Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Marilena Pariano
 -- 2148 2023-03-06 16:34:21 |
2 Reference format revised.
Lindsay Dong
Meta information modification 2148 2023-03-07 09:54:19 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Puccetti, M.; Pariano, M.; Wojtylo, P.; Schoubben, A.; Giovagnoli, S.; Ricci, M. Turning Indoles into Therapeutics via Targeted Delivery Technologies. Encyclopedia. Available online: https://encyclopedia.pub/entry/41907 (accessed on 05 July 2024).
Puccetti M, Pariano M, Wojtylo P, Schoubben A, Giovagnoli S, Ricci M. Turning Indoles into Therapeutics via Targeted Delivery Technologies. Encyclopedia. Available at: https://encyclopedia.pub/entry/41907. Accessed July 05, 2024.
Puccetti, Matteo, Marilena Pariano, Paulina Wojtylo, Aurélie Schoubben, Stefano Giovagnoli, Maurizio Ricci. "Turning Indoles into Therapeutics via Targeted Delivery Technologies" Encyclopedia, https://encyclopedia.pub/entry/41907 (accessed July 05, 2024).
Puccetti, M., Pariano, M., Wojtylo, P., Schoubben, A., Giovagnoli, S., & Ricci, M. (2023, March 06). Turning Indoles into Therapeutics via Targeted Delivery Technologies. In Encyclopedia. https://encyclopedia.pub/entry/41907
Puccetti, Matteo, et al. "Turning Indoles into Therapeutics via Targeted Delivery Technologies." Encyclopedia. Web. 06 March, 2023.
Turning Indoles into Therapeutics via Targeted Delivery Technologies
Edit
This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15020506

Developing therapeutics for inflammatory diseases is challenging due to physiological mucosal barriers, systemic side effects, and the local microbiota. In the search for novel methods to overcome some of these problems, drug delivery systems that improve tissue-targeted drug delivery and modulate the microbiota are highly desirable. Microbial metabolites are known to regulate immune responses, an observation that has resulted in important conceptual advances in areas such as metabolite pharmacology and metabolite therapeutics. Indeed, the doctrine of “one molecule, one target, one disease” that has dominated the pharmaceutical industry in the 20th century is being replaced by developing therapeutics which simultaneously manipulate multiple targets through novel formulation approaches, including the multitarget-directed ligands. Thus, metabolites may not only represent biomarkers for disease development, but also, being causally linked to human diseases, an unexploited source of therapeutics.

drug delivery postbiotics aryl hydrocarbon receptor indole-3-aldehyde

1. Introduction

Changes in gastrointestinal microbiome composition and function can adversely impact host physiology and are associated with local and systemic inflammatory diseases, cancer, metabolic disorders, and opportunistic and recurrent pathogen infections. It is estimated that noncommunicable illnesses contribute to 70% of worldwide mortality. Due to the presence of biosynthetic or metabolic gene clusters encoding the biosynthetic machinery to produce primary and specialized metabolites [1], microbes are highly metabolically active and produce trans-kingdom signaling molecules that interact with competing microorganisms and the host [2]. The fermentation of undigested protein in the large intestine results in the formation of branched-chain amino acids, biogenic amines, short-chain fatty acids, ammonia, phenolic and indolic compounds, hydrogen sulfide, and nitric oxide [3]. All these metabolites play important pathophysiological roles [4] such that their identification along with the study of their effector pathways can lead to the discovery of incredibly innovative diagnostics and therapeutics.

2. Metabolite-Based Therapeutics: The Postbiotic Concept

The metabolome is contributed by diet, the host, and its microbiota. Under homeostatic conditions, the intestinal microbiota produce, modify, and degrade metabolites which serve as an effective means of communication in host–microbe interactions and profoundly affect human health. Metabolites are bioactive, and their functional activity includes the modulation of signaling and metabolic pathways that contribute to mucosal immune homeostasis [5][6]. Despite the fact that the microbiome is estimated to account for more than half of all fecal and urinary metabolites, only about a dozen metabolites currently have a well-characterized effect on the host; these include target cells, receptors, signaling pathways, and physiological outcomes [7].
Quantitative or qualitative variation in metabolites is perceived by the host as an alteration of its microbial community, potentially an early indication of dysbiosis. Dysbiosis leads to subsequent alterations in metabolite composition, which has been shown to have direct consequences on host health in the context of multiple diseases. Thus, metabolite-based therapeutics, or “postbiotics”, may work as replacement therapy that is potentially effective against dysbiosis and its inflammatory consequences [6].
Metabolites have a clear chemical structure and a long shelf life, occur naturally in a broad range of concentrations, are functionally pleiotropic, are easy to administer, are suitable for different routes of administration, show tissue bioavailability, are present at most body sites, are generally stable in the blood, and are therefore amenable for scalable modulation of their concentration. Because of these properties, they are attractive and uniquely suited for therapeutic strategies. However, although highly promising, biopharmaceutical approaches for their in vivo delivery are critically needed to turn beneficial pleiotropic activity into effective therapeutics for human illnesses. This demands for drug delivery systems (DSS) that pivotally contribute to the development of an ideal postbiotic capable of fostering the holistic balance for the homeostatic control of inflammation at the mucosal and tissue levels.

3. Tissue-Specific Drug Delivery

The field of drug delivery systems, including routes of delivery and delivery vehicles, has advanced dramatically in the past few decades, thanks to the increased understanding of the physiological barriers for efficient drug delivery and the development of several new modes of drug delivery that have entered clinical practice. These include lipid nanoparticles (essential for effective delivery of mRNA), the microneedle patch (for sustained delivery to low-income people or people with mental-health conditions), the robotic pill (for oral drug delivery of complex drugs), and cellular delivery via red blood cells or bacteria, to name a few [8]. However, despite improving the drug’s efficacy, side effects may still occur because the unwanted drugs interact with healthy organs or tissues. Thus, targeted drug delivery approaches are of great interest in the pharmaceutical sciences, as they enable the concentrated delivery of a drug compound to its desired target—increasing efficacy and reducing off-target effects as compared to conventional formulations [8]. DDS have enabled the development of many pharmaceutical products that improve patient health by enhancing the delivery of a therapeutic to its target site, minimizing off-target accumulation and facilitating patient compliance [9].

4. The Ubiquitous AhR Signaling Pathway

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that acts as a heterodimeric transcriptional regulator [10]. Animal and human data indicate that the AhR is involved in various signaling pathways critical to normal cell homeostasis, which covers multiple aspects of physiology, such as cell proliferation and differentiation, gene regulation, cell motility and migration, inflammation, and host–microbiota interplay [11][12]. Signal molecules function as ligands for AhR, and activated AhR forms heterodimers at promoter recognition sequences of the target genes. The AhR/AhR nuclear translocator complex may then require coactivators (including members of other families of transcription factors) in order to initiate transcription and to unwind histone-bound DNA for exposing additional promoter recognition sites via their histone acetyltransferase function. Within this scenario, three major factors appear to contribute to the outcome of gene transcriptional regulation by AhR: the nature of the ligand, the local tissue microenvironment, and the presence of coactivators in the cell [10][11].

5. The Tryptophan-Indole Microbial Pathway

Trp is an essential amino acid supplied by dietary protein whose degradation occurs throughout the small intestine [13][14]. The gastrointestinal tract harbors numerous species with the capacity to synthesize indole and indole-containing compounds. The bacterial synthesis of indole compounds occurs via different metabolic pathways mainly involving the activity of tryptophanase, aromatic amino acid, aminotransferases, and tryptophan deaminases generating indole and a number of indole derivatives [15]. Indoles exert significant biological effects, including immune modulation, epithelial barrier regulation, and pathogen colonization, through which they may contribute to the etiology of a variety of human diseases, including dysbiosis [16]. More recently, an impaired microbial Trp catabolism was associated with critical COVID-19 patients [17]. These observations suggest that the exploration of indoles to support beneficial bacterial/host symbiosis and cooperation may lead to the rational design of effective clinical interventions in human chronic inflammatory conditions in which the epithelial barrier disruption and microbial dysbiosis are causally linked [18]. From an evolutionary perspective, many of the endogenous Trp metabolites exhibit greater activation potential for the human AhR when compared to the rodent AhR, an observation highlighting the importance of the AhR in human barrier tissues [19].

6. Turning Indoles into Therapeutics via Targeted Delivery Technologies

Within Lactobacilli, L. reuteri was found to convert Trp to indole-3-aldehyde (3-IAld) via the aromatic amino acid aminotransferase [20]. Mice exposed to a tryptophan-enriched diet expand L. reuteri in the gut that produce 3-IAld; this promotes AhR-dependent transcription of the IL-22–encoding gene by host innate lymphoid cells and thus prevents microbial infections and local inflammation [20]. 3-IAld, like indoles, moonlights as a metabolite and signaling molecule and is increasingly being associated with the regulation of wide-ranging physiological processes [21]. Being rapidly metabolized upon administration [22], 3-IAld may potentially act as a rapidly metabolized AhR ligand within the range of concentrations found in murine and human gut, despite not being among the most active endogenous ligands of murine and human AhR [23][24].
Recently, resorting to targeted delivery technologies has highlighted the possible translation to a clinical application of 3-IAld. Targeted delivery of 3-IAld via dry powder inhalation or orally was an efficient strategy to restore immune and microbial homeostasis in [22][25][26] in preclinical models of lung or gut inflammation (Figure 1).
/media/item_content/202303/6406fa61032c3pharmaceutics-15-00506-g001.png
Figure 1. Therapeutic activity of 3-IAld in experimental models of human inflammatory diseases. (A) Pulmonary insufflation of 3-IAld dry powder (DP) either before (P, prophylaxis) or after (T, therapy) prevents lung inflammatory pathology in CftrF508del/F508del mice infected with Aspergillus fumigatus conidia, as revealed by the fungal growth, lung histopathology, and neutrophil recruitment ([25]). Photographs were taken using a high-resolution Olympus DP71 microscope using a 10× objective. Scale bar 400 μm. Values represent the mean ± SD of four mice per group or are representative of three experiments. Naïve, uninfected mice; None, infected mice. ** p < 0.01, one-way ANOVA—Bonferroni’s, P or T vs. None. (B) 3-IAld microparticles (MP) reduces liver injury and fibrosis in C57BL/6 mice fed with a DDC-containing diet (active phase) and subjected to a recovery time (recovery phase) as revealed by serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, fibroblast activation, and collagen deposition ([27]). Photographs were taken with a high-resolution microscope (Olympus BX51), 40× magnification (scale bars, 100 μm). ** p < 0.01, **** p < 0.0001, DDC-treated vs untreated (none) mice, and DDC vs. DDC + 3-IAld-MP. One-way ANOVA, Bonferroni post-test. (C) Oral administration of 3-IAld-MP decreases glycemia, promotes glucose tolerance, restores tissue architecture in the ileum, and promotes epithelial cell renewal (BrdU) in C57BL/6 mice on a high-fed diet. Control; control mice. None; high-fed diet-mice with MP alone ([22]). Photographs were taken with a high-resolution microscope (Olympus BX51), 20× magnification (scale bars, 200 μm). **** p < 0.001, 3-IAld-MP-treated vs MP-treated mice and None vs Control. (D) 3-IAld-MP protects mice from immune check-point inhibitor (ICI)-induced colitis. C57BL/6 mice were treated with DSS and anti-CTLA-4 mAb with and without 3-IAld and assessed for weight change, disease activity index, colon histopathology, and gross pathology (insets) ([28]). Photographs were taken with a high-resolution microscope (Olympus BX51), ×20 magnification (scale bars, 200 µm). wo-way analysis of variance, Bonferroni post hoc test. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. anti-CTLA-4 + 3-IAld- versus anti-CTLA-4-treated mice.
Inhaled dry powder of 3-IAld demonstrated a good pharmacological and toxicological profile upon delivery for pulmonary administration and was superior to other administration modalities (oral and intranasal) in reducing the disease score [29]. When assessed in a relevant preclinical model, the site-specific delivery of 3-IAld was an efficient strategy to control infection and restore immune homeostasis in the lungs of mice with cystic fibrosis infected with Aspergillus fumigatus conidia. 3-IAld exerted significant control on the infection and ensuing inflammatory response administered either before (P) or after (T) the fungal challenge, as revealed by the reduced fungal growth, lung inflammatory pathology, and neutrophils recruitment (Figure 1A).
3-IAld was also effective when microencapsulated on enteric microparticles (MP) for intestinal delivery. Although spray-drying is not a conventional preparation process for enteric formulations, scholarsfound it suitable in the manufacturing of gastro-resistant 3-IAld [26]. As a matter of fact,  demonstrated that 3-IAld is released from MP in the intestine where it activates AhR [22]. Pharmacokinetics studies revealed that 3-IAld was detected at high levels in the intestine within 1 h after its administration at very low levels in the serum, lung, liver, and brain, suggesting a rapid local and/or systemic transformation of the molecule, likely occurring via host and/or microbial metabolic pathways, including AhR-induced Cytochrome P450 genes. However, AhR-activated genes were detected long after the sharp dropping of 3-IAld levels and could also be detected at distant organs, a finding suggesting that 3-IAld could be metabolically converted into downstream AhR agonists. Whatever the nature of the metabolite(s), scholars found that 3-IAld-MP was very active in a murine model of primary sclerosing cholangitis (PSC), a long-term liver disease characterized by a progressive course of cholestasis with liver inflammation and fibrosis. Given the contribution of the intestinal barrier dysfunction and the consequent bacterial/bacterial product translocation to the PSC pathogenesis [30], the ability of 3-IAld to preserve epithelial barrier integrity and maintain local immune homeostasis [22] would predict a beneficial effect in PSC. The scholars found that 3-IAld-MP reduced liver injury and fibrosis in C57BL/6 mice fed with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diet (active phase) and subjected to a recovery time (recovery phase) as revealed by the reduced serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin. 3-IAld-MP also reduced fibroblast activation and collagen deposition (Figure 1B) in DDC-fed mice (Figure 1B). 
On the basis of the same mechanism of activity, it was not surprising to find a protective role for 3-IAld-MP in the murine model of metabolic syndrome, a disorder characterized by a cluster of diseases associated with the reduced capacity of the microbiota to metabolize Trt into AhR ligands [31]. Accordingly, it showed that 3-IAld-MP, locally released, decreased inflammatory pathology, restored tissue architecture, and induced epithelial cell proliferation in C57BL/6 mice on a high-fed diet (Figure 1C). Concomitantly, 3-IAld-MP prevented the metabolic complications associated with the metabolic syndrome, such as hyperglycemia (Figure 1C). Finally, 3-IAld-MP protected mice from intestinal damage by activating the AhR/IL-22-dependent pathway in a murine model of immune checkpoint inhibitor (ICI)-induced colitis as shown by the prevention of weight loss and disease activity and by the amelioration of gross and colon intestinal pathology (Figure 1D).

References

  1. Pascal Andreu, V.; Roel-Touris, J.; Dodd, D.; Fischbach, M.A.; Medema, M.H. The gutSMASH web server: Automated identification of primary metabolic gene clusters from the gut microbiota. Nucleic Acids Res. 2021, 49, W263–W270.
  2. Krautkramer, K.A.; Fan, J.; Backhed, F. Gut microbial metabolites as multi-kingdom intermediates. Nat. Rev. Microbiol. 2021, 19, 77–94.
  3. Gilbert, J.A.; Blaser, M.J.; Caporaso, J.G.; Jansson, J.K.; Lynch, S.V.; Knight, R. Current understanding of the human microbiome. Nat. Med. 2018, 24, 392–400.
  4. Hosseinkhani, F.; Heinken, A.; Thiele, I.; Lindenburg, P.W.; Harms, A.C.; Hankemeier, T. The contribution of gut bacterial metabolites in the human immune signaling pathway of non-communicable diseases. Gut Microbes 2021, 13, 1–22.
  5. Levy, M.; Blacher, E.; Elinav, E. Microbiome, metabolites and host immunity. Curr. Opin. Microbiol. 2017, 35, 8–15.
  6. Levy, M.; Kolodziejczyk, A.A.; Thaiss, C.A.; Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 2017, 17, 219–232.
  7. Zheng, X.; Xie, G.; Zhao, A.; Zhao, L.; Yao, C.; Chiu, N.H.; Jia, W. The footprints of gut microbial–Mammalian co-metabolism. J. Proteome Res. 2011, 10, 5512–5522.
  8. Allen, T.M.; Cullis, P.R. Drug delivery systems: Entering the mainstream. Science 2004, 303, 1818–1822.
  9. May, M. Why drug delivery is the key to new medicines. Nat. Med. 2022, 28, 1100–1102.
  10. Rothhammer, V.; Quintana, F.J. The aryl hydrocarbon receptor: An environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 2019, 19, 184–197.
  11. Stockinger, B.; Meglio, P.D.; Gialitakis, M.; Duarte, J.H. The aryl hydrocarbon receptor: Multitasking in the immune system. Annu. Rev. Immunol. 2014, 32, 403–432.
  12. Dong, F.; Perdew, G.H. The aryl hydrocarbon receptor as a mediator of host-microbiota interplay. Gut Microbes 2020, 12, 1859812.
  13. Roager, H.M.; Licht, T.R. Microbial tryptophan catabolites in health and disease. Nat. Commun. 2018, 9, 3294.
  14. Medvedev, A.; Buneeva, O. Tryptophan Metabolites as Mediators of Microbiota-Gut-Brain Communication: Focus on Isatin. Front. Behav. Neurosci. 2022, 16, 922274.
  15. Liu, Y.; Hou, Y.; Wang, G.; Zheng, X.; Hao, H. Gut microbial metabolites of aromatic amino acids as signals in host–microbe interplay. Trends Endocrinol. Metab. 2020, 31, 818–834.
  16. Ye, X.; Li, H.; Anjum, K.; Zhong, X.; Miao, S.; Zheng, G.; Li, L. Dual role of indoles derived from intestinal microbiota on human health. Front. Immunol. 2022, 13, 903526.
  17. Yokoyama, Y.; Ichiki, T.; Yamakawa, T.; Tsuji, Y.; Kuronuma, K.; Takahashi, S.; Nakase, H. Impaired tryptophan metabolism in the gastrointestinal tract of patients with critical coronavirus disease 2019. Front. Med. 2022, 9, 941422.
  18. Su, X.; Gao, Y.; Yang, R. Gut Microbiota-Derived Tryptophan Metabolites Maintain Gut and Systemic Homeostasis. Cells 2022, 11, 2296.
  19. Hubbard, T.D.; Murray, I.A.; Bisson, W.H.; Lahoti, T.S.; Gowda, K.; Amin, S.G.; Perdew, G.H. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci. Rep. 2015, 5, 12689.
  20. Zelante, T.; Iannitti, R.G.; Cunha, C.; De Luca, A.; Giovannini, G.; Pieraccini, G.; Romani, L. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 2013, 39, 372–385.
  21. Zelante, T.; Puccetti, M.; Giovagnoli, S.; Romani, L. Regulation of host physiology and immunity by microbial indole-3-aldehyde. Curr. Opin. Immunol. 2021, 70, 27–32.
  22. Puccetti, M.; Pariano, M.; Borghi, M.; Barola, C.; Moretti, S.; Galarini, R.; Giovagnoli, S. Enteric formulated indole-3-carboxaldehyde targets the aryl hydrocarbon receptor for protection in a murine model of metabolic syndrome. Int. J. Pharm. 2021, 602, 120610.
  23. Dvorak, Z.; Sokol, H.; Mani, S. Drug Mimicry: Promiscuous Receptors PXR and AhR, and Microbial Metabolite Interactions in the Intestine. Trends Pharm. Sci. 2020, 41, 900–908.
  24. Vyhlídalová, B.; Krasulová, K.; Pečinková, P.; Marcalíková, A.; Vrzal, R.; Zemánková, L.; Dvořák, Z. Gut microbial catabolites of tryptophan are ligands and agonists of the aryl hydrocarbon receptor: A detailed characterization. Int. J. Mol. Sci. 2020, 21, 2614.
  25. Puccetti, M.; Pariano, M.; Renga, G.; Santarelli, I.; D’Onofrio, F.; Bellet, M.M.; Giovagnoli, S. Targeted drug delivery technologies potentiate the overall therapeutic efficacy of an indole derivative in a mouse cystic fibrosis setting. Cells 2021, 10, 1601.
  26. Puccetti, M.; Giovagnoli, S.; Zelante, T.; Romani, L.; Ricci, M. Development of novel indole-3-aldehyde–loaded gastro-resistant spray-dried microparticles for postbiotic small intestine local delivery. J. Pharm. Sci. 2018, 107, 2341–2353.
  27. D’Onofrio, F.; Renga, G.; Puccetti, M.; Pariano, M.; Bellet, M.M.; Santarelli, I.; Romani, L. Indole-3-carboxaldehyde restores gut mucosal integrity and protects from liver fibrosis in murine sclerosing cholangitis. Cells 2021, 10, 1622.
  28. Renga, G.; Nunzi, E.; Pariano, M.; Puccetti, M.; Bellet, M.M.; Pieraccini, G.; Costantini, C. Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite. J. Immunother. Cancer 2022, 10, e003725.
  29. Puccetti, M.; Dos Reis, L.G.; Pariano, M.; Costantini, C.; Renga, G.; Ricci, M.; Giovagnoli, S. Development and in vitro-in vivo performances of an inhalable indole-3-carboxaldehyde dry powder to target pulmonary inflammation and infection. Int. J. Pharm. 2021, 607, 121004.
  30. Vesterhus, M.; Karlsen, T.H. Emerging therapies in primary sclerosing cholangitis: Pathophysiological basis and clinical opportunities. J. Gastroenterol. 2020, 55, 588–614.
  31. Natividad, J.M.; Agus, A.; Planchais, J.; Lamas, B.; Jarry, A.C.; Martin, R.; Sokol, H. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab. 2018, 28, 737–749.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Others
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Matteo Puccetti
,
Marilena Pariano
,
Paulina Wojtylo
,
Aurélie Schoubben
,
Stefano Giovagnoli
,
Maurizio Ricci
View Times: 309
Revisions: 2 times (View History)
Update Date: 07 Mar 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback