Re: 폴리아민... 장내 유해균.. 과도한 폴리아민 생산.. .. 질병...

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Front Endocrinol (Lausanne)

. 2023 Jan 13;13:1094258. doi: 10.3389/fendo.2022.1094258

Probiotic induced synthesis of microbiota polyamine as a nutraceutical for metabolic syndrome and obesity-related type 2 diabetes

Tina I Bui 1, Emily A Britt 1, Gowrishankar Muthukrishnan 1,2,3, Steven R Gill 1,2,*

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PMCID: PMC9880209  PMID: 36714575

Abstract

The gut microbiota regulates multiple facets of host metabolism and immunity through the production of signaling metabolites, such as polyamines which are small organic compounds that are essential to host cell growth and lymphocyte activation. Polyamines are most abundant in the intestinal lumen, where their synthesis by the gut microbiota is influenced by microbiome composition and host diet. Disruption of the host gut microbiome in metabolic syndrome and obesity-related type 2 diabetes (obesity/T2D) results in potential dysregulation of polyamine synthesis. A growing body of evidence suggests that restoration of the dysbiotic gut microbiota and polyamine synthesis is effective in ameliorating metabolic syndrome and strengthening the impaired immune responses of obesity/T2D. In this review, we discuss existing studies on gut microbiome determinants of polyamine synthesis, polyamine production in obesity/T2D, and evidence that demonstrates the potential of polyamines as a nutraceutical in obesity/T2D hosts.

장 미생물군은 

신호 전달 대사물인 폴리아민과 같은 소분자 유기 화합물을 생성함으로써 

호스트의 대사 및 면역 체계의 다양한 측면을 조절합니다. 

폴리아민은 

호스트 세포의 성장과 림프구 활성화에 필수적인 역할을 합니다. 

폴리아민은 

장 내강에서 가장 풍부하게 존재하며, 

그 합성은 장 미생물군집의 구성과 호스트의 식단에 의해 영향을 받습니다. 

대사증후군과 비만 관련 제2형 당뇨병(비만/T2D)에서 

호스트 장 미생물군집의 교란은 

폴리아민 합성의 잠재적 조절 장애를 초래합니다. 

증가하는 연구 결과는 

장내 미생물군집의 불균형 회복과 폴리아민 합성 회복이 

대사증후군을 완화하고 

비만/T2D 환자의 손상된 면역 반응을 강화하는 데 효과적임을 시사합니다. 

본 리뷰에서는 

폴리아민 합성의 장내 미생물군집 결정 요인, 

비만/T2D에서의 폴리아민 생산, 

그리고 비만/T2D 환자에게서 폴리아민이 영양 기능성 물질로서의 잠재성을 입증하는 증거를 논의합니다.

Keywords: polyamine, obesity, type 2 diabetes, metabolic syndrome, nutraceutical

Introduction

More than 90% of diabetes is attributed to obesity and it is therefore referred to as obesity-related type 2 diabetes (obesity/T2D) (1). The majority of individuals with obesity/T2D are also diagnosed with metabolic syndrome, based on diagnostic criteria that includes increased waist circumference (i.e., central obesity), elevated triglycerides, and abnormally high fasting glucose indicative of insulin resistance (2, 3). Based on predictions from 2007, the preval‎ence of diabetes is expected to reach 366 million worldwide by 2030 (4). However, recent epidemiological findings suggest 537 million individuals were already affected by obesity/T2D globally in 2021 (5), surpassing the original 2007 estimate (4). Parallel increases in obesity and type 2 diabetes are major public health concerns as both are associated with lower health-related quality of life (6, 7) such as adverse post-infection clinical outcomes (8–12). For example, both obesity and diabetes increase the risk for post-operative periprosthetic joint infections (PJIs) (9) and surgical site infections (SSIs) (10). During the COVID-19 pandemic, individuals with obesity/T2D were more likely to be hospitalized (11, 12) with some studies suggesting higher in-hospital mortality rates (13) likely due to increased incidence of cytokine storms preceding septic shock (12). Thus, obesity/T2D is linked to deficits in overall immunity that are associated with severe infections across body sites at higher mortality and morbidity rates compared to non-obese/T2D counterparts. This in part occurs due to chronic low-grade inflammation that is associated with a disturbance in gut microbiome composition and metabolism as compared to a healthy or homeostatic baseline known as gut dysbiosis (14–22).

It is well accepted that long-term exposure to prototypical Western diets characterized by highly processed foods is at the core of obesity/T2D-related metabolic syndrome (23–25) and chronic low-grade inflammation (26). The gut microbiome as the mediator linking diet and obesity has been established in multiple human and animal studies, with diet identified as the primary contributor to changes in gut microbiome diversity and functional capacity associated with obesity and impaired immunity (27–29). Metabolomic studies have identified several groups of gut microbiota metabolites associated with obesity/T2D, including short-chain fatty acids (30–33), triethylamine-N-oxide (34–36), and bile acids (30, 37–39), which regulate host metabolism and immunity. In this review, we focus on polyamines, a group of metabolites increasingly associated with obesity/T2D.

Polyamine metabolites are essential to mammalian health in multiple organs (40) where they regulate cellular metabolism, proliferation, and differentiation (40, 41). Despite extensive work on polyamines in cancer, autoimmune diseases, and aging, the role of polyamines in immunity remains obscure. More importantly, the role of polyamines in obesity/T2D immunity is not well-studied. Herein, we review the contribution of polyamine biosynthesis and function to obesity/T2D, host immunity, and eval‎uate new work that utilizes polyamines to mitigate metabolic syndrome and complications of obesity/T2D. Understanding the role of polyamines on immunity and metabolic diseases will lead to identification of novel, alternative therapeutics for immunocompromised obese/T2D patients.

소개

당뇨병의 90% 이상은 비만에 기인하며, 따라서 이를 비만 관련 제2형 당뇨병(비만/T2D)이라고 부릅니다(1). 비만/T2D를 가진 대부분의 개인은 진단 기준에 따라 복부 비만(즉, 중앙 비만), 트리글리세라이드 수치 상승, 인슐린 저항성을 나타내는 공복 혈당 수치 상승을 포함하는 대사 증후군으로 진단됩니다(2, 3). 2007년 예측에 따르면, 2030년까지 전 세계 당뇨병 유병률은 3억 6,600만 명에 달할 것으로 예상되었습니다(4). 그러나 최근 역학 연구 결과에 따르면 2021년 기준 전 세계에서 이미 5억 3,700만 명이 비만/T2D로 영향을 받았으며(5), 이는 2007년 초기 추정치(4)를 초과했습니다. 비만과 제2형 당뇨병의 병행 증가 는 건강 관련 삶의 질 저하(6, 7)와 같은 주요 공중 보건 문제로, 특히 감염 후 임상 결과 악화(8–12)와 연관되어 있습니다. 예를 들어, 비만과 당뇨병은 수술 후 인공 관절 주변 감염(PJIs)(9) 및 수술 부위 감염(SSIs)(10) 위험을 증가시킵니다. 코로나19 팬데믹 기간 동안 비만/T2D 환자는 입원 가능성이 더 높았으며(11, 12), 일부 연구에서는 입원 중 사망률이 더 높았다는 결과가 나왔습니다(13). 이는 세균성 쇼크를 앞선 사이토카인 폭풍의 발생률 증가 때문일 가능성이 있습니다(12). 따라서 비만/T2D는 비비만/T2D 대비 사망률과 morbid rate가 높은 전신 감염과 연관된 전반적인 면역 결핍과 관련이 있습니다. 이는 부분적으로 건강한 상태나 균형 상태인 장내 미생물군집(gut microbiome)과 비교했을 때 장내 미생물군집의 구성과 대사 장애와 연관된 만성 저등급 염증(chronic low-grade inflammation) 때문으로 알려져 있습니다(14–22).

장기간에 걸친 가공식품이 풍부한 전형적인 서구식 식단에의 노출이 비만/T2D 관련 대사증후군(23–25)과 만성 저등급 염증(26)의 핵심 요인이라는 것은 널리 인정되고 있습니다. 장 미생물이 식이와 비만을 연결하는 매개체로 작용한다는 것은 인간과 동물 연구에서 다수 입증되었으며, 식이는 비만과 면역 기능 저하와 관련된 장 미생물 다양성과 기능적 능력 변화의 주요 요인으로 확인되었습니다(27–29).

대사체학 연구는

비만/T2D와 연관된 장 미생물 대사산물 그룹을 여러 가지 식별했으며,

이는 단쇄 지방산(30–33),

트리에틸아민-N-옥사이드(34–36),

담즙산(30, 37–39) 등이 포함되며,

이는 호스트의 대사 및 면역 기능을 조절합니다.

본 리뷰에서는

비만/T2D와 연관성이 점점 더 강조되고 있는 대사산물 그룹인

폴리아민에 초점을 맞춥니다.

폴리아민 대사산물은

포유류 건강에 필수적이며(40)

다양한 장기에서 세포 대사, 증식, 분화를 조절합니다(40, 41).

암, 자가면역 질환, 노화 분야에서 폴리아민에 대한 광범위한 연구가 진행되었지만,

폴리아민의 면역 역할은 여전히 불분명합니다.

더욱 중요한 것은

폴리아민의 비만/T2D 면역 역할이 충분히 연구되지 않았다는 점입니다.

본 연구에서는

폴리아민 생합성과 기능이

비만/T2D, 호스트 면역에 미치는 기여를 검토하고,

폴리아민을 활용해 대사 증후군 및 비만/T2D 합병증을 완화하는 새로운 연구를 평가합니다.

폴리아민이

면역과 대사 질환에 미치는 역할을 이해하는 것은

면역력이 약화된 비만/T2D 환자를 위한 새로운 대체 치료법 개발로 이어질 것입니다.

Polyamine and obesity-related type 2 diabetesThe gut microbiota is a major contributor to the host polyamine pool

Polyamines are produced primarily from amino acid precursors arginine, ornithine, and methionine (42). Diamine putrescine, triamine spermine, and tetraamine spermidine are the most abundant natural polyamines found in mammals (43). The total polyamine reservoir in mammals is regulated endogenously by host cells (43) and exogenously by gut bacteria (44–47) and diet (48, 49). Putrescine, spermidine, and spermine exist in the micromolar to millimolar range in various foods (48, 49) and across body sites of healthy adults as summarized in Figure 1 . The use of radiolabeled polyamines demonstrated that polyamines are readily absorbed and enter the circulation (48), where they are distributed across different organs and metabolic fluids, including the brain (50), kidneys (51), breastmilk (52–54), urine (55–58), and serum/plasma (55, 56, 59–62). Notably, the largest accumulation of polyamines occurs in the intestinal lumen as determined with fecal samples from healthy donors where putrescine is the most abundant followed by spermidine and spermine (63, 64). Fecal levels of polyamines have been shown to correlate with gut microbiota composition in humans (63–65) and rodent models (66, 67). Oral supplementation in rodents with arginine led to increased polyamine concentrations in feces in a dose-dependent manner, which was eliminated when these animals were treated with antibiotics prior to arginine administration (66). This implicates the role of the gut microbiota in amino acid metabolism that results in synthesis of polyamines in mammals. Additionally, both Gram-positive and Gram-negative bacteria isolated from human fecal samples, including Bifidobacterium, Clostridium, Enterococcus, and Lactobacillus, are able to produce polyamines in vitro (68). Of these genera, the abundance of Bifidobacterium animalis is decreased and Lactobacillus reuteri increased in obese individuals (69, 70). Together, these studies demonstrate that the gut microbiota is a major contributor to the total polyamine pool in vivo. Moreover, with the direct link between obesity/T2D and gut dysbiosis (71, 72), there is a compelling and urgent need to study host-microbiota-polyamine interactions and the contribution of polyamines in obesity/T2D.

폴리아민과 비만 관련 제2형 당뇨병장내 미생물은 호스트 폴리아민 풀의 주요 기여자

폴리아민은

주로 아르기닌, 오르니틴, 메티오닌과 같은 아미노산 전구체에서 생성됩니다 (42).

디아민 푸트레신,

트리아민 스퍼민,

테트라아민 스퍼미딘은

포유류에서 가장 풍부하게 발견되는 자연 발생 폴리아민입니다 (43).

포유류의 총 폴리아민 저장량은

호스트 세포에 의해 내인성으로 조절되며(43),

장 세균(44–47)과 식이(48, 49)에 의해 외인성으로 조절됩니다.

푸트레신, 스퍼미딘, 스퍼민은

건강한 성인의 다양한 식품(48, 49)과 신체 부위에서 마이크로몰에서 밀리몰 범위에서 존재하며,

이는 그림 1 에 요약되어 있습니다.

방사성 표지된 폴리아민을 사용한 연구는 폴리아민이 쉽게 흡수되어 순환계로 들어간다는 것을 보여주었습니다(48),

여기서 그들은

뇌(50), 신장(51), 모유(52–54), 소변(55–58), 혈청/혈장(55, 56, 59–62) 등

다양한 장기 및 대사액에 분포됩니다.

특히,

폴리아민의 가장 높은 축적은

건강한 기부자의 대변 샘플에서 장 내강에서 관찰되었으며,

여기서 푸트레신(putrescine)이 가장 풍부하며

그 다음으로 스퍼미딘(spermidine)과 스퍼민(spermine)이 이어집니다(63, 64).

인간(63–65)과 설치류 모델(66, 67)에서 폴리아민의 대변 수준은 장 미생물군 구성과 상관관계가 있음을 보여주었습니다. 쥐에게 아르기닌을 경구 투여했을 때 분변 내 폴리아민 농도가 용량 의존적으로 증가했으며, 아르기닌 투여 전에 항생제로 치료한 동물에서는 이 효과가 사라졌습니다(66). 이는 포유류에서 아미노산 대사 과정에서 장 미생물이 폴리아민 합성에 역할을 한다는 것을 시사합니다. 또한 인간 분변 샘플에서 분리된 그람양성균과 그람음성균, 특히 Bifidobacterium, Clostridium, Enterococcus, Lactobacillus는 체외에서 폴리아민을 생성할 수 있습니다(68). 이 중 Bifidobacterium animalis의 풍부도는 비만 환자에서 감소하고 Lactobacillus reuteri는 증가합니다(69, 70). 이러한 연구 결과는 장 미생물이 체내 폴리아민 총량에 주요 기여 요인임을 보여줍니다. 또한 비만/제2형 당뇨병과 장 미생물 불균형 간의 직접적인 연관성(71, 72)을 고려할 때, 호스트-미생물-폴리아민 상호작용 및 폴리아민이 비만/제2형 당뇨병에 미치는 기여도를 연구하는 것이 시급하고 필수적입니다.

Figure 1.

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Distribution of natural polyamines in healthy adults.

The three most abundant polyamines in humans are putrescine, spermidine, and spermine. Total polyamine is highest in the intestine because diet and gut microbiome are the primary sources of polyamines. From the gastrointestinal tract, polyamines are readily absorbed and enter circulation where they are found in a variety of organs including the brain, kidneys, and in metabolic fluids such as urine, and breastmilk. Studies that reported concentrations in ng/mL or μg/mL were transformed to μM using the molecular weights of putrescine (88.15 g/mol), spermidine (145.25 g/mol), and spermine (202.34 g/mol) for better comparisons.

건강한 성인에서의 자연 발생 폴리아민 분포.
인간에서 가장 풍부한 세 가지 폴리아민은 푸트레신, 스페르미딘, 스페르민입니다. 총 폴리아민은 장에서 가장 높게 측정되며, 이는 식이와 장 미생물이 폴리아민의 주요 공급원이기 때문입니다. 소화관으로부터 폴리아민은 쉽게 흡수되어 순환계로 들어가 뇌, 신장 등 다양한 장기 및 소변, 모유와 같은 대사액에서 발견됩니다. ng/mL 또는 μg/mL 단위로 보고된 농도는 푸트레신(88.15 g/mol), 스페르미딘(145.25 g/mol), 스페르민(202.34 g/mol)의 분자량을 사용하여 μM로 변환하여 비교를 용이하게 했습니다.

Polyamine synthesis in obesity/type 2 diabetes

Thus far, there are only a handful of studies that have reported polyamine levels in obese individuals, all of which examined circulating polyamines in serum or plasma (73–75). In a study of 114 overweight/obese adults (BMI=27-40 kg/m2) with and without type 2 diabetes, it was concluded that individuals with obesity/T2D had elevated levels of putrescine as compared to obese, non-diabetic participants (73). This study did not have an additional control group of healthy adults but levels of putrescine (0.076μM), spermidine (0.15μM), and spermine (0.027μM) were in range when compared to previously reported levels in plasma/serum of healthy adults (putrescine = 0.053-0.49μM, spermidine = 0.004-11μM, spermine = 0.009-5.9μM) (55, 56, 59–62). In a second cohort of morbidly obese adults, the same group of authors noted increases in serum putrescine that was associated with failure to ameliorate metabolic syndrome six months after bariatric surgery (74). These results differ from a third study of 102 obese adults that demonstrated there were no differences circulating levels of putrescine, spermine, and spermidine in male vs female obese adults (76). Unfortunately, this study also did not have healthy adult controls but when compared to studies in healthy adults, only putrescine was elevated whereas spermine and spermidine were in the range of previously reported levels (55, 56, 59–62). More recently, spermidine was found to be positively associated with obesity in rural Chinese residents (75). However, these individuals were more likely to decrease their BMI over two years in a follow-up study (75). This suggests that spermidine exert protective effects against weight gain but of unknown mechanism. Large ranges can be seen across these studies illustrated in Figure 1 .

Variation in these studies likely originates from: i) different methods used to extract and analyze polyamines; e.g., HPLC was used in all obese/T2D studies whereas LCMS is considered to be more accurate and sensitive, ii) only including male participants (59), iii) not considering potential correlation between age and polyamines that has been previously identified (40, 63, 77). Therefore, although the majority of existing studies suggest polyamines are elevated in obesity/T2D, it is difficult to make substantial conclusions without control non-obese, non-diabetic healthy adults because exogenous polyamines have anti-obesity effects in preclinical studies (78–81). Additionally, patients with type 2 diabetes expressed reduced levels of polyamine synthetic enzymes such as ornithine decarboxylase that is necessary for putrescine production (82). Because these studies suggest an elevation in only putrescine when compared to healthy adults of other studies, it is important to identify changes in individual polyamine metabolites in future works. Note that these trends were also concluded from studies primarily in European or rural Chinese residents (59, 73–76). Additional studies are required in countries where obesity/T2D affect over 20% of the population including the United States, Mexico, Russia, and Brazil (83, 84).

Results from animal models of obesity-related diseases are also difficult to interpret due to the use of heterogenous models of obesity/T2D and sampling of tissues. Adipocytes from obese Zucker rats demonstrated a 4-fold increase in concentration of spermine and spermidine that was positively associated with adipose triacylglycerol formation (85). However, two-month-old leptin-deficient obese/T2D mice exhibited 31% less spermidine but 24% higher spermine in whole pancreatic islets (86). Obesity/T2D decreased expression‎ of polyamine synthetic genes Odc (ornithine decarboxylase), Srm (spermidine synthase), and Sms (spermine synthase) that concomitantly resulted in a ~30% reduction in spermidine in the colon (87). These results differed from another study in diet-induced obese/T2D murine model that demonstrated no deficiency in polyamines due to obesity/T2D locally in the gut or systemically in plasma (88). Despite the variations in both humans and animal models of obesity/T2D, polyamines are essential to white adipose tissue homeostasis by stimulating adipocyte lipolysis (81) and the deletion of a spermidine to spermine conversion enzyme, spermidine/spermine N1-acetyltransferase, leads to late-onset obesity and insulin resistance (89–91).

비만/제2형 당뇨병에서의 폴리아민 합성

현재까지 비만 환자의 폴리아민 수치를 보고한 연구는 극히 드물며, 모든 연구는 혈청 또는 혈장 내 순환 폴리아민을 대상으로 진행되었습니다 (73–75). 비만/2형 당뇨병을 가진 114명의 과체중/비만 성인(BMI=27-40 kg/m²)을 대상으로 한 연구에서, 비만/2형 당뇨병 환자는 비만이지만 당뇨병이 없는 참가자보다 푸트레신 수치가 높다는 결론이 나왔습니다(73). 이 연구에는 건강한 성인 대조군이 추가로 포함되지 않았지만, 푸트레신(0.076μM), 스페르미딘(0.15μM), 스페르민(0.027μM)의 수치는 이전에 보고된 건강한 성인의 혈장/혈청 수치 범위 내에 있었습니다(푸트레신 = 0.053-0. 49μM, 스페르미딘 = 0.004-11μM, 스페르민 = 0.009-5.9μM) (55, 56, 59–62). 두 번째 코호트 연구에서 동일한 연구진은 비만 수술 후 6개월 후 대사 증후군 개선에 실패한 경우 혈청 푸트레신 수치가 증가했다는 점을 보고했습니다(74). 이 결과는 102명의 비만 성인 대상 제3의 연구와 차이가 있습니다. 이 연구에서는 남성 및 여성 비만 성인 간 순환 푸트레신, 스퍼민, 스퍼미딘 수치에 차이가 없었습니다 (76). 불행히도 이 연구에도 건강한 성인 대조군이 없었지만, 건강한 성인 대상 연구와 비교 시 푸트레신만 증가했으며 스퍼민과 스퍼미딘은 이전 보고 수준 범위 내에 있었습니다 (55, 56, 59–62). 최근 연구에서는 중국 농촌 거주자에서 스퍼미딘이 비만과 긍정적으로 연관되었다고 보고되었습니다(75). 그러나 후속 연구에서 이 대상자들은 2년 동안 체질량 지수(BMI)가 감소할 가능성이 높았습니다(75). 이는 스퍼미딘이 체중 증가에 대한 보호 효과를 발휘하지만 그 메커니즘은 알려지지 않았음을 시사합니다. 이러한 연구 결과의 광범위한 범위는 그림 1 에 표시되어 있습니다.

이러한 연구 간의 차이는 다음과 같은 요인에서 기인할 수 있습니다: i) 폴리아민 추출 및 분석에 사용된 방법의 차이; 예를 들어, 모든 비만/T2D 연구에서는 HPLC가 사용되었으나 LCMS가 더 정확하고 민감한 방법으로 알려져 있습니다, ii) 남성 참가자만 포함(59), iii) 이전에 확인된 연령과 폴리아민 간의 잠재적 상관관계를 고려하지 않았습니다(40, 63, 77). 따라서, 대부분의 기존 연구가 비만/T2D에서 폴리아민 수치가 증가함을 제시하지만, 비만 및 당뇨병이 없는 건강한 성인 대조군이 포함되지 않아 외인성 폴리아민이 전임상 연구에서 항비만 효과를 보인 점을 고려할 때(78–81), 실질적인 결론을 내리기 어렵습니다. 또한 제2형 당뇨병 환자는 푸트레신 생성에 필요한 오르니틴 탈카복실화효소와 같은 폴리아민 합성 효소의 수준이 감소했습니다(82). 이러한 연구는 다른 연구의 건강한 성인 대비 푸트레신만 증가함을 시사하므로, 향후 연구에서는 개별 폴리아민 대사물의 변화를 확인하는 것이 중요합니다. 이 추세는 주로 유럽 또는 중국 농촌 지역 주민을 대상으로 한 연구에서 도출되었습니다(59, 73–76). 비만/제2형 당뇨병이 인구 20% 이상을 차지하는 국가(미국, 멕시코, 러시아, 브라질 등)에서 추가 연구가 필요합니다(83, 84).

비만 관련 질환의 동물 모델에서 얻은 결과는 비만/제2형 당뇨병의 이질적인 모델과 조직 채취 방법 때문에 해석이 어렵습니다. 비만 쥐커 쥐의 지방세포는 스퍼민과 스퍼미딘 농도가 4배 증가했으며, 이는 지방 조직의 트리아실글리세롤 형성과 양의 상관관계를 보였습니다(85). 그러나 2개월령 레프틴 결핍 비만/T2D 마우스는 전체 췌장 섬에서 스퍼미딘이 31% 감소했지만 스퍼민은 24% 증가했습니다(86). 비만/T2D는 폴리아민 합성 유전자 Odc(오르니틴 탈카복실화효소), Srm(스퍼미딘 합성효소), 및 Sms(스퍼민 합성효소)의 발현을 감소시켰으며, 이는 대장에서 스퍼미딘 농도가 약 30% 감소하는 것과 동시에 발생했습니다(87). 이 결과는 식이 유발성 비만/T2D 쥐 모델에서 비만/T2D로 인해 장 내 또는 혈장 내 폴리아민 결핍이 관찰되지 않았다는 다른 연구 결과와 달랐습니다(88). 인간과 동물 모델에서 비만/T2D의 변이에도 불구하고, 폴리아민은 지방세포의 지방 분해를 자극함으로써 백색 지방 조직의 균형 유지에 필수적이며(81), 스페르미딘에서 스페르민으로의 전환 효소인 스페르미딘/스페르민 N1-아세틸트랜스퍼레이즈의 결손은 후기 발병 비만과 인슐린 저항성을 유발합니다(89–91).

Polyamines regulate host immunity

Polyamines regulate a variety of cellular functions in both innate and adaptive immune cells that are often described to be immunosuppressive (41). At neutral pH, polyamines exist as positively charged molecules that interact with negatively charged macromolecules such as DNA, RNA, and proteins (43). As a result, polyamines are necessary for molecular regulation of growth, autophagy, differentiation, and activation of lymphocytes. Polyamine depletion with enzyme inhibitors induced abnormal differentiation of cytolytic T lymphocytes (92) and caused defects in B-cell production of immunoglobulins (93). Both of these phenotypes were rescued upon exogenous addition of polyamines. T helper cells are the most well-studied when investigating the role of polyamines. Polyamines regulate CD4+ T cell differentiation as demonstrated by spermidine induction of Foxp3 expression‎ to polarize naïve T cells to become regulatory T cells in an autophagy-dependent manner (94). In addition to Tregs, polyamines have been proposed to regulate transcription factors such as Tbx21 (T-Bet), Gata3, and Rorc that mediate CD4+ T cell differentiation into other subsets Th1, Th2, and Th17 epigenetically (95). This suggests that polyamines have significant impacts on adaptive immunity.

The role of polyamines in innate immune cells are less clearly defined. Polyamine synthesis is required for natural killer cell metabolism and effector function including the production of granzyme B and IFN-γ (96). In neutrophils, polyamines regulate effector functions by promoting superoxide and myeloperoxidase production. In healthy human neutrophils, depletion of polyamines treatment led to decreased production of superoxides ( O−2 , H2O2) and release of myeloperoxidase (97). This is congruent with a second study demonstrating physiological concentrations of spermidine induced superoxide generation in human neutrophils stimulated with chemotactic peptide fMet-Leu-Phe (98). While the effects of polyamines are pro-inflammatory in natural killer cells and neutrophils, polyamines are immunosuppressive in monocytes/macrophages. Spermine inhibited synthesis of pro-inflammatory cytokines (TNF, IL-1, IL-6, MIP-1α, MIP-1β) in LPS-stimulated human peripheral blood mononuclear cells (99) and inhibited the production of nitric oxide in J774 murine macrophages stimulated with LPS or IFN-γ (100). Spermidine promoted hypusination of the eukaryotic translation factor eIF5A that switches macrophage metabolism to oxidative phosphorylation, a phenotype associated with M2-like anti-inflammatory macrophages (95, 101). However, depletion of polyamines in the same cell line induced nitric oxide synthesis when macrophages were stimulated with LPS (102). Thus, the exact role of polyamines in immune cells, particularly innate immune cells, remains unclear. It is particularly interesting to investigate the role of polyamines in innate immune cell dysfunction in obesity/T2D.

Polyamines as a nutraceuticalPolyamines as a nutraceutical for metabolic syndrome in obesity/T2D

Several studies have demonstrated beneficial effects of increased polyamine concentrations in correcting the metabolic complications of obesity/T2D (78–81, 87, 103). The total host polyamine pool can be increased either with diet ( Figure 1 ) or by supplementation with probiotics or prebiotics which increase the abundance of gut bacteria that synthesize polyamines (44–47, 68). Bifidobacterium spp. are often regarded as beneficial bacteria due to their production of short-chain fatty acids, which has a myriad of physiological effects on the host (104). More recently, Bifidobacterium spp. have also been linked to polyamine synthesis in animal models of obesity/T2D and importantly, improved clinical outcomes (67, 87, 88). In a diet-induced model of obesity/T2D, mice fed Bifidobacterium animalis subsp. lactis for 12 weeks rescued polyamine production with a concomitant correction of lipid and glucose metabolism, reduction in metabolic endotoxemia, and strengthening of gut barrier function (87). Similarly, administration of B. lactis with arginine, an amino acid precursor to polyamine synthesis, resulted in increased levels of circulating and colonic levels of polyamines that correlated with reduced inflammation in senescent mice (67). Furthermore, in another diet-induced obese/T2D mouse model, supplementation with oligofructose, a bifidogenic indigestible carbohydrate, led to increases in abundance of B. pseudolongum that was associated with elevation of bacteria-specific polyamine precursor acetyl-ornithine and down-stream levels of spermine and spermidine (88).

Together, these studies demonstrated that restoration of polyamine synthesis by B. lactis and B. pseudolongum ameliorated complications associated with obesity/T2D. Moreover, direct administration of polyamines reduced body weight, adipocyte differentiation, and lipid accumulation in obese mice (78–81). Enhancement of polyamine synthetic enzyme, SAT1, by triethylenetetramine dihydrochloride was also associated with anti-obesity and anti-diabetic effects in mice (103). There is an ongoing need to study the direct effects of polyamines on development of diabetes. In summary, these studies provide evidence that polyamines are integral to regulating metabolic syndrome and illustrate its potential as a nutraceutical for metabolic complications of obesity/T2D ( Figure 2 ).

Figure 2.

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Proposed health benefits of dietary polyamines in obesity-related diseases. Polyamines are essential to human health, with their abundance altered by obesity-related diseases. This figure highlights a summary of potential benefits of polyamines on obesity-related diseases including metabolic syndrome and type 2 diabetes. Polyamines ameliorate metabolic syndrome by reducing weight gain, insulin resistance, lipid metabolism, gut barrier function, and metabolic endotoxemia. Polyamines also regulate both innate and adaptive immunity including proinflammatory cytokine production, autophagy, macrophage polarization, T cell differentiation, and B cell senescence. Further investigation is needed to elucidate polyamine-mediated health benefits in obesity-related diseases.

Polyamines as a nutraceutical to improve immunity against bacterial infections in obesity/T2D

Obesity/T2D is associated with increased risk for adverse clinical outcomes post-infection likely due to deficits in the immune system that have been likened to that of aging (105). It is particularly interesting because aging has been linked to declining levels of polyamines (40, 77), chronic low-grade inflammation (termed “inflammaging”) (106), and higher morbidity and mortality during infections (107). In fact, spermidine levels are depleted in the elderly and polyamine treatment corrects autophagy and B-cell senescence (108, 109). Similar dysregulation of polyamines in obesity/T2D would affect bacteria-host immune interactions that govern infection outcomes. In preclinical studies, obesity/T2D exacerbates inflammation and infection severity in models of osteomyelitis (110, 111), bacteremia (112), and skin infections (113, 114). Although not in the context of infection, administration of polyamines or associated probiotic and prebiotics have alleviated inflammation in a variety of disease models. Treatment with B. lactis and arginine, an amino acid precursor to polyamine synthesis, resulted in increased levels of circulating and colonic levels of polyamines that was associated with reduced inflammatory signaling in serum of mice (67). In a model of T-cell transfer colitis, spermidine potentiated Treg differentiation and ameliorated disease pathology in the gut (94). Injection of spermine protected mice from developing acute footpad inflammation (99), which may be important for mitigating excessive inflammation in diabetic foot ulcers (114). Therefore, polyamines are emerging players in dictating bacterial-host immune interactions in obesity/T2D by regulating inflammation ( Figure 2 ).

More recently, polyamines have been directly shown to reduce osteomyelitis severity in a murine model of obesity/T2D (88). Supplementation with oligofructose, a bifidogenic prebiotic, decreased Staphylococcus aureus burden in infected bone and tissue in obese/T2D mice. Oligofructose dampened systemic inflammatory signaling that normally exacerbates infections in obesity/T2D (111, 114, 115), consistent with prior studies (99, 116). The authors determined a 6-log fold-change in B. pseudolongum in the gut microbiota of obese/T2D mice due to oligofructose treatment. This compositional change was associated with elevated polyamines in the cecum and plasma of obese/T2D mice. Remarkably, direct oral administration of spermine and spermidine led to a reduction in osteomyelitis severity similar to oligofructose. These results suggest that polyamines promote beneficial effects during infections in obesity/T2D and is an unexplored area that warrants further investigation.

Conclusion and perspectives

In this review, we propose that polyamines metabolites have the potential to ameliorate metabolic syndrome and the complications of obesity/T2D. Increasing evidence suggests that polyamines contribute to regulation of metabolic health and immunity in obesity/T2D. However, preclinical and clinical studies that examine polyamines in obesity/T2D are inconsistent due to heterogenous methods and tissue sampling. With their pleiotropic effects on transcription and translation in both eukaryotes and prokaryotes, the mechanisms by which polyamines affect human health remain unknown. In addition to the cautionary points we raise with current human data, future preclinical studies are needed to fully define the role of polyamines in obesity-associated metabolic disorders. First, obesity/T2D occurs through different mechanisms in the established diet-induced, transgenic leptin-deficient, and leptin receptor-deficient animal obesity models (117). The distinct gut microbiota and drug responses in these models affect microbiome compositional and metabolomic studies of obese/T2D animals and lean/controls (117–119). Second, the frequent use of male animals which gain weight more consistently in diet-induced murine models ignores the effect of sex on complications of obesity/T2D (120). Third, animal studies that implement probiotic, prebiotic, or post-biotics like polyamines often treat animals in parallel during the development of obesity/T2D. However, individuals with obesity/T2D often seek medical care after they have developed obesity/T2D and the complications of metabolic syndrome. Finally, previous literature has only analyzed polyamines in plasma of obese/T2D individuals, which does not consider the contributions of the gut microbiota as the primary driver of polyamine production. Further studies are needed to investigate polyamine levels in fecal samples to better understand polyamine production in obese/T2D individuals. Therefore, it is difficult to translate the results of animal experiments to personalized nutrition and precision medicine in humans.

With polyamines found as ubiquitous metabolites among eukaryotes and prokaryotes, their role in infectious disease is more complex than other microbiota-derived metabolites. Polyamines have been shown to be critical for survival and virulence of human bacterial pathogens (121, 122). While some pathogens produce polyamines, others rely on the extracellular polyamine pool regulated by host cells and the gut microbiota through uptake via transporter systems (121, 122) where polyamines have been shown negative effects on infectious bacteria. For example, spermine directly inhibits the growth of pathogenic Escherichia coli, Salmonella enterica serovar Typhimurium, and Staphylococcus aureus, while increasing susceptibility to β-lactam antibiotics in Pseudomonas aeruginosa (123). Because polyamines regulate survival and proliferation of bacteria and mammalian cells, this suggests that the host and bacteria pathogens compete for the extracellular polyamines pool during infections. For example, the polyamine transport operon potABCD in Streptococcus pneumoniae is required for resistance to neutrophil killing in vivo (124).This further implies a need to investigate the intracellular levels of polyamines in both mammalian cells and bacterial pathogens.

In conclusion, a growing body of evidence suggests that dysregulation of polyamines is associated with obesity/T2D and the related complications of immune deficits and metabolic disorders. The obesity/T2D epidemic is a public health concern and calls for alternative therapeutics. Probiotics, prebiotics, and post-biotics serve as mediators of metabolic syndrome and immunity in obesity/T2D. Prebiotics like oligofructose and probiotics like Bifidobacterium spp. that is associated polyamine production can be therapeutic alternatives to treating metabolic syndrome and strengthening of immunity, but relies on modulation of the gut microbiome. Therefore, direct application of the post-biotic, polyamines, to obese/T2D patients is a more attractive target. However, the biology of polyamines is heavily understudied outside the context cancer and remains to be investigated. Further research is needed to elucidate the mechanisms of polyamine regulation that contribute to diminished gut health, chronic inflammation in obesity, and development of diabetes, which will aid in the use of polyamines as a diagnostic tool for these complications.

Author contributions

TB conducted the literature review and prepared the manuscript. TB, SG, GM, and EB contributed to writing and manuscript preparation. All authors contributed to the article and approved the submitted version.

Funding Statement

This work was supported by NIH NIDCR T90-DE021985 (TB); University of Rochester Sproull Fellowship (EB); NIH NIAID R21 AI69736 and University of Rochester Research Award (GM); NIH NIAMS R01 AR078414, DoD W81XWH-19-10808, and NIH NIMH R01 MH125103 (SG).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

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