Authors: Veit Rothhammer, Ivan D Mascanfroni, Lukas Bunse...

Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.

Topics: Animals; Astrocytes; Case-Control Studies; Cell Proliferation; Central Nervous System; Chemokine CCL2; Chromatin Immunoprecipitation; Chromatography, High Pressure Liquid; Encephalomyelitis, Autoimmune, Experimental; Fluorescent Antibody Technique; Gastrointestinal Microbiome; Gene Expression Profiling; Gene Knockdown Techniques; Glial Fibrillary Acidic Protein; Humans; Immunoblotting; Indican; Indoles; Inflammation; Interferon Type I; Interferon-beta; Limosilactobacillus reuteri; Mice; Mice, Knockout; Multiple Sclerosis; Myxovirus Resistance Proteins; Nitric Oxide Synthase Type II; Optical Imaging; Polymerase Chain Reaction; Receptor, Interferon alpha-beta; Receptors, Aryl Hydrocarbon; STAT1 Transcription Factor; Serotonin; Suppressor of Cytokine Signaling Proteins; T-Lymphocytes; Tryptophan; Tryptophanase

PubMed: 27158906
DOI: 10.1038/nm.4106

Review

Authors: Qiao Ma, Xuwang Zhang, Yuanyuan Qu...

Indole is long regarded as a typical -heterocyclic aromatic pollutant in industrial and agricultural wastewater, and recently it has been identified as a versatile signaling molecule with wide environmental distributions. An exponentially growing number of researches have been reported on indole due to its significant roles in bacterial physiology, pathogenesis, animal behavior and human diseases. From the viewpoint of both environmental bioremediation and biological studies, the researches on metabolism and fates of indole are important to realize environmental treatment and illuminate its biological function. Indole can be produced from tryptophan by tryptophanase in many bacterial species. Meanwhile, various bacterial strains have obtained the ability to transform and degrade indole. The characteristics and pathways for indole degradation have been investigated for a century, and the functional genes for indole aerobic degradation have also been uncovered recently. Interestingly, many oxygenases have proven to be able to oxidize indole to indigo, and this historic and motivating case for biological applications has attracted intensive attention for decades. Herein, the bacteria, enzymes and pathways for indole production, biodegradation and biotransformation are systematically summarized, and the future researches on indole-microbe interactions are also prospected.

PubMed: 30443243
DOI: 10.3389/fmicb.2018.02625

Review

Authors: Lirit Duchovni, Genrieta Shmunis, Lior Lobel...

The microbiome plays a vital role in human health, with changes in its composition impacting various aspects of the body. Posttranslational modification (PTM) regulates protein activity by attaching chemical groups to amino acids in an enzymatic or non-enzymatic manner. PTMs offer fast and dynamic regulation of protein expression and can be influenced by specific dietary components that induce PTM events in gut microbiomes and their hosts. PTMs on microbiome proteins have been found to contribute to host-microbe interactions. For example, in , S-sulfhydration of tryptophanase regulates uremic toxin production and chronic kidney disease in mice. On a broader microbial scale, the microbiomes of patients with inflammatory bowel disease exhibit distinct PTM patterns in their metaproteomes. Moreover, pathogens and commensals can alter host PTM profiles through protein secretion and diet-regulated metabolic shifts. The emerging field of metaPTMomics focuses on understanding PTM profiles in the microbiota, their association with lifestyle factors like diet, and their functional effects on host-microbe interactions.

Topics: Protein Processing, Post-Translational; Humans; Host Microbial Interactions; Animals; Gastrointestinal Microbiome; Diet; Mice; Bacteria

PubMed: 39254316
DOI: 10.1128/mbio.02387-24

Authors: Jing Ding, Lingping Tan, Lingzhi Wu...

Pathogenesis of periodontitis is marked by microbiota dysbiosis and disrupted host responses. Porphyromonas gingivalis is a keystone pathogen of periodontitis which expresses various crucial virulence factors. This study aimed to clarify the role and mechanisms of P. gingivalis tryptophan-indole metabolic pathway in the pathogenesis of periodontitis. This study showed that periodontitis patients exhibited elevated tryptophan metabolism and salivary pathogen abundance. Tryptophanase gene-deficiency altered proteome and metabolome of P. gingivalis, inhibited P. gingivalis virulent factors expression, biofilm growth, hemin utilization, cell adhesion/invasion and pro-inflammation ability. Tryptophan-indole pathway of P. gingivalis stimulated periodontitis biofilm formation and induced oral microbiota dysbiosis. In periodontitis mice, this pathway of P. gingivalis aggravated alveolar bone loss and gingival tissue destruction, causing oral and gut microbiota dysbiosis. This study indicates that the tryptophan-indole pathway serves as a significant regulator of P. gingivalis virulence and oral microbiota dysbiosis, which is also associated with gut dysbiosis.

Topics: Porphyromonas gingivalis; Tryptophan; Periodontitis; Dysbiosis; Animals; Humans; Mice; Indoles; Virulence; Biofilms; Male; Metabolic Networks and Pathways; Virulence Factors; Female; Tryptophanase; Disease Models, Animal; Bacteroidaceae Infections

PubMed: 40011497
DOI: 10.1038/s41522-025-00669-y

Review

Authors: Takayuki Matsumoto, Mihoka Kojima, Keisuke Takayanagi...

Gut microbiota have been emerging as important contributors to the regulation of host homeostasis. Accordingly, several substances converted by gut microbiota can have beneficial or adverse effects on human health. Among them, S-equol, which is produced from the isoflavone daidzein in the human and animal gut by certain microbiota, exerts estrogenic and antioxidant activities. Indoxyl sulfate, which is metabolized in the liver from indole converted from dietary tryptophan by bacterial tryptophanases in the colon, is known as a protein-bound uremic toxin. Trimethylamine N-oxide, which is generated via the oxidization of gut microbiota-derived trimethylamine by hepatic flavin monooxygenases, is known as an accelerator of atherosclerosis. The aforementioned gut-derived substances could be potential regulators of systematic tissue/organ function, including the vascular system. Macro- and microvascular complications of cardiovascular and metabolic diseases, including atherosclerosis, hypertension, and diabetes, occur systemically and represent the principal cause of morbidity and mortality. Vascular endothelial and smooth muscle dysfunction play pivotal roles in the development and progression of vasculopathies. We herein review the link between the aforementioned gut-derived substances and endothelial and vascular smooth muscle cell function. This information will provide a conceptual framework that would allow the development of novel preventive and/or therapeutic approaches against vasculopathies.

Topics: Animals; Endothelial Cells; Endothelium, Vascular; Equol; Gastrointestinal Microbiome; Humans; Indican; Methylamines; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Vascular Diseases

PubMed: 32300778
DOI: 10.1093/ajh/hpaa053

Authors: Bharath Reddy Boya, Prasun Kumar, Jin-Hyung Lee...

Tryptophanase encoded by the gene is a pyridoxal phosphate-dependent enzyme that catalyses the conversion of tryptophan to indole, which is commonly used as an intra- and interspecies signalling molecule, particularly by microbes. However, the production of indole is rare in eukaryotic organisms. A nucleotide and protein database search revealed is commonly reported in various Gram-negative bacteria, but that only a few Gram-positive bacteria and archaea possess the gene. The presence of in eukaryotes, particularly protozoans and marine organisms, demonstrates the importance of this gene in the animal kingdom. Here, we document the distribution of and its acquisition and expansion among different taxonomic groups, many of which are usually categorized as non-indole producers. This study provides an opportunity to understand the intriguing role played by , and its distribution among various types of organisms.

PubMed: 34683477
DOI: 10.3390/microorganisms9102156

Authors: Amanda L Graboski, Mark E Kowalewski, Joshua B Simpson...

Indoxyl sulfate is a microbially derived uremic toxin that accumulates in late-stage chronic kidney disease and contributes to both renal and cardiovascular toxicity. Indoxyl sulfate is generated by the metabolism of indole, a compound created solely by gut microbial tryptophanases. Here, we characterize the landscape of tryptophanase enzymes in the human gut microbiome and find remarkable structural and functional similarities across diverse taxa. We leverage this homology through a medicinal chemistry campaign to create a potent pan-inhibitor, (3S) ALG-05, and validate its action as a transition-state analog. (3S) ALG-05 successfully reduces indole production in microbial culture and displays minimal toxicity against microbial and mammalian cells. Mice treated with (3S) ALG-05 show reduced cecal indole and serum indoxyl sulfate levels with minimal changes in other tryptophan-metabolizing pathways. These studies present a non-bactericidal pan-inhibitor of gut microbial tryptophanases with potential promise for reducing indoxyl sulfate in chronic kidney disease.

Topics: Humans; Mice; Animals; Indican; Tryptophanase; Gastrointestinal Microbiome; Indoles; Renal Insufficiency, Chronic; Mammals

PubMed: 37633277
DOI: 10.1016/j.chembiol.2023.07.015

Authors: Ziad A Massy, Tilman B Drueke

Topics: Animals; Diet; Disease Progression; Gastrointestinal Microbiome; Indican; Kidney; Mice; Proteome

PubMed: 33245991
DOI: 10.1016/j.kint.2020.11.006

Authors: Lingyan Du, Jianming Yue, Yiying Zhu...

Indigo is an important pigment widely used in industries of food, cosmetics, and textile. In this work, the styrene monooxygenase StyAB from was co-expressed with the tryptophanase TnaA and the chaperone groES-groEL in for indigo production. Over-expression of the gene endowed the recombinant AB with the capacity of indigo biosynthesis from indole and tryptophan. Tryptophan fermentation in AB generated about five times more indigo than that from indole, and the maximum 530 mg/L of indigo was obtained from 1.2 mg/mL of tryptophan. The gene was then co-expressed with , and the tryptophanase activity significantly increased in the recombinant ABT. However, expression led to a decrease in the activity of StyAB and indigo yield in ABT. Furthermore, the plasmid pGro7 harboring groES-groEL was introduced into AB, which obviously promoted the activity of StyAB and accelerated indigo biosynthesis in the recombinant ABP. In addition, the maximum yield of indigo was further increased to 550 mg/L from 1.2 mg/mL of tryptophan in ABP. The genetic manipulation strategy proposed in this work could provide new insights into construction of indigo biosynthesis cell factory for industrial production.

PubMed: 35885360
DOI: 10.3390/foods11142117

Authors: Kanika Bhardwaj, Arunima Kalita, Neha Verma...

The termination factor Rho, an ATP-dependent RNA translocase, preempts pervasive transcription processes, thereby rendering genome integrity in bacteria. Here, we show that the loss of Rho function raised the intracellular pH to >8.0 in . The loss of Rho function upregulates tryptophanase-A (TnaA), an enzyme that catabolizes tryptophan to produce indole, pyruvate, and ammonia. We demonstrate that the enhanced TnaA function had produced the conjugate base ammonia, raising the cellular pH in the Rho-dependent termination defective strains. On the other hand, the constitutively overexpressed Rho lowered the cellular pH to about 6.2, independent of cellular ammonia levels. Since Rho overexpression may increase termination activities, the decrease in cellular pH could result from an excess H ion production during ATP hydrolysis by overproduced Rho. Furthermore, we performed termination assays to show that the efficiency of Rho-dependent termination was increased at both acidic and basic pH ranges. Given that the Rho level remained unchanged, the alkaline pH increases the termination efficiency by stimulating Rho's catalytic activity. We conducted the Rho-mediated RNA release assay from a stalled elongation complex to show an efficient RNA release at alkaline pH, compared to the neutral or acidic pH, that supports our observation. Whereas acidic pH appeared to increase the termination function by elevating the cellular level of Rho. This study is the first to link Rho function to the cellular pH homeostasis in bacteria. IMPORTANCE The current study shows that the loss or gain of Rho-dependent termination alkalizes or acidifies the cytoplasm, respectively. In the case of loss of Rho function, the tryptophanase-A enzyme is upregulated, and degrades tryptophan, producing ammonia to alkalize cytoplasm. We hypothesize that Rho overproduction by deleting its autoregulatory DNA portion increases termination function, causing excessive ATP hydrolysis to produce H ions and cytoplasmic acidification. Therefore, this study is the first to unravel a relationship between Rho function and intrinsic cellular pH homeostasis. Furthermore, the Rho level increases in the absence of autoregulation, causing cytoplasmic acidification. As intracellular pH plays a critical role in enzyme function, such a connection between Rho function and alkalization will have far-reaching implications for bacterial physiology.

Topics: Transcription, Genetic; Tryptophan; Tryptophanase; Ammonia; Rho Factor; Escherichia coli; RNA; Homeostasis; Adenosine Triphosphate; Hydrogen-Ion Concentration

PubMed: 38169297
DOI: 10.1128/jb.00356-23