Aronia Berry Supplementation Mitigates Inflammation in T Cell Transfer-Induced Colitis by Decreasing Oxidative Stress

doi:10.3390/nu11061316

. 2019 Jun 12;11(6):1316.

doi: 10.3390/nu11061316.

Aronia Berry Supplementation Mitigates Inflammation in T Cell Transfer-Induced Colitis by Decreasing Oxidative Stress

Ruisong Pei¹, Jiyuan Liu^{2

3}, Derek A Martin⁴, Jonathan C Valdez⁵, Justin Jeffery⁶, Gregory A Barrett-Wilt⁷, Zhenhua Liu⁸, Bradley W Bolling⁹

Affiliations

¹ Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr., Madison, WI 53706, USA. ruisong.pei@wisc.edu.
² Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr., Madison, WI 53706, USA. jliu678@wisc.edu.
³ China Agricultural University, College of Food Science and Nutritional Engineering, No.17 Qinghua Dong Lu, Beijing 100083, China. jliu678@wisc.edu.
⁴ Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr., Madison, WI 53706, USA. mrtn.drk@gmail.com.
⁵ Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr., Madison, WI 53706, USA. jcvaldez@wisc.edu.
⁶ Wisconsin Institutes for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53706, USA. jjjeffery@wisc.edu.
⁷ Mass Spectrometry Facility, Biotechnology Center, University of Wisconsin-Madison, 425 Henry Mall, Madison, WI 53706, USA. barrettwilt@wisc.edu.
⁸ University of Massachusetts, Amherst, School of Public Health and Health Sciences, 100 Holdsworth Way, Amherst, MA 01003, USA. zliu@nutrition.umass.edu.
⁹ Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr., Madison, WI 53706, USA. bwbolling@wisc.edu.

PMID: 31212794
PMCID: PMC6627224
DOI: 10.3390/nu11061316

Aronia Berry Supplementation Mitigates Inflammation in T Cell Transfer-Induced Colitis by Decreasing Oxidative Stress

Ruisong Pei et al. Nutrients. 2019.

. 2019 Jun 12;11(6):1316.

doi: 10.3390/nu11061316.

Authors

Ruisong Pei¹, Jiyuan Liu^{2

3}, Derek A Martin⁴, Jonathan C Valdez⁵, Justin Jeffery⁶, Gregory A Barrett-Wilt⁷, Zhenhua Liu⁸, Bradley W Bolling⁹

Affiliations

¹ Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr., Madison, WI 53706, USA. ruisong.pei@wisc.edu.
² Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr., Madison, WI 53706, USA. jliu678@wisc.edu.
³ China Agricultural University, College of Food Science and Nutritional Engineering, No.17 Qinghua Dong Lu, Beijing 100083, China. jliu678@wisc.edu.
⁴ Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr., Madison, WI 53706, USA. mrtn.drk@gmail.com.
⁵ Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr., Madison, WI 53706, USA. jcvaldez@wisc.edu.
⁶ Wisconsin Institutes for Medical Research, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53706, USA. jjjeffery@wisc.edu.
⁷ Mass Spectrometry Facility, Biotechnology Center, University of Wisconsin-Madison, 425 Henry Mall, Madison, WI 53706, USA. barrettwilt@wisc.edu.
⁸ University of Massachusetts, Amherst, School of Public Health and Health Sciences, 100 Holdsworth Way, Amherst, MA 01003, USA. zliu@nutrition.umass.edu.
⁹ Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr., Madison, WI 53706, USA. bwbolling@wisc.edu.

PMID: 31212794
PMCID: PMC6627224
DOI: 10.3390/nu11061316

Abstract

Oxidative stress is involved in the pathogenesis and progression of inflammatory bowel disease. Consumption of aronia berry inhibits T cell transfer colitis, but the antioxidant mechanisms pertinent to immune function are unclear. We hypothesized that aronia berry consumption could inhibit inflammation by modulating the antioxidant function of immunocytes and gastrointestinal tissues. Colitis was induced in recombinase activating gene-1 deficient (Rag1^-/-) mice injected with syngeneic CD4⁺CD62L⁺ naïve T cells. Concurrent with transfer, mice consumed either 4.5% w/w aronia berry-supplemented or a control diet for five weeks. Aronia berry inhibited intestinal inflammation evidenced by lower colon weight/length ratios, 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) uptake, mRNA expressions of tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) in the colon. Aronia berry also suppressed systemic inflammation evidenced by lower FDG uptake in the spleen, liver, and lung. Colitis induced increased colon malondialdehyde (MDA), decreased colon glutathione peroxidase (GPx) activity, reduced glutathione (rGSH) level, and suppressed expression of antioxidant enzymes in the colon and mesenteric lymph node (MLN). Aronia berry upregulated expression of antioxidant enzymes, prevented colitis-associated depletion of rGSH, and maintained GPx activity. Moreover, aronia berry modulated mitochondria-specific antioxidant activity and decreased splenic mitochondrial H₂O₂ production in colitic mice. Thus, aronia berry consumption inhibits oxidative stress in the colon during T cell transfer colitis because of its multifaceted antioxidant function in both the cytosol and mitochondria of immunocytes.

Keywords: adoptive transfer colitis; aronia berry; inflammatory bowel disease; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Consumption of 4.5% aronia berry-supplemented diet mitigates wasting induced by T cell transfer colitis in mice. Splenic CD4⁺CD62L⁺ cells from C57BL/6J mice were transferred to *Rag1*^-/- mice. Mice consumed the AIN-93M diet (colitic control) or aronia-supplemented diet for five weeks. A third group of *Rag1*^-/- mice received splenic CD4⁺ cells, consumed AIN-93M diet, and served as the non-colitic control. (A) Body weight changes after T cell transfer, as mean percentage of initial body weight at transfer (n = 9–10/group). Data bearing different letters indicate significant within-week differences (p < 0.05). (B) Colon weight/length ratio (n = 9–10/group). (C) Tissue 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) uptakes at 1 h after intravenous injection of approximately 1.85 MBq of FDG (n = 4–6/group). Groups bearing different letters indicate significant differences between treatments (p < 0.05). Data are means ± SEMs.

**Figure 2**
Aronia consumption downregulates mRNA expression of pro-inflammatory cytokines and up-regulates anti-inflammatory cytokines. Splenic CD4⁺CD62L⁺ cells from C57BL/6J mice were transferred to *Rag1*^-/- mice. Mice consumed the AIN-93M diet (colitic control) or aronia-supplemented diet for five weeks. A third group of *Rag1*^-/- mice received splenic CD4⁺ cells, consumed AIN-93M diet and served as the non-colitic control. The mRNA expressions of transcription factors of *Foxp3* (forkhead box P3) and *Rorc* (RAR-related orphan receptor gamma), and cytokines of *Il17a* (interleukin 17A), *Il22* (interleukin 22), *Il6* (interleukin 6), *Il10* (interleukin 10), *Ifng* (interferon-gamma), and *Tnf* (tumor necrosis factors) in the (A) colon (n = 4–5/group), (B) mesenteric lymph node (MLN) (n = 8–10/group), and (C) spleen (n = 3–5/group). The mRNA expressions were normalized to *Eef2* (eukaryotic translation elongation factor 2) and *Rplp0* (ribosomal protein large P0) genes. Data are means ± SEMs.

**Figure 3**
Aronia consumption reduces mitochondria H₂O₂. Splenic CD4⁺CD62L⁺ cells from C57BL/6J mice were transferred to *Rag1*^-/- mice. Mice consumed the AIN-93M diet (colitic control) or aronia-supplemented diet for five weeks. A third group of *Rag1*^-/- mice received splenic CD4⁺ cells, consumed AIN-93M diet, and served as non-colitic control. MitoP/MitoB ratio in (A) spleen and (B) colon (n = 4–5/group). Groups bearing different letters indicate significant differences between treatments (p < 0.05). Data are means ± SEMs.

**Figure 4**
Aronia consumption reduces malondialdehyde (MDA) and prevents depletion of antioxidant enzymes in colon. Splenic CD4⁺CD62L⁺ cells from C57BL/6J mice were transferred to *Rag1*^-/- mice. Mice consumed the AIN-93M diet (colitic control) or aronia-supplemented diet for five weeks. A third group of *Rag1*^-/- mice received splenic CD4⁺ cells, consumed AIN-93M diet, and served as the non-colitic control. (A) Colon MDA (n = 4–5/group). (B) Colon glutathione peroxidase (GPx) activity (n = 8–10/group). (C) Colon reduced glutathione (rGSH) (n = 8–10/group). Groups bearing different letters indicate significant differences between treatments (p < 0.05). Data are means ± SEMs.

**Figure 5**
Aronia consumption maintains mRNA expression of endogenous antioxidant enzymes. Splenic CD4⁺CD62L⁺ cells from C57BL/6J mice were transferred to *Rag1*^-/- mice. Mice consumed the AIN-93M diet (colitic control) or aronia-supplemented diet for five weeks. A third group of *Rag1*^-/- mice received splenic CD4⁺ cells, consumed AIN-93M diet, and served as the non-colitic control. The mRNA expressions of transcription factor of Nfe2l2 (erythroid-derived 2-like 2) and the downstream antioxidant enzymes of *Gclc* (glutamate-cysteine ligase-catalytic subunit), *Gsr* (glutathione reductase), *Sod2* (superoxide dismutase 2), *Gpx1* (glutathione peroxidase 1), *Gpx2* (glutathione peroxidase 2), and *Prdx1* (peroxiredoxin 1) in the (A) colon (n = 4–5/group), (B) mesenteric lymph node (MLN) (n = 9–10/group), and (C) spleen (n = 3–5/group). Gene expression was normalized to *Eef2* (eukaryotic translation elongation factor 2) and *Rplp0* (ribosomal protein large P0) genes. Bars bearing different letters indicate significant differences between treatments (p < 0.05). Data are means ± SEMs.

**Figure 6**
Aronia berry does not affect the expression of glucose transporters in colitic mice. Splenic CD4⁺CD62L⁺ cells from C57BL/6J mice were transferred to *Rag1*^-/- mice. Mice consumed the AIN-93M diet (colitic control) or aronia-supplemented diet for five weeks. A third group of *Rag1*^-/- mice received splenic CD4⁺ cells, consumed AIN-93M diet, and served as the non-colitic control. (A) *Glut1* (glucose transporter 1) in the colon (n = 4–5/group), mesenteric lymph node (MLN) (n = 9–10/group), and spleen (n = 3–5/group). (B) *Sglt1* (sodium glucose cotransporter 1) expression in colon (n = 4–5/group). The mRNA expressions in *Rag1*^-/- mice were normalized to *Eef2* (eukaryotic translation elongation factor 2) and *Rplp0* (ribosomal protein large P0) genes. Bars bearing different letters indicate significant differences between treatments (p < 0.05).

**Figure 7**
Aronia consumption decreases mitochondria H₂O₂ in MLN but does not affect the expression of antioxidant enzymes and cytokines in the spleen. C57BL/6J mice consumed the AIN-93M diet or aronia-supplemented diet for five weeks. (A) The mRNA expressions of transcription factors of *Foxp3* (forkhead box P3) and *Rorc* (RAR-related orphan receptor gamma), and cytokines of *Il17a* (interleukin 17A), *Il6* (interleukin 6), *Il10* (interleukin 10), *Ifng* (interferon-γ), and *Tnf* (tumor necrosis factors) in the spleen (n = 5–7/group). (B) The mRNA expressions of transcription factor of Nfe2l2 (erythroid-derived 2-like 2) and the downstream antioxidant enzymes of *Gclc* (glutamate-cysteine ligase-catalytic subunit), *Gsr* (glutathione reductase), *Sod2* (superoxide dismutase 2), *Gpx1* (glutathione peroxidase 1), *Gpx2* (glutathione peroxidase 2), and *Prdx1* (peroxiredoxin 1) in the spleen (n = 6–7/group). (C) The mRNA expressions of *Glut1* (glucose transporter 1) in the spleen (n = 6–7/group). (D) MitoP/MitoB ratio in mesenteric lymph node (MLN) (n = 4–5/group). The mRNA expressions (normalized to *Eef2* (eukaryotic translation elongation factor 2) and *Rplp0* (ribosomal protein large P0)). Data are means ± SEMs.

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References

1. Ng S.C., Shi H.Y., Hamidi N., Underwood F.E., Tang W., Benchimol E.I., Panaccione R., Ghosh S., Wu J.C.Y., Chan F.K.L., et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet. 2017;390:2769–2778. doi: 10.1016/S0140-6736(17)32448-0. - DOI - PubMed
1. Biasi F., Leonarduzzi G., Oteiza P.I., Poli G. Inflammatory bowel disease: Mechanisms, redox considerations, and therapeutic targets. Antioxid. Redox Signal. 2013;19:1711–1747. doi: 10.1089/ars.2012.4530. - DOI - PMC - PubMed
1. Jones R.M., Neish A.S. Redox signaling mediated by the gut microbiota. Free Radic. Biol. Med. 2017;105:41–47. doi: 10.1016/j.freeradbiomed.2016.10.495. - DOI - PubMed
1. Rutgeerts P., Vermeire S., Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology. 2009;136:1182–1197. doi: 10.1053/j.gastro.2009.02.001. - DOI - PubMed
1. Sartor R.B. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: Antibiotics, probiotics, and prebiotics. Gastroenterology. 2004;126:1620–1633. doi: 10.1053/j.gastro.2004.03.024. - DOI - PubMed

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[1] Ng S.C., Shi H.Y., Hamidi N., Underwood F.E., Tang W., Benchimol E.I., Panaccione R., Ghosh S., Wu J.C.Y., Chan F.K.L., et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet. 2017;390:2769–2778. doi: 10.1016/S0140-6736(17)32448-0. - DOI - PubMed

[2] Ng S.C., Shi H.Y., Hamidi N., Underwood F.E., Tang W., Benchimol E.I., Panaccione R., Ghosh S., Wu J.C.Y., Chan F.K.L., et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of population-based studies. Lancet. 2017;390:2769–2778. doi: 10.1016/S0140-6736(17)32448-0. - DOI - PubMed

[3] Biasi F., Leonarduzzi G., Oteiza P.I., Poli G. Inflammatory bowel disease: Mechanisms, redox considerations, and therapeutic targets. Antioxid. Redox Signal. 2013;19:1711–1747. doi: 10.1089/ars.2012.4530. - DOI - PMC - PubMed

[4] Biasi F., Leonarduzzi G., Oteiza P.I., Poli G. Inflammatory bowel disease: Mechanisms, redox considerations, and therapeutic targets. Antioxid. Redox Signal. 2013;19:1711–1747. doi: 10.1089/ars.2012.4530. - DOI - PMC - PubMed

[5] Jones R.M., Neish A.S. Redox signaling mediated by the gut microbiota. Free Radic. Biol. Med. 2017;105:41–47. doi: 10.1016/j.freeradbiomed.2016.10.495. - DOI - PubMed

[6] Jones R.M., Neish A.S. Redox signaling mediated by the gut microbiota. Free Radic. Biol. Med. 2017;105:41–47. doi: 10.1016/j.freeradbiomed.2016.10.495. - DOI - PubMed

[7] Rutgeerts P., Vermeire S., Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology. 2009;136:1182–1197. doi: 10.1053/j.gastro.2009.02.001. - DOI - PubMed

[8] Rutgeerts P., Vermeire S., Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology. 2009;136:1182–1197. doi: 10.1053/j.gastro.2009.02.001. - DOI - PubMed

[9] Sartor R.B. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: Antibiotics, probiotics, and prebiotics. Gastroenterology. 2004;126:1620–1633. doi: 10.1053/j.gastro.2004.03.024. - DOI - PubMed

[10] Sartor R.B. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: Antibiotics, probiotics, and prebiotics. Gastroenterology. 2004;126:1620–1633. doi: 10.1053/j.gastro.2004.03.024. - DOI - PubMed

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Aronia Berry Supplementation Mitigates Inflammation in T Cell Transfer-Induced Colitis by Decreasing Oxidative Stress

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Aronia Berry Supplementation Mitigates Inflammation in T Cell Transfer-Induced Colitis by Decreasing Oxidative Stress

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Abstract

Conflict of interest statement

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