key: cord-0257274-he2a89ur
authors: Greto, V. L.; Cvetko, A.; Stambuk, T.; Dempster, N. J.; Kifer, D.; Deris, H.; Cindric, A.; Vuckovic, F.; Falchi, M.; Gillies, R. S.; Tomlinson, J. W.; Gornik, O.; Sgromo, B.; Spector, T. D.; Menni, C.; Geremia, A.; Arancibia-Carcamo, C. V.; Lauc, G.
title: Extensive weight loss can reduce immune age by altering IgG N-glycosylation
date: 2020-04-29
journal: nan
DOI: 10.1101/2020.04.24.20077867
sha: 805be73069d1352486d1543cc391f258d81b73fd
doc_id: 257274
cord_uid: he2a89ur

Background Obesity represents a global health threat, and is associated not only with exponentially increased cardiometabolic morbidity and mortality, but with adverse clinical outcomes in patients infected with SARS-CoV-2 as well. Enzymatic attachment of complex oligosaccharides to proteins (glycosylation) is highly responsive to numerous (patho)physiological conditions and ageing, which is perhaps best exemplified on IgG. The prospect of immune age reduction, by reverting induced glycosylation changes through metabolic intervention, opens many possibilities. Herein, we have investigated whether weight loss interventions affect inflammation- and ageing-related glycosylation alterations, in a longitudinal cohort of bariatric-surgery patients. To support potential findings, BMI-related glycosylation changes were monitored in a longitudinal TwinsUK cohort. Methods IgG and plasma N-glycans were chromatographically profiled in 37 obese patients, subjected to low-calorie diet and then to bariatric surgery, across multiple timepoints. Similarly, plasma glycome was analysed in 1,680 TwinsUK participants and longitudinally monitored during a 20-year follow-up. Findings Low-calorie diet induced marked increase in low branched and significant decrease in highly branched, more complex plasma N-glycans - the change opposite to the one typically observed in inflammatory conditions. Bariatric surgery resulted in extensive, gradual alterations in IgG glycome, that accompanied progressive weight loss during one year follow-up. We observed significant increase in digalactosylated and sialylated, and substantial decrease in agalactosylated and core fucosylated IgG glycans. In general, such IgG glycan profile is associated with a younger biological age and reflects enhanced anti-inflammatory IgG potential. The TwinsUK cohort replicated weight loss-associated agalactosylation decrease and digalactosylation increase, estimated through BMI decrease over a 20-year period. Interpretation Altogether, these findings highlight that weight loss substantially affects both plasma and IgG N-glycosylation, resulting in improved biological and immune age.

• Obesity is associated to circulating pro-inflammatory high branched N-glycans and 40

IgG agalactosylation 41 42

• High branching of N-glycans from total plasma proteins decreases after 3-week low-43 calorie diet 44 45

• IgG galactosylation and sialylation increase after bariatric surgery-induced weight 46 loss 47 48

• Decrease of BMI over time is associated with increased IgG galactosylation and 49 improvement of biological age 50 51 52 KEYWORDS 53 N-glycosylation; bariatric surgery; weight loss; imunoglobulin G; COVID-19; biological age 54 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020.04.24.20077867 doi: medRxiv preprint

The global prevalence of obesity has risen dramatically, to the point that it is now considered 56 of the EPIC-Potsdam cohort confirmed that changes in plasma N-glycome composition are 87 predictive of future CVD events, with comparable predictive power to the American Heart 88 Association (AHA) score in men and even better predictive power in women (16). The link 89 between an "old", proinflammatory IgG N-glycome and hypertension has also been 90 profoundly studied (17) (18) (19) , and similar IgG glycosylation patterns were associated with 91 increased body mass index (BMI) and measures of central adiposity (20, 21) . 92

Studies on mouse models further corroborate the importance of differential IgG glycoforms 93 in CVD pathogenesis. Namely, it has been shown that hyposialylated IgG (corresponding to an 94 "old" IgG glycome) can induce obesity-related hypertension and insulin resistance in B-cell-95 deficient mice, through activation of the endothelial FcγRIIB (22,23). These findings indicate 96 that the IgG N-glycome could represent more than a biomarker of inflammation and aging, 97 since distinctive IgG glycoforms act as effector molecules in certain pathologies. Furthermore, 98 supplementation with N-acetylmannosamine (ManNAc), a precursor of sialic acid, protects 99 obese mice from hypertension and insulin resistance induction by reverting an "old" IgG N-100 glycome into a "young" one (23,24). However, studies exploring the possibilities of converting 101 an "old" IgG glycome into a "young" one by metabolic intervention in humans are limited. Of 102 note, only one small study indicated that high-intensity interval training can "rejuvenate" the 103 IgG N-glycome (25). 104

Finally, severe obesity can be resolved only through bariatric surgery and subsequent weight 105 loss (26). The resulting weight loss impacts energy balance and metabolism, contributing to 106 the increased insulin response, improved glycaemic control and reduction of total body fat, 107 leading to decreased CVD risk and mortality (27) . In this study we aimed to determine whether 108 weight loss affects glycan markers related to inflammation and ageing, in a longitudinally-109 monitored cohort of obese individuals undergoing low-calorie diet and then bariatric surgical 110

interventions. In order to support potential findings, we also investigated the BMI-related 111 glycosylation changes in a longitudinal TwinsUK cohort. The analysis of samples obtained from 112 the largest longitudinal twins cohort in the UK allowed us to observe the changes of BMI in 113 relation to the IgG N-glycosylation alterations over time. 114

METHODS 116

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 29, 2020. Patients with a history of alcoholism and/or ongoing anticoagulant treatment were excluded. 123

Patients were also excluded in case of pregnancy, active substance abuse or uncontrolled 124 psychiatric condition including eating disorders. Participants were sampled at baseline and 125 subjected to 3-week low calorie carbohydrate-restricted diet (900 cal, maximum 100 g of 126 carbohydrates per day), followed by bariatric surgery. The sequential follow-up timepoints 127 included the day of the surgery (baseline), after 6.54 ± 3.4 months (mean ± IQR) and 12.47 ± 128 6.55 months post-op. Characteristics of the bariatric cohort are shown in Table 1 . 129 TwinsUK cohort. We have analysed a total of 6,032 plasma samples from 2,146 participants of 135 the TwinsUK study, collected at multiple timepoints over a 20 year-period (28). These included 136 1,865 individuals sampled at 3 timepoints, 156 individuals sampled at 2 timepoints and 125 137 individuals sampled only once. Following the plasma N-glycome analysis, glycan data 138 underwent quality control (see Statistical analysis section), which decreased the dataset to 139 5,889 samples (measurements). Out of these 5,889 measurements, we have proceeded with 140 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 29, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. TwinsUK cohort are presented in Supplementary Table 4 . 210

Bariatric cohort. In order to remove experimental variation from the measurements, 212 normalization and batch correction were performed on the UPLC glycan data. To make 213 measurements across samples comparable, normalization by total area was performed. Prior 214 to batch correction, normalized glycan measurements were log-transformed due to right-215 skewness of their distributions and the multiplicative nature of batch effects. Batch correction 216 was performed on log-transformed measurements using the ComBat method (R package sva 217 (30), where the technical source of variation (which sample was analysed on which plate) was 218 modelled as batch covariate. To correct measurements for experimental noise, estimated 219 batch effects were subtracted from log-transformed measurements. 220

Longitudinal analysis of patient samples through their observation period was performed by 221 implementing a linear mixed effects model, where time was modelled as fixed effect, while 222 the individual ID was modelled as random effect. Prior to the analyses, glycan variables were 223 all transformed to standard Normal distribution by inverse transformation of ranks to 224 Normality (R package "GenABEL", function rntransform). Using rank transformed variables 225 makes estimated effects of different glycans comparable, as these will have the same 226 standardized variance. False discovery rate (FDR) was controlled by the Benjamini-Hochberg 227 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020.04.24.20077867 doi: medRxiv preprint procedure at the specified level of 0.05. Data was analysed and visualized using R 228 programming language (version 3.5.2)(31). 229

TwinsUK cohort. Normalization of peak intensities to the total chromatogram area was 230 performed for each measured sample separately. Calculated proportions were then batch 231 corrected using ComBat method (R package sva)(30). After the batch correction the first 11 232 peaks, which predominantly originate from IgG (32), were used to calculate 6 derived glycan 

We profiled both plasma and IgG N-glycome in a cohort of bariatric surgery-candidate patients 251 at the beginning and at the end of their pre-operative diet. We calculated corresponding 252 derived glycan traits, which average particular glycosylation features. By employing a linear 253 mixed model, we observed ample changes in plasma N-glycome, as 10 out of 16 calculated 254 derived traits displayed significant alterations after the low-calorie diet. Namely, low 255 branched (LB), agalactosylated (G0), monogalactosylated (G1), asialylated (S0), 256 monosialylated (S1), core fucosylated (CF) and glycans bearing a bisecting GlcNAc (B) showed 257 a substantial increase in their abundances (Table 3) . Conversely, high branched (HB), 258 trisialylated (S3) and trigalactosylated (G3) glycan abundances decreased (Table 3) . 259 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020.04.24.20077867 doi: medRxiv preprint Interestingly, IgG glycome was not affected by the low-calorie diet, as its derived traits did not 260 display any significant changes after the dieting period. Graphical representation of the 261 longitudinal alterations in plasma N-glycome after low calorie diet are depicted in Figure 1 . 262 263 Red -significant decrease; green -significant increase; blue -non-significant change. 268

GlcNAc -N-acetylglucosamine; SE -standard error 269 270 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. (Table 4 ). On the 281 other hand, IgG N-glycome showed more extensive changes, following the bariatric 282 procedure. Namely, four out of eight tested derived traits showed marked changes: core 283 fucosylated (CF) and agalactosylated (G0) glycans decreased, while digalactosylated (G2) and 284 monosialylated (S1) glycans increased after the surgery (Table 4 ). The IgG glycans whose 285 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020.04.24.20077867 doi: medRxiv preprint abundances were increased after bariatric surgery are major components of a "young" IgG 286 glycome, as they are typically associated with a younger age. The opposite applies to 287 agalactosylated structures , which are usual denominators of an "old" IgG glycome profile. We 288 also examined the correlation of patients' clinical data with plasma and IgG glycome features 289 using multivariate analysis, but found no statistically significant associations (data not shown). CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. 

Using the same chromatographic approach, we profiled plasma protein N-glycome from 1,680 310

TwinsUK study participants sampled at several timepoints over a 20-year-period. This served 311 as a replication of the findings from the bariatric cohort, whose participants exhibited the 312 reversal from ''old'' to ''young'' IgG N-glycome due to weight loss. As these results showed 313 prominent changes in IgG composite glycan traits only, herein we focused on IgG glycosylation 314 changes. Due to the fact that for TwinsUK cohort plasma glycome was profiled, we calculated 315 derived traits and performed statistical analysis only on the first 11 glycan peaks, 316 corresponding to the glycans predominantly originating from IgG (32). Six derived traits were 317 calculated -agalactosylation (G0), monogalactosylation (G1), digalactosylation (G2), 318 incidence of bisecting GlcNAc (B), core fucosylation (CF) and incidence of high mannose 319 structures (HM). We examined IgG glycome alterations associated with changes in BMI using 320 a mixed model on a subset of 3,742 samples. Out of six examined IgG glycosylation features 321 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020.04.24.20077867 doi: medRxiv preprint (derived traits), three displayed significant BMI-related changes -agalactosylation (G0), 322 digalactosylation (G2) and incidence of high mannose structures (HM) (Table 5) Red -significant decrease; green -significant increase; blue -non-significant change. 334

GlcNAc -N-acetylglucosamine; SE -standard error 335 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. In this study, we have observed extensive changes in both plasma and IgG N-glycome 351 associated with weight loss following low-calorie diet and bariatric surgery, or expressed 352 through BMI decrease. To the best of our knowledge, this is the first study to investigate 353 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020.04.24.20077867 doi: medRxiv preprint plasma and IgG N-glycome alterations in patients who underwent a low-calorie diet followed 354 by bariatric surgery. 355

Prior to bariatric surgery, patients were subjected to a low-calorie diet which caused 356 significant and extensive changes to the plasma protein N-glycome. The observed changes can 357 be summarized as significant increase in low-branched, biantennary structures (S0, S1, G0, 358 G1…) and, conversely, substantial decrease in high-branched, triantennary, more complex 359 structures (S3, G3). The glycosylation alterations induced by a low-calorie diet are showing 360 exactly the opposite direction of change than those seen in various inflammatory conditions, 361 such as type 2 diabetes, chronic obstructive pulmonary disease and inflammatory bowel 362 disease (16,29,34,35), suggesting a gradual attenuation of inflammation. Interestingly, no 363 significant changes were found for the IgG N-glycome alone after the diet, probably due to 364 the relatively short follow-up period (3 weeks), which matches IgG serum half-life. Altogether, 365 our glycomic data suggest that the overall inflammatory body status improves after a short 366 time of low-calorie diet, reflecting a quickly noticeable and beneficial metabolic effect. 367

We have analysed both plasma and IgG N-glycome from individuals who underwent bariatric 369 surgery, in a longitudinal manner. We observed significant changes in both plasma and IgG N-370 glycome. In particular, plasma N-glycome showed significant alterations only in 371 agalactosylated (G0) glycans, whose abundance decreased during the follow-up period. Since 372 the majority of agalactosylated species in plasma originates from IgG (32), it is no surprise that 373 this glycosylation feature was also found to be significantly decreased in IgG glycome analysis. 374

Elevated levels of G0 IgG glycoforms are typically associated with aging, a pro-inflammatory 375

IgG glycan profile and various inflammatory diseases (11). On the other hand, the levels of 376 digalactosylated (G2) glycans increased after bariatric surgery and at sequential timepoints, in 377 accordance with a reduced inflammatory potential of the circulating IgG. Interestingly, the 378 increased levels of IgG galactosylation are associated with a younger biological age and are 379 considered, in a way, as a measure of an individual's well-being (14). Converesely, IgG 380 galactosylation levels substantially decrease with ageing and during inflammation (11,13). Our 381 results demonstrate that weight loss, resulting from bariatric surgery, can initiate the reversal 382 from an ''old'' to a ''young'' IgG N-glycome, potentially reversing the clock for the 383 immune/biological age. Furthermore, bariatric surgery also resulted in significant IgG glycome 384 alteration inducing a decrease in core fucosylation. The vast majority of circulating IgG 385 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020.04.24.20077867 doi: medRxiv preprint molecules bears core fucose (approximately 95%), which profoundly decreases IgG binding 386 affinity to FcγRIIIA receptor and sequential antibody-dependent cellular cytotoxicity (ADCC) 387

infections. This would suggest that an extensive weight loss ameliorates immune responses 389 dedicated to combat viral infections, by altering IgG glycosylation and modulating its effector 390 functions. Lastly, bariatric surgery-related weight loss led to an increase in IgG sialylation, 391 which is the main modulator of the IgG anti-inflammatory actions (37). In addition to its anti-392 inflammatory actions, the level of IgG sialylation has been implicated in the pathogenesis of 393 obesity-induced insulin resistance and hypertension, as already mentioned (22,23). Namely, 394

inhibitory IgG receptor FcγRIIB was found to be expressed in the microvascular endothelium. 395

Sequentially, it was shown that hyposialylated IgG acts as its operating ligand, leading to the 396 induction of obesity-related insulin resistance and hypertension. On the other hand, the 397 sialylated glycoform is not activating the signalling pathways responsible for the insulin 398 resistance and hypertension development, but is rather preserving insulin sensitivity and 399 normal vasomotor tone, even in obese mice. Interestingly, the same group made another 400 significant discovery -promotion of IgG sialylation breaks the link between obesity and 401 hypertension/insulin resistance (23,24). Namely, supplementation with the sialic acid 402 precursor restored IgG sialylation, highlighting a potential approach to improve both 403 metabolic and cardiovascular health in humans, with a single intervention. Our data suggest 404 that a similar effect might be achieved by weight loss interventions, through restoring of IgG 405 sialylation levels. Altogether, it is quite fascinating that such marked effects could be observed 406 on a rather small number of participants, which further highlights their significance in a given 407 biological setting. 408 409 Lastly, in order to confirm the effects of weight loss on the biological/immune age, we 410 investigated how BMI decrease affects IgG N-glycome during a 20-year-period. We observed 411 the prominent inverse changes of agalactosylated (G0) and digalactosylated (G2) IgG glycans. 412

Namely, agalactosylated IgG glycans significantly decreased, while digalactosylated ones 413 substantially increased as the BMI decreased. These observations corroborated our earlier 414 findings, confirming that the body weight reduction reverses IgG glycome from "old" to 415 "young", implying at the same time a likely reduction in the biological/ immune age. 416

Nonetheless, we have to acknowledge the following limitations of TwinsUK as a replication 417 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020.04.24.20077867 doi: medRxiv preprint cohort: first -TwinsUK participants have not experienced such an extensive weight loss, which 418 potentially influenced the replication of other significant glycan changes from the bariatric 419 cohort; second -herein, the weight loss was approximated by BMI decrease, which is usually 420 a legitimate assumption, however, it does not have to apply to all cases; and third -herein we 421 profiled plasma glycome, while the IgG glycan traits were only approximated and the 422 information on IgG sialylation was confounded by other plasma glycoproteins. Ideally, these 423 issues could be circumvented in the future studies whose experimental design would allow 424 the simultaneous, multi-centre follow-up of larger groups of patients. 425

Intense physical exercise can also shift IgG N-glycome towards a "younger" profile by 426

increasing IgG galactosylation (25). Although another study reported that prolonged intensive 427 exercise can have the opposite effect and promote pro-inflammatory changes of IgG N-428 glycome (38), its findings are not surprising since it recruited healthy, normal-weight female 429 participants, subjected to the intense energy deprivation and exercise levels, to induce 430 substantial fat loss in a rather short time period. The authors also highlighted that starting 431 weight and the way in which weight loss is achieved could be crucial for the final effect on the 432 immune system. Therefore, it seems that exercise overall has a positive impact on the immune 433 system and biological clock, but its intensity and duration should be personalized in order to 434 provide the optimal results. 435

To summarize, our results indicate that weight loss has impact on inflammation and biological 436 aging by altering plasma and IgG N-glycosylation patterns. Glycosylation changes can be 437 reliably quantified and used to estimate the "age" of the immune system. This could represent 438 a valuable tool in the context of COVID-19 patient stratification. Since inter-individual 439 variation in protein glycosylation is extensive, its functional implications on membrane CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 29, 2020. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 29, 2020. . https://doi.org/10.1101/2020.04.24.20077867 doi: medRxiv preprint

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