabrese G, Freire R, Zaja-Milatovic S, van Opstal E, Figler R, Linden J, Guerrant R. Contribution of adenosine A(2B) receptors in Clostridium difficile intoxication and infection. Infection and immunity. 2012;80(12): 4463-73. PMID: 23045479 | PMCID: PMC3497433
  • Warren C, van Opstal E, Ballard T, Kennedy A, Wang X, Riggins M, Olekhnovich I, Warthan M, Kolling G, Guerrant R, Macdonald T, Hoffman P. Amixicile, a novel inhibitor of pyruvate: ferredoxin oxidoreductase, shows efficacy against Clostridium difficile in a mouse infection model. Antimicrobial agents and chemotherapy. 2012;56(8): 4103-11. PMID: 22585229 | PMCID: PMC3421617
  • Warren C, van Opstal E, Riggins M, Li Y, Moore J, Kolling G, Guerrant R, Hoffman P. Vancomycin treatment's association with delayed intestinal tissue injury, clostridial overgrowth, and recurrence of Clostridium difficile infection in mice. Antimicrobial agents and chemotherapy. 2012;57(2): 689-96. PMID: 23147742 | PMCID: PMC3553708
  • Costa L, JohnBull E, Reeves J, Sevilleja J, Freire R, Hoffman P, Lima A, Oriá R, Roche J, Guerrant R, Warren C. Cryptosporidium-malnutrition interactions: mucosal disruption, cytokines, and TLR signaling in a weaned murine model. The Journal of parasitology. 2011;97(6): 1113-20. PMID: 21711105 | PMCID: PMC3247658
  • Guerrant R, Oria R, Moore S, Scharf R, Lima A. Enteric protozoa and human potential. Annals of tropical paediatrics. 2011;31(3): 201-3. PMID: 21781413
  • Moore S, Lima A, Guerrant R. Infection: Preventing 5 million child deaths from diarrhea in the next 5 years. Nature reviews. Gastroenterology & hepatology. 2011;8(7): 363-4. PMID: 21725348
  • Pinkerton R, Oriá R, Kent J, Kohli A, Abreu C, Bushen O, Lima A, Blangero J, Williams-Blangero S, Guerrant R. Evidence for genetic susceptibility to developing early childhood diarrhea among shantytown children living in northeastern Brazil. The American journal of tropical medicine and hygiene. 2011;85(5): 893-6. PMID: 22049044
  • Ueno P, Oriá R, Maier E, Guedes M, de Azevedo O, Wu D, Willson T, Hogan S, Lima A, Guerrant R, Polk D, Denson L, Moore S. Alanyl-glutamine promotes intestinal epithelial cell homeostasis in vitro and in a murine model of weanling undernutrition. American journal of physiology. Gastrointestinal and liver physiology. 2011;301(4): G612-22. PMID: 21799183
  • Costa L, Johnbull E, Reeves J, Sevilleja J, Freire R, Hoffman P, Lima A, Oria R, Roche J, Guerrant R, Warren C. CRYPTOSPORIDIUM- MALNUTRITION INTERACTIONS: MUCOSAL DISRUPTION, CYTOKINES AND TLR SIGNALING IN A WEANED MURINE MODEL. J Parasitol. .
  • Dillingham R, Leger P, Beauharnais C, Miller E, Kashuba A, Jennings S, Dupnik K, Samie A, Eyma E, Guerrant R, Pape J, Fitzgerald D. AIDS diarrhea and antiretroviral drug concentrations: a matched-pair cohort study in Port au Prince, Haiti. Am J Trop Med Hyg. 84(6): 878-82. PMCID: PMC3110379
  • Guerrant R, Oria R, Moore S, Lima A. Enteric protozoa and human potential. Ann Trop Paediatr. 31(3): 201-3.