About

Ronaldo P. Ferraris is a Professor in the Department of Pharmacology, Physiology & Neuroscience at Rutgers New Jersey Medical School. He received his undergraduate and graduate degrees in Biology from Xavier University in the Philippines and a PhD in 1982 from the University of Hawaii, where he also earned his MS in 1977. His early career included work with international development agencies serving Southeast Asia, but an early career shift was prompted by political upheaval in the Philippines. He then completed a postdoctoral fellowship at UCLA in Professor Jared Diamond's laboratory, focusing on the intestinal epithelium and the cell types involved in perceiving luminal signals that regulate sugar transporter site density. His research interests involve studying integrative regulatory processes related to nutrient transport and metabolism, particularly in the context of the gut. Currently, he uses intestinal organoids to investigate whether pure cultures of intestinal stem and differentiated absorptive cells can perceive and respond to luminal signals. His work encompasses cell differentiation, junctional permeability, fructose transport and metabolism, gut microbiota metabolism of diet, nutrient signaling in the small intestine, probiotic regulation of gut epithelia, and the role of nutrients in epithelial cell differentiation.

Research topics

• Microbiology
• Biochemistry
• Biology
• Immunology
• Medicine
• Pathology

Selected publications

• LGG Enhances Gut Barrier Function by Modulating Arginine Metabolism and Vitamin B₃Synthesis

  Physiology · 2025-05-01

  articleSenior author

  Gut barrier dysfunction is a hallmark of inflammatory bowel disease (IBD), characterized by increased intestinal permeability, epithelial disruption, and chronic inflammation. Despite growing insights into the gut microbiota’s role, the mechanisms underlying probiotic-driven metabolic reprogramming of gut barrier function remain elusive. This study hypothesizes that Lacticaseibacillus rhamnosus GG (LGG), in synergy with dietary tryptophan, reprograms host metabolism to restore intestinal homeostasis and enhance barrier integrity. Using germ-free mice colonized with LGG and fed tryptophan-deficient or -sufficient diets, we employed untargeted metabolomics, transcriptomics, and a novel metabolome-transcriptome correlation analysis (METRCA). Functional validation was performed via in vitro assays, ex vivo organoids, and DSS-induced colitis mouse models. LGG robustly enhanced gut barrier function through two complementary mechanisms. First, LGG significantly upregulated argininosuccinate lyase (ASL), a critical enzyme in arginine biosynthesis, alleviating the accumulation of argininosuccinate (ASA)—a barrier-disrupting metabolite that perturbs tight junction proteins such as Ocln and Tjp1. These effects were evident in both experimental colitis and human IBD, where reduced ASL expression correlated with disease severity. Second, LGG stimulated the production of methylnicotinamide (MNA), a vitamin B 3 derivative that exhibited potent barrier-protective effects by enhancing epithelial tight junctions and promoting healing in DSS-induced colitis. METRCA analyses revealed strong correlations between LGG-regulated metabolites, including indole derivatives and MNA, and genes associated with arginine metabolism and epithelial barrier integrity. Notably, MNA reduced intestinal permeability and inflammatory cytokine production, positioning it as a key effector in LGG’s mechanism of action. These findings were further validated by in silico analyses of human IBD datasets, demonstrating that LGG and dietary tryptophan synergistically modulate arginine biosynthesis and reduce ASA levels, ultimately mitigating gut barrier dysfunction. This study highlights LGG’s dual capacity to enhance gut barrier function by leveraging dietary tryptophan to drive arginine metabolism and vitamin B3 synthesis. By targeting the metabolic disruptions underlying IBD, LGG emerges as a transformative precision probiotic. These exciting findings establish a framework for microbiome-based therapeutic strategies, emphasizing the potential of dietary and probiotic interventions to restore intestinal barrier integrity in IBD and related disorders. (NIH R01-AT010243, R01-DK102934, R01-DK119198 and NSF 1754783) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

  PublisherDOI

• <i>Lacticaseibacillus rhamnosus GG</i>-driven remodeling of arginine metabolism mitigates gut barrier dysfunction

  American Journal of Physiology-Gastrointestinal and Liver Physiology · 2025-05-26 · 2 citations

  articleOpen accessSenior authorCorresponding

  This study identifies a novel probiotic-driven mechanism linking dietary tryptophan and host arginine metabolism. Lacticaseibacillus rhamnosus GG, in synergy with tryptophan, enhances gut barrier integrity by upregulating argininosuccinate lyase (ASL), a critical enzyme in arginine biosynthesis. Furthermore, we uncover ASL downregulation and serum argininosuccinate elevation in experimental colitis in mice, suggesting a target to guide precision probiotics.

  PublisherDOI

• Probiotic LGG's Metabolites Repair Disrupted Gut Barrier In Vitro

  Physiology · 2025-05-01

  articleSenior author

  The objective of this experiment is to monitor the effects of microbiota-derived metabolites of tryptophan, indoles, when applied basolaterally and luminally on a compromised tight junction system. Human IBD data of the metabolome of patients with Crohn's Disease, Ulcerative Colitis, or C Diff were compared to that of healthy control individuals and demonstrated defects in tryptophan metabolism, with deficiencies of certain indoles – exogenous metabolites of tryptophan produced by LGG. Dr. Ferraris’s lab studies the effects of tryptophan and Lactobacillus rhamnosus GG (LGG), a popular probiotic, on germ-free mice. Metabolome Transcriptomic analysis (MeTRcA) revealed that tight junctional genes had the highest enrichment score, and that indoles are positively correlated with barrier function genes such as Occludin – dependent on whether the serum or feces is being analyzed. However, functional analyses is required to demonstrate their barrier protective effects. To study these correlations further, colon carcinoma (Caco-2 BBE) cells were grown for 21 days on inserts with a semipermeable membrane to mimic the luminal and basolateral polarity of enterocytes. In the context of the correlations, the presence of metabolites in the feces was explored with luminal application, and presence in the serum with basolateral application. Following 48hr incubation of treatment with metabolites (applied luminally or basolaterally) or their DMSO solvent, application of C. difficile (CD) cell-free supernatant was used to mimic a leaky gut model by inactivating Rho enzymes, causing actin adhesion plaques to disengage. The two main readouts were transepithelial electrical resistance (TEER) and FITC-dextran. TEER reads the electrical resistance across the epithelial layer, which is a measure of paracellular ion permeability. Flux of FITC-dextran from the luminal to basolateral media measured paracellular macromolecular permeability. Cells with healthy tight junctions will have high TEER and low FITC absorbance. Luminal administration of indole-3-acetonitrile, indole-3-acetic acid, and indole-3-carboxylic acid improved TEER by 168%, 91%, and 39%, respectively, after 48 hours of incubation compared with vehicle. Treating cells with CD supernatant provoked a 46% reduction in TEER, consistent with an increased permeability of the paracellular pathway measured by FITC-dextran flux. Under an impaired barrier, the luminal application of indole-3-lactic acid, indole-3-propionic acid, indole-3-acetonitrile, indole-3-acetamide, indole-3-acetic acid, and indole-3-carboxylic acid restored TEER with efficacies ranging from 29% to 96%. Basolateral treatment of indole-3-acetamide and indole-3-carboxyaldehyde exhibited a remarkable increase in baseline TEER, with 1.3- and 1.6-fold enhancements, respectively, in comparison with the vehicle. Under CD treatment, the basolateral indole-3-lactic acid, indole-3-acetamide, and indole-3-carboxyaldehyde restored TEER by 57.5%–72.4%. FITC-dextran permeability assays were largely consistent with TEER results. Indole-3-carboxylic acid (ICA), and indole-3-acetic acid (IAA) can reduce the levels of the pro-inflammatory transcription factor NF-κB when applied luminally. Certain cocktails of high performing LGG-derived metabolites of tryptophan, including indoles, were additionally able to maintain higher TEER values under tight junctions impaired with CD toxin controls. In summary, multiple metabolites in the indole pathway provide significant rescue from intestinal permeability in a compromised tight junction model. NIHR01-AT010243 (NG, RF), R01DK119198 (NG), NSF 1754783 (RF). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

  PublisherDOI

• Intestinal lysozyme engagement of Salmonella Typhimurium stimulates the release of barrier-impairing InvE and Lpp1

  Journal of Biological Chemistry · 2024-05-31 · 9 citations

  articleOpen access

  mice demonstrate exacerbated infection and inflammation. The growth and invasion of Salmonella in vitro are not affected by human or chicken lysozyme, whereas lysozyme encountering of live Salmonella stimulates the release of barrier-disrupting factors, InvE-sipC and Lpp1, which directly or indirectly impair the tight junctions. The direct engagement of host intestinal lysozyme with an enteric pathogen such as Salmonella promotes the release of virulence factors that are barrier-impairing and pro-inflammatory. Controlling lysozyme function may help alleviate the inflammatory progression.

  PublisherDOI

• Metabolomic and Transcriptomic Correlative Analyses in Germ-Free Mice Link Lacticaseibacillus rhamnosus GG-Associated Metabolites to Host Intestinal Fatty Acid Metabolism and β-Oxidation

  Laboratory Investigation · 2024-01-20 · 4 citations

  articleOpen accessCorresponding
  PublisherOA PDFDOI

• <i>Ruminococcus gnavus</i> in the gut: driver, contributor, or innocent bystander in steatotic liver disease?

  FEBS Journal · 2024-11-26 · 19 citations

  reviewOpen access

  The human gut microbiome plays a crucial role in regulating intestinal and systemic health, impacting host immune response and metabolic function. Dysbiosis of the gut microbiome is linked to various diseases, including steatotic liver diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic liver disease characterized by excess hepatic lipid content and impaired metabolism, is the leading cause of liver disease worldwide. Among the gut microbes, Ruminococcus gnavus (R. gnavus) has garnered attention for its association with inflammatory and metabolic diseases. While R. gnavus abundance correlates to liver fat accumulation, further research is needed to identify a causal role or therapeutic intervention in steatotic liver disease. This review surveys our current understanding of R. gnavus in the development and progression of steatotic liver diseases, highlighting its potential mechanisms through metabolite secretion, and emphasizes the need for comprehensive microbiome analyses and longitudinal studies to better understand R. gnavus' impact on liver health. This knowledge could pave the way for targeted interventions aimed at modulating gut microbiota to treat and prevent MASLD and its comorbidities.

  PublisherOA PDFDOI

• Lactobacillus rhamnosus GG Stimulates Dietary Tryptophan-Dependent Production of Barrier-Protecting Methylnicotinamide

  Cellular and Molecular Gastroenterology and Hepatology · 2024-01-01 · 13 citations

  articleOpen accessSenior author

  BACKGROUND & AIMS: Lacticaseibacillus rhamnosus GG (LGG) is the world's most consumed probiotic but its mechanism of action on intestinal permeability and differentiation along with its interactions with an essential source of signaling metabolites, dietary tryptophan (trp), are unclear. METHODS: Untargeted metabolomic and transcriptomic analyses were performed in LGG monocolonized germ-free mice fed trp-free or -sufficient diets. LGG-derived metabolites were profiled in vitro under anaerobic and aerobic conditions. Multiomic correlations using a newly developed algorithm discovered novel metabolites tightly linked to tight junction and cell differentiation genes whose abundances were regulated by LGG and dietary trp. Barrier-modulation by these metabolites were functionally tested in Caco2 cells, mouse enteroids, and dextran sulfate sodium experimental colitis. The contribution of these metabolites to barrier protection is delineated at specific tight junction proteins and enterocyte-promoting factors with gain and loss of function approaches. RESULTS: absorption abolishes barrier recovery in vivo. CONCLUSIONS: Our study uncovers a novel LGG-regulated dietary trp-dependent production of MNA that protects the gut barrier against colitis.

  PublisherDOI

• The arginine and nitric oxide metabolic pathway regulate the gut colonization and expansion of Ruminococcous gnavus

  Journal of Biological Chemistry · 2024-07-30 · 8 citations

  articleOpen access

  Ruminococcus gnavus is a mucolytic commensal bacterium whose increased gut colonization has been associated with chronic inflammatory and metabolic diseases in humans. Whether R. gnavus metabolites can modulate host intestinal physiology remains largely understudied. We performed untargeted metabolomic and bulk RNA-seq analyses using R. gnavus monocolonization in germ-free mice. Based on transcriptome-metabolome correlations, we tested the impact of specific arginine metabolites on intestinal epithelial production of nitric oxide (NO) and examined the effect of NO on the growth of various strains of R. gnavus in vitro and in nitric oxide synthase 2 (Nos2)-deficient mice. R. gnavus produces specific arginine, tryptophan, and tyrosine metabolites, some of which are regulated by the environmental richness of sialic acid and mucin. R. gnavus colonization promotes expression of amino acid transporters and enzymes involved in metabolic flux of arginine and associated metabolites into NO. R. gnavus induced elevated levels of NOS2, while Nos2 ablation resulted in R. gnavus expansion in vivo. The growth of various R. gnavus strains can be inhibited by NO. Specific R. gnavus metabolites modulate intestinal epithelial cell NOS2 abundance and reduce epithelial barrier function at higher concentrations. Intestinal colonization and interaction with R. gnavus are partially regulated by an arginine-NO metabolic pathway, whereby a balanced control by the gut epithelium may restrain R. gnavus growth in healthy individuals. Disruption in this arginine metabolic regulation will contribute to the expansion and blooming of R. gnavus.

  PublisherOA PDFDOI

• Supplementary Figure 6 from Recycling Endosomes in Mature Epithelia Restrain Tumorigenic Signaling

  2023-03-31

  preprintOpen access

  &lt;p&gt;RAB11A-KD cells show increased YAP signaling and proliferation.&lt;/p&gt;

  PublisherDOI

• Supplementary Figure 1 from Recycling Endosomes in Mature Epithelia Restrain Tumorigenic Signaling

  2023-03-31

  preprintOpen access

  &lt;p&gt;Mice with intestinal epithelium specific deletion of Rab11a develop epithelial hyperplasia and dysplasia&lt;/p&gt;

  PublisherDOI

Recent grants

• Plasticity of Renewable Epithelia in the Mammalian Small Intestine

  NSF · $570k · 2015–2019

• Nutrient-nutrient interactions in the small intestine

  NSF · $550k · 2011–2014

• Developmental Regulation of Intestinal Sugar Transport

  NSF · $359k · 2007–2011

• NIH Grant R29AG011403

  NIH · $644k · 2000

• NIH Grant R21DK075617

  NIH · $424k · 2011

Frequent coauthors

• Véronique Douard

  Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement

  109 shared

• Nan Gao

  Chinese Academy of Medical Sciences & Peking Union Medical College

  49 shared

• Shiyan Yu

  48 shared

• Shozo H. Sugiura

  University of Shiga Prefecture

  42 shared

• D. Casirola

  39 shared

• Lanjing Zhang

  Peking University

  38 shared

• Elmer S David

  35 shared

• Edward M. Bonder

  Rutgers, The State University of New Jersey

  31 shared

Education

• B.S.

  Xavier University, Philippines

  1974

• M.S.

  University of Hawaii

  1977

• Ph.D.

  University of Hawaii

  1982