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Research Highlights

Flossmann, Viktoria1; Cross, Amy PhD1; Issa, Fadi DPhil1

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doi: 10.1097/TP.0000000000003273
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Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism

Duscha A, Gisevius B, Hirschberg S, et al. Cell. 2020;180:1067–1080.e16.

The diversity and composition of gut microbiota has been shown to modulate immune responses both in local and distant tissues. One mechanism by which commensal bacteria get involved is through the production of metabolites, such as small chain fatty acids, that can cross the intestinal wall and enter circulation. Small chain fatty acids have been previously found to expand gut-associated regulatory T cell (Treg) populations, ameliorating outcomes in animal models such as autoimmune encephalomyelitis, inflammatory bowel disease, and type 1 diabetes.1 Based on those preclinical data, Duscha et al2 carried out a proof-of-principle study to investigate the potential immunomodulatory properties of propionic acid in multiple sclerosis (MS) patients. Cohorts of newly diagnosed and disease-established patients received daily oral propionic acid, supplementing standard treatments.

MS patients had a characteristically low peripheral blood proportions of anti-inflammatory Tregs and a high proportion of pro-inflammatory T helper 17 cells. Additionally, less propionic acid was detected in the sera and stool of MS patients in comparison to healthy controls. Changes in this microbial metabolite prompted investigations of potential gut dysbiosis, which found a loss in the abundance of short-chain fatty acid-producing bacteria (such as Butyricimonas).

Propionic acid supplements successfully led to a 30% increase in Tregs within 14 days, shifting the inflammatory profile of circulating lymphocytes. Transcriptomic analysis of whole blood revealed an upregulation of genes involved in T cell-specific pathways, underlining the systemic impact of this metabolite on adaptive immunity. Long-term administration (>1 y) was well tolerated, with no serious adverse events and rare mild events. Moreover, propionic acid provided clinical benefit through a reduced annual relapse rates, reduced brain atrophy, and stabilized disability scores.

Propionic acid also directly increased the suppressive ability of Tregs in vitro and ex vivo in an interleukin-10–dependent manner. The authors noted dysfunctional mitochondrial respiration and morphology in Tregs from MS patients that could be rescued by 90 days of propionic acid treatment. Furthermore, fecal samples from responsive patients following propionic acid doses upregulated genes implicated in Treg induction in mouse intestinal tissue, suggesting that supplements modified the microbiome to, in turn, promote local Treg induction.

As so often with therapeutic advances in autoimmune disease, this study may have applicability to transplantation. The gut microbiome changes significantly in diversity and composition within the first month following transplantation and changes in composition have been associated with alloimmune responses in clinical and preclinical studies.3,4 It remains to be investigated whether there is a relationship between the abundance of small chain fatty acid-producing bacteria or reduced propionic acid levels and transplant rejections. Indeed, modifications to small chain fatty acid levels, such as through high-fiber diets or oral supplements, may represent a relatively low-risk strategy to bolster tolerogenic immunity.

Sex-specific Adipose Tissue Imprinting of Regulatory T Cells

Vasanthakumar A, Chisanga D, Blume J, et al. Nature. 2020;579:581–585.

Sex-specific differences in immunity are being increasingly recognized. Prominent examples include the higher prevalence of autoimmune disease and the lower mortality rates for cardiovascular disease among women. Likewise, sex can influence transplant outcome, resulting for instance, in reduced kidney allograft survival from female donors.5

Here, Vasanthakumar et al6 have shed light on stark differences between male and female immunoregulation in visceral adipose tissue (VAT) of lean mice.

In both male and female mice, VAT-resident regulatory T cells (Treg) exhibited an activated phenotype. Notably, the authors discovered that Tregs were more abundant in male VAT and that cells expressed higher amounts of anti-inflammatory interleukin (IL)-10. This sexual dimorphism was unique to the perigonadal VAT and to VAT-resident Tregs as other immune cells within the VAT or Tregs did not differ in abundance or IL-10 production. Moreover, the transcriptomic analysis confirmed a distinctive phenotype in male VAT Tregs, compared with male splenic Tregs or female VAT Tregs.

Male VAT Treg abundance and phenotype was not dependent on the direct action of androgens on Tregs. Sexual dimorphism in VAT Tregs was rather driven by androgen regulation of the VAT niche. The male VAT was transcriptomically distinct from subcutaneous adipose tissue and female VAT. Notably, there was an elevated mRNA expression of the chemokine CCL-2. Its receptor, CCR-2, was highly expressed on male VAT Tregs and required for the population of male VAT by Tregs. Continuous recruitment of Tregs from splenic precursors to the VAT where they developed the tissue-specific VAT signature was supported by parabiosis studies.

VAT stromal cells showed marked differential expression of CD90 and CD73 between male and female mice. Stromal cell production of IL-33 was enhanced in male VAT and was crucial for the expansion of VAT Tregs in male mice. Indeed, exogenous IL-33 or loss of estrogen signaling resulted in an expansion of male VAT Treg-like cells in female mice. The authors conclude that the augmented inflammation in male VAT and male-specific IL-33–producing stromal cells fuel the active recruitment and local fine-tuning of VAT Tregs.

This study raises questions about sex-specific differences in immunoregulation between male and female transplant recipients. However, it is important to note that this sexual dimorphism was only present in 1 specific mouse tissue, the perigonadal adipose tissue, which may not have a direct human homolog.7 Further work is therefore needed to understand whether these findings have a physiological role in humans.

REFERENCES

1. Haghikia A, Jörg S, Duscha A, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity. 2015; 43:817–829
2. Duscha A, Gisevius B, Hirschberg S, et al. Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism. Cell. 2020; 180:1067–1080.e16
3. Sepulveda M, Pirozzolo I, Alegre ML. Impact of the microbiota on solid organ transplant rejection. Curr Opin Organ Transplant. 2019; 24:679–686
4. Fricke WF, Maddox C, Song Y, et al. Human microbiota characterization in the course of renal transplantation. Am J Transplant. 2014; 14:416–427
5. Zeier M, Döhler B, Opelz G, et al. The effect of donor gender on graft survival. J Am Soc Nephrol. 2002; 13:2570–2576
6. Vasanthakumar A, Chisanga D, Blume J, et al. Sex-specific adipose tissue imprinting of regulatory T cells. Nature. 2020; 579:581–585
7. Chusyd DE, Wang D, Huffman DM, et al. Relationships between rodent white adipose fat pads and human white adipose fat depots. Front Nutr. 2016; 3:10
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