Re: 장내 유익균(L. casei zhang) 신장질환 치료기전 !! 2021 Cell 영향력지수 30점

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PreviewVolume 33, Issue 10p1901-1903October 05, 2021Open Archive

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Happy gut, happy kidneys?

Restoration of gut microbiome ameliorates acute and chronic kidney disease

Samuel Mon-Wei Yu1 ∙ John Cijiang He1,2,3 cijiang.he@mssm.edu

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Abstract

In a new study, Zhu et al. (2021) show that mitigating dysbiosis by the probiotic L. casei Zhang reduces kidney inflammation via restoring short-chain fatty acid-producing gut microbiome and nicotinamide metabolism. These findings shed light on the underlying mechanisms of probiotics in treating human kidney diseases.

초록

새로운 연구에서 Zhu 등(2021)은

프로바이오틱스 L. casei Zhang이

장내 미생물군집의 단쇄 지방산 생성 및 니코틴아미드 대사를 회복시켜

장내 불균형을 완화함으로써 신장 염증을 감소시킨다는 사실을 보여주었다.

https://www.nature.com/articles/s41392-020-00311-7

니코틴아미드 아데닌 디뉴클레오티드(NAD+)와 그 대사산물은 생리적 과정을 유지하는 핵심 조절자로 기능하며, 영양소 교란, 유전독성 인자, 생체리듬 장애, 감염, 염증 및 이물질 등 환경 변화에 적응할 수 있도록 세포의 가소성을 가능하게 한다. 이러한 효과는 주로 산화-환원 반응에서 수소 전달을 담당하는 효소 보조인자로서 NAD+가 대사 경로에 미치는 촉진 효과에 의해 달성된다. 또한 다수의 NAD+ 의존성 효소들은 DNA, RNA 및 단백질의 합성 후 화학적 변형을 통해, 또는 제2신호물질인 순환형 ADP-리보스(cADPR) 및 NAADP+를 방출함으로써 생리학에 관여한다. NAD+ 대사의 장기적 불균형은 생리 기능을 교란시켜 대사 질환, 암, 노화 및 신경퇴행성 장애를 포함한 질병을 초래한다. 본 리뷰에서는 스트레스에 대한 NAD+ 조절 생리적 반응의 분자적 메커니즘에 대한 최근 이해, 세포 통신 네트워크 조작을 통한 NAD+ 결핍의 다양한 질환 유발 기여도, 그리고 치료적 개입을 위한 잠재적 새로운 접근법에 대해 요약한다.

이러한 결과는

인간 신장 질환 치료에서

프로바이오틱스의 근본적 작용 기전에 대한 통찰을 제공한다.

Main text

Dysregulation of the gut microbiota, also known as dysbiosis, has been increasingly recognized as an important pathophysiology in different organs, including the kidneys. The abundance of resident immune cells in the gut provides a logical and physiological link between the so-called gut-and-kidney axis, supported by evidence such as IgA nephropathy. Emerging data in murine models further suggest the aberrancy of gut microbiota-derived metabolites could affect the outcomes of acute kidney injury (AKI) and, in part, explain the presence of circulating uremic toxins in chronic kidney disease (CKD) (Knauf et al., 2019). These findings have led to several clinical trials using probiotics in patients with CKD with promising results, conceptualized by their potential benefits of correcting dysbiosis (Koppe et al., 2015). Yet exactly how probiotics restore kidney health remains poorly understood, and in particular, how the gut-and-kidney axis potentially facilitates the AKI-to-CKD transition is unclear. In this issue of Cell Metabolism, Zhu et al. (2021) demonstrate renoprotective effects of the probiotic Lactobacillus casei Zhang (L. casei Zhang) in AKI and CKD progression and revealed an important metabolic switch to prevent overt inflammation after kidney injury (Figure 1).

본문

장내 미생물군집의 불균형,

즉 장내 미생물 불균형(dysbiosis)은

신장을 포함한 다양한 장기에서 중요한 병리생리학적 요인으로 점차 인식되고 있다.

장내에 상주하는 면역 세포의 풍부함은

소위 장-신장 축(gut-and-kidney axis) 사이의 논리적·생리학적 연결고리를 제공하며,

이는 IgA 신증과 같은 증거로 뒷받침된다.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11719742/

생쥐 모델에서 새롭게 제시된 데이터는

장내 미생물군집 유래 대사물질의 이상이 급성 신장 손상(AKI)의 결과에 영향을 미칠 수 있으며,

만성 신장 질환(CKD)에서 순환성 요독성 독소의 존재를 부분적으로 설명할 수 있음을 시사한다(Knauf et al., 2019).

이러한 발견은

장내 미생물 불균형 교정의 잠재적 이점을 바탕으로 개념화된,

CKD 환자 대상 프로바이오틱스 사용 임상시험 여러 건으로 이어졌으며

유망한 결과를 보였다(Koppe et al., 2015).

그러나

프로바이오틱스가 신장 건강을 회복시키는 정확한 기전은 여전히 불분명하며,

특히 장-신장 축이 AKI에서 CKD로의 전환을 어떻게 촉진할 수 있는지는 명확하지 않다.

이번 Cell Metabolism호에서 Zhu 등(2021)은

급성 신장손상(AKI) 및 만성 신장질환(CKD) 진행에서

프로바이오틱스 락토바실러스 카제이 장(L. casei Zhang)의

신장 보호 효과를 입증하고,

신장 손상 후 명백한 염증을 예방하는 중요한 대사 전환을 밝혀냈다(그림 1).

Figure viewer

Figure 1 Schematic of the kidney-and-gut axis mediating maladaptive kidney repair to kidney fibrosis

Based on its known anti-inflammatory properties, Zhu et al. focused on L. casei Zhang (Lac.z) and the commonly used probiotic supplement L. acidophilus (Lact) and their effects on AKI and kidney fibrosis outcomes. First, the authors used both surgical and chemical-induced AKI and CKD to avoid possible variances of the renal outcome among different models. Based on histology and function, they showed that Lac.z treatment resulted in a consistently better renoprotective profile compared to Lact or to no treatment across the models. Then, in order to prove the link between gut microbiota and kidney outcomes, they analyzed the stool samples collected from mice treated by Lac.z and demonstrated improved intestinal homeostasis with a higher percentage of Bacteroidetes population closer to the sham animals and greater abundance of short-chain fatty acid (SCFA)-producing bacteria after ischemia-reperfusion (IR) injury. They used occludin expression‎ level by immunofluorescence and RT-PCR as a surrogate to prove that Lac.z treatment preserved intestinal physical barrier, another essential player to maintain gut microbiota integrity. Intriguingly, similar effects of Lac.z were reproduced after depleting the original intestinal microbiome by broad-spectrum antibiotics administration followed by probiotics treatment or fecal microbiota transplants prior to IR injury. The authors then concluded that renoprotection by Lac.z treatment might not be limited to modulation of gut microbiome but also have direct effects on kidney resident cells.

주(Zhu) 등은 알려진 항염증 특성에 기반하여 

L. casei Zhang(Lac.z)과 흔히 사용되는 프로바이오틱 보충제 L. acidophilus(Lact)가

급성 신장 손상(AKI) 및 신장 섬유화 결과에 미치는 영향에 주목했다.

먼저 저자들은

다양한 모델 간 신장 결과의 잠재적 편차를 피하기 위해

외과적 및 화학적 유도 AKI와 CKD를 모두 사용했습니다.

조직학적 및 기능적 분석을 바탕으로,

그들은 모든 모델에서 Lact 또는 무치료 대비 Lac.z 치료가

일관되게 우수한 신장 보호 프로파일을 보인다는 것을 입증했습니다.

다음으로 장내 미생물군과 신장 결과 간의 연관성을 입증하기 위해,

연구진은 Lac.z로 치료한 마우스에서 채취한 분변 샘플을 분석하여

허혈-재관류(IR) 손상 후 장내 항상성 개선을 확인했다.

이는 가짜 수술군에 가까운 높은 비율의 박테로이데테스(Bacteroidetes) 군집과

단쇄지방산(SCFA) 생성균의 풍부한 존재로 나타났으며,

이는 장내 미생물군집의 무결성을 유지하는

또 다른 핵심 요소이다.

면역형광 및 RT-PCR을 통한 오클루딘 발현 수준을 대용 지표로 사용하여,

Lac.z 치료가 장내 미생물군집 무결성 유지에

또 다른 핵심 요소인 장 물리적 장벽을 보존함을 입증했다.

흥미롭게도,

광범위 항생제 투여 후 프로바이오틱스 치료 또는 분변 미생물군집 이식(FMT)을 통해

원초적 장내 미생물군집을 제거한 후

IR 손상 전에 Lac.z를 투여했을 때도 유사한 효과가 재현되었다.

이에 연구진은

Lac.z 치료에 의한 신장 보호 효과가 장내 미생물군 조절에 국한되지 않고

신장 상주 세포에 직접적인 영향을 미칠 수 있다고 결론지었다.

Mechanistically, these data were somewhat consistent with the prior findings and the general concept in the field that the presence of SCFA-producing bacteria is crucial in maintaining kidney homeostasis and can be restored by Lac.z treatment after kidney injury (Gong et al., 2019). Zhu et al. took a further step using UHPLC-MRM-MS/MS technique to analyze the kidney metabolites and found that mice treated with Lac.z after IR injury at day 5 had higher nicotinamide metabolism. Nicotinamide adenine dinucleotide (NAD+) is an essential molecule in mitochondrial fatty acid β-oxidation and ATP production, which proximal renal tubules heavily depend on. Augmentation of NAD+ metabolism by supplementing the mice with the NAD precursor niacinamide was shown to ameliorate AKI in murine models (Tran et al., 2016), although the subsequent clinical trial (NCT03176628) did not demonstrate significant clinical improvement (Simic et al., 2020). Nevertheless, exactly how Lac.z affects nicotinamide metabolism in the kidneys (presumably mediated by kidney tubules) and whether this was independent of the gut microbiome remains unclear based on these data.

기전적으로, 이러한 결과는

SCFA 생성 세균의 존재가 신장 항상성 유지에 중요하며

신장 손상 후 Lac.z 치료로 회복될 수 있다는

기존 연구 결과 및 해당 분야의 일반적 개념과 어느 정도 일치한다(Gong et al., 2019).

Zhu 등은 UHPLC-MRM-MS/MS 기법을 활용해

신장 대사물을 분석하는 한 걸음 더 나아갔으며,

IR 손상 5일 후 Lac.z로 치료한 마우스에서

니코틴아미드 대사 수준이 더 높음을 발견했다.

니코틴아미드 아데닌 디뉴클레오티드(NAD+)는

미토콘드리아 지방산 β-산화 및 ATP 생산에 필수적인 분자로,

근위 신세관 기능이 크게 의존한다.

마우스 모델에서

NAD 전구체인 나이아신아마이드를 보충하여

NAD+ 대사를 증강시키는 것이

급성 신장 손상(AKI)을 완화시키는 것으로 나타났습니다(Tran et al., 2016).

그러나

후속 임상 시험(NCT03176628)에서는

유의미한 임상적 개선이 입증되지 않았습니다(Simic et al., 2020).

그럼에도 불구하고,

Lac.z가 신장(아마도 신장 세뇨관을 매개로)에서

니코틴아미드 대사에 정확히 어떻게 영향을 미치는지,

그리고 이것이 장내 미생물군집과 무관한지 여부는 이 데이터만으로는 불분명하다.

다음으로 Zhu 등은

Lac.z 치료에 대한 신장 내 반응을 규명하기 위해

단일 세포 분석을 수행했다.

그들은 Lac.z 처리 마우스에서

신장 손상 5일차에 대다수 대식세포 하위 군집이 감소했음을 입증했으며,

이는 Lac.z의 신장 보호 효과가 대식세포 침윤 감소에 의해 매개될 수 있음을 시사한다.

또한, 각 세포 하위 유형에서

Lac.z 처리 마우스의 섬유화 촉진 및 염증 유발 유전자 발현이 감소했으며,

이 차이는 RNA 수준에서 단쇄지방산 수용체(GPR43) 또는

두 가지 단쇄지방산 관련 수송체(Slc5a8 및 Slc18a1) 발현에 따라 유의미하게 유지되었다.

마지막으로, Zhu 등은

3-5기 만성 신장 질환(CKD) 환자를 대상으로

경구 Lac.z 사용에 대한 위약 대조 연구를 수행했다.

3개월 치료 후, 저자들은

각각 3개월 및 12개월 추적 관찰 시 혈청 시스타틴 C 및 크레아티닌 수치를 기반으로

신기능 저하가 감소한 것을 확인했으며,

이는 CKD 진행에 대한 잠재적 치료 효과를 시사한다.

이러한 데이터는

생쥐 모델에서의 기능적 지표 및 조직학적 분석과 인간 임상시험의 임상적 매개변수를 통해

프로바이오틱스가 급성 신부전(AKI) 및 만성 신장병(CKD)의 결과를 개선하는 메커니즘을

더욱 명확히 밝혀줍니다.

그러나

여전히 해결해야 할 몇 가지 질문이 남아 있습니다.

첫째, 조절 T 세포 및 CD4+ T 세포와 같은 T 세포는

장 내 국소 면역 반응과 후속 대식세포 표현형 변화 조절에 핵심적 역할을 한다(Gong et al., 2019).

그렇다면

Lac.z 치료 후 관찰된 신장 염증 감소 역시 T 세포 매개였을까?

둘째, 대식세포 침윤 정도는

AKI에서 세뇨관 손상과 상관관계가 있는 것으로 알려져 있다(Zuk and Bonventre, 2016).

저자들은

IR 손상 5일차에 Lac.z 그룹에서

대부분의 대식세포 하위 군집(네 군집 중 가장 적은 수를 차지하는 Mø 3 제외)이

더 적게 관찰되었다고 언급했다.

이러한 표현형은

주로 세뇨관 손상 감소에 따른 대식세포 침윤 감소에 의해 유발된 것인가?

더 중요한 것은,

리포솜 클로드로네이트 및 CD11b-DTR 연구를 통해

대식세포 고갈이 섬유증 증가와 함께 부적응적 회복을 악화시킨다는 점이

명확히 입증되었다는 점이다(Zhang et al., 2012).

저자들은

면역형질(기능적 연구가 아닌 단일 세포 분석으로 확인)과

Ccr2−/− 마우스의 5일차 데이터만 제시했다.

따라서

순수 표면 마커에 기반한 대식세포 분류가 연구마다 상충될 수 있음을 고려할 때,

기능적 연구를 통한 면역형질의 동적 변화(특히 후기 시점)를 입증하는

후속 연구가 필요하다.

저자들이 적절히 지적했듯이,

SCFA 수용체 발현은 이질적이므로

관상세포 또는 단핵구 특이적 녹아웃 마우스를 활용하는 것이 이 질문에 답하는 데 도움이 될 것이다.

마지막으로,

본 연구에서 Lac.z의 인간 대상 안전성 프로파일은 유망해 보였으나,

혈중 요소질소(BUN) 및 크레아티닌과 같은 가장 흔히 사용되는 임상 지표들은

프로바이오틱스 사용 자체에 크게 영향을 받을 수 있습니다(Lempert, 2019).

소변 알부민-크레아티닌 비율과 부갑상선 호르몬의 차이는 흥미롭지만,

이는 관상 병리생물학 및 신장 염증과는

별개의 병리생리학을 반영할 수 있습니다.

신장 질환 치료에 장-신장 축 조절을 임상적으로 적용하는 것은

가공 식품 섭취와 신장 염증의 연관성에 대한

또 다른 최근 보고서에 의해 뒷받침됩니다 (Snelson et al., 2021).

따라서

프로바이오틱스는 여전히 매력적인 접근법으로 남아 있으며,

성공으로 가는 길을 열기 위해서는

더 큰 규모의 이중맹검 임상시험이 필요할 것이다.

Next, Zhu et al. performed a single-cell analysis to decipher the intrarenal responses to Lac.z treatment. They demonstrated that in Lac.z-treated mice, most subclusters of macrophages were diminished at day 5 of IR injury, suggesting the renoprotective effects of Lac.z might be mediated by the reduction of the macrophage infiltrate. In addition, expression‎ of profibrotic and proinflammatory genes was reduced in Lac.z-treated mice in each cell subtype, and the differences remained significant depending on the expression‎ of either an SCFA receptor (GPR43) or two SCFA-related transporters (Slc5a8 and Slc18a1) at the RNA level. Lastly, Zhu et al. conducted a placebo-controlled study of oral Lac.z use in patients with stage 3–5 CKD. After 3 months of treatment, the authors noted a diminished decline of kidney function based on serum cystatin C and creatinine level at 3- and 12-month follow-ups, respectively, suggesting potential therapeutic effects on CKD progression.

These data indeed shed more light on how probiotics can improve outcomes of AKI and CKD, supported by functional readouts and histological analysis in murine models and clinical parameters of a human clinical trial. However, several questions remain to be answered. First, T cells, such as regulatory T cells and CD4+ T cells, are pivotal to regulate local immunological responses in the gut and subsequent phenotypic changes of macrophage (Gong et al., 2019), so was the reduced kidney inflammation mediated by T cells after Lac.z treatment? Second, the degree of macrophage infiltrate is known to correlate with tubular damage in AKI (Zuk and Bonventre, 2016), and the authors noted that there were fewer of most of the macrophage subclusters (excepted for Mø 3, the smallest population among the four) in the Lac.z group at IR injury day 5. Was this phenotype mostly driven by reduced tubular damage followed by less macrophage infiltration? More importantly, depletion of macrophages has been clearly shown to exacerbate maladaptive repair with increased fibrosis by liposomal clodronate and CD11b-DTR studies (Zhang et al., 2012). The authors only demonstrated the immunophenotype (determined by single-cell analysis instead of more functional studies) and the Ccr2−/− mice data at day 5. Therefore, future studies would be warranted to demonstrate the dynamic changes, especially at the later time points, of immunophenotypes with functional studies, given that macrophage classification based purely on surface markers might conflict from study to study. As the authors rightfully pointed out, the expression‎ of SCFA receptors is heterogeneous, and therefore using tubular or monocyte-specific knockout mice would be helpful to answer this question. Lastly, although the safety profile of Lac.z use in humans appeared to be promising in the present study, most commonly used clinical parameters such as blood urea nitrogen (BUN) and creatinine could be largely affected by probiotics use itself (Lempert, 2019). The differences in urine albumin-to-creatinine ratio and parathyroid hormone were intriguing, but they might reflect pathophysiology aside from tubular pathobiology and kidney inflammation.

The clinical application of modulating the gut-kidney axis in treating kidney diseases is supported by another recent report on the association between processed food intake and kidney inflammation (Snelson et al., 2021). Thus, probiotics remain an attractive approach and will need larger double-blinded clinical trials to pave their way to success.

Acknowledgments

S.M.-W.Y. is supported by NIH/NIDDK T32DK007757. J.C.H. is supported by NIH/NIDDK R01DK122980, R01DK121846, R01DK109683, R01DK129467, and P01DK56492, and Veterans Affairs Merit Award IBX000345C.

Declaration of interests

The authors declare no competing interests.

References

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Gong, J. ∙ Noel, S. ∙ Pluznick, J.L. ...

Gut microbiota-kidney cross-talk in acute kidney injury

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Immunity, microbiota and kidney disease

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Probiotics and chronic kidney disease

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Probiotics and CKD progression: are creatinine-based estimates of GFR applicable?

Am. J. Kidney Dis. 2019; 74:429-431

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Simic, P. ∙ Vela Parada, X.F. ∙ Parikh, S.M. ...

Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI

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Tran, M.T. ∙ Zsengeller, Z.K. ∙ Berg, A.H. ...

PreviewVolume 33, Issue 10p1901-1903October 05, 2021Open Archive

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Happy gut, happy kidneys? Restoration of gut microbiome ameliorates acute and chronic kidney disease

Samuel Mon-Wei Yu1 ∙ John Cijiang He1,2,3 cijiang.he@mssm.edu

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Abstract

In a new study, Zhu et al. (2021) show that mitigating dysbiosis by the probiotic L. casei Zhang reduces kidney inflammation via restoring short-chain fatty acid-producing gut microbiome and nicotinamide metabolism. These findings shed light on the underlying mechanisms of probiotics in treating human kidney diseases.

Main text

Dysregulation of the gut microbiota, also known as dysbiosis, has been increasingly recognized as an important pathophysiology in different organs, including the kidneys. The abundance of resident immune cells in the gut provides a logical and physiological link between the so-called gut-and-kidney axis, supported by evidence such as IgA nephropathy. Emerging data in murine models further suggest the aberrancy of gut microbiota-derived metabolites could affect the outcomes of acute kidney injury (AKI) and, in part, explain the presence of circulating uremic toxins in chronic kidney disease (CKD) (Knauf et al., 2019). These findings have led to several clinical trials using probiotics in patients with CKD with promising results, conceptualized by their potential benefits of correcting dysbiosis (Koppe et al., 2015). Yet exactly how probiotics restore kidney health remains poorly understood, and in particular, how the gut-and-kidney axis potentially facilitates the AKI-to-CKD transition is unclear. In this issue of Cell Metabolism, Zhu et al. (2021) demonstrate renoprotective effects of the probiotic Lactobacillus casei Zhang (L. casei Zhang) in AKI and CKD progression and revealed an important metabolic switch to prevent overt inflammation after kidney injury (Figure 1).

Figure viewer

Figure 1 Schematic of the kidney-and-gut axis mediating maladaptive kidney repair to kidney fibrosis

Based on its known anti-inflammatory properties, Zhu et al. focused on L. casei Zhang (Lac.z) and the commonly used probiotic supplement L. acidophilus (Lact) and their effects on AKI and kidney fibrosis outcomes. First, the authors used both surgical and chemical-induced AKI and CKD to avoid possible variances of the renal outcome among different models. Based on histology and function, they showed that Lac.z treatment resulted in a consistently better renoprotective profile compared to Lact or to no treatment across the models. Then, in order to prove the link between gut microbiota and kidney outcomes, they analyzed the stool samples collected from mice treated by Lac.z and demonstrated improved intestinal homeostasis with a higher percentage of Bacteroidetes population closer to the sham animals and greater abundance of short-chain fatty acid (SCFA)-producing bacteria after ischemia-reperfusion (IR) injury. They used occludin expression‎ level by immunofluorescence and RT-PCR as a surrogate to prove that Lac.z treatment preserved intestinal physical barrier, another essential player to maintain gut microbiota integrity. Intriguingly, similar effects of Lac.z were reproduced after depleting the original intestinal microbiome by broad-spectrum antibiotics administration followed by probiotics treatment or fecal microbiota transplants prior to IR injury. The authors then concluded that renoprotection by Lac.z treatment might not be limited to modulation of gut microbiome but also have direct effects on kidney resident cells.

Mechanistically, these data were somewhat consistent with the prior findings and the general concept in the field that the presence of SCFA-producing bacteria is crucial in maintaining kidney homeostasis and can be restored by Lac.z treatment after kidney injury (Gong et al., 2019). Zhu et al. took a further step using UHPLC-MRM-MS/MS technique to analyze the kidney metabolites and found that mice treated with Lac.z after IR injury at day 5 had higher nicotinamide metabolism. Nicotinamide adenine dinucleotide (NAD+) is an essential molecule in mitochondrial fatty acid β-oxidation and ATP production, which proximal renal tubules heavily depend on. Augmentation of NAD+ metabolism by supplementing the mice with the NAD precursor niacinamide was shown to ameliorate AKI in murine models (Tran et al., 2016), although the subsequent clinical trial (NCT03176628) did not demonstrate significant clinical improvement (Simic et al., 2020). Nevertheless, exactly how Lac.z affects nicotinamide metabolism in the kidneys (presumably mediated by kidney tubules) and whether this was independent of the gut microbiome remains unclear based on these data.

Next, Zhu et al. performed a single-cell analysis to decipher the intrarenal responses to Lac.z treatment. They demonstrated that in Lac.z-treated mice, most subclusters of macrophages were diminished at day 5 of IR injury, suggesting the renoprotective effects of Lac.z might be mediated by the reduction of the macrophage infiltrate. In addition, expression‎ of profibrotic and proinflammatory genes was reduced in Lac.z-treated mice in each cell subtype, and the differences remained significant depending on the expression‎ of either an SCFA receptor (GPR43) or two SCFA-related transporters (Slc5a8 and Slc18a1) at the RNA level. Lastly, Zhu et al. conducted a placebo-controlled study of oral Lac.z use in patients with stage 3–5 CKD. After 3 months of treatment, the authors noted a diminished decline of kidney function based on serum cystatin C and creatinine level at 3- and 12-month follow-ups, respectively, suggesting potential therapeutic effects on CKD progression.

These data indeed shed more light on how probiotics can improve outcomes of AKI and CKD, supported by functional readouts and histological analysis in murine models and clinical parameters of a human clinical trial. However, several questions remain to be answered. First, T cells, such as regulatory T cells and CD4+ T cells, are pivotal to regulate local immunological responses in the gut and subsequent phenotypic changes of macrophage (Gong et al., 2019), so was the reduced kidney inflammation mediated by T cells after Lac.z treatment? Second, the degree of macrophage infiltrate is known to correlate with tubular damage in AKI (Zuk and Bonventre, 2016), and the authors noted that there were fewer of most of the macrophage subclusters (excepted for Mø 3, the smallest population among the four) in the Lac.z group at IR injury day 5. Was this phenotype mostly driven by reduced tubular damage followed by less macrophage infiltration? More importantly, depletion of macrophages has been clearly shown to exacerbate maladaptive repair with increased fibrosis by liposomal clodronate and CD11b-DTR studies (Zhang et al., 2012). The authors only demonstrated the immunophenotype (determined by single-cell analysis instead of more functional studies) and the Ccr2−/− mice data at day 5. Therefore, future studies would be warranted to demonstrate the dynamic changes, especially at the later time points, of immunophenotypes with functional studies, given that macrophage classification based purely on surface markers might conflict from study to study. As the authors rightfully pointed out, the expression‎ of SCFA receptors is heterogeneous, and therefore using tubular or monocyte-specific knockout mice would be helpful to answer this question. Lastly, although the safety profile of Lac.z use in humans appeared to be promising in the present study, most commonly used clinical parameters such as blood urea nitrogen (BUN) and creatinine could be largely affected by probiotics use itself (Lempert, 2019). The differences in urine albumin-to-creatinine ratio and parathyroid hormone were intriguing, but they might reflect pathophysiology aside from tubular pathobiology and kidney inflammation.

The clinical application of modulating the gut-kidney axis in treating kidney diseases is supported by another recent report on the association between processed food intake and kidney inflammation (Snelson et al., 2021). Thus, probiotics remain an attractive approach and will need larger double-blinded clinical trials to pave their way to success.

Acknowledgments

S.M.-W.Y. is supported by NIH/NIDDK T32DK007757. J.C.H. is supported by NIH/NIDDK R01DK122980, R01DK121846, R01DK109683, R01DK129467, and P01DK56492, and Veterans Affairs Merit Award IBX000345C.

Declaration of interests

The authors declare no competing interests.

References

1.

Gong, J. ∙ Noel, S. ∙ Pluznick, J.L. ...

Gut microbiota-kidney cross-talk in acute kidney injury

Semin. Nephrol. 2019; 39:107-116

Full Text

Full Text (PDF)

Scopus (74)

PubMed

Google Scholar

2.

Knauf, F. ∙ Brewer, J.R. ∙ Flavell, R.A.

Immunity, microbiota and kidney disease

Nat. Rev. Nephrol. 2019; 15:263-274

Crossref

Scopus (83)

PubMed

Google Scholar

3.

Koppe, L. ∙ Mafra, D. ∙ Fouque, D.

Probiotics and chronic kidney disease

Kidney Int. 2015; 88:958-966

Full Text

Full Text (PDF)

Scopus (182)

PubMed

Google Scholar

4.

Lempert, K.D.

Probiotics and CKD progression: are creatinine-based estimates of GFR applicable?

Am. J. Kidney Dis. 2019; 74:429-431

Full Text

Full Text (PDF)

Scopus (9)

PubMed

Google Scholar

5.

Simic, P. ∙ Vela Parada, X.F. ∙ Parikh, S.M. ...

Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI

BMC Nephrol. 2020; 21:342

Crossref

Scopus (25)

PubMed

Google Scholar

6.

Snelson, M. ∙ Tan, S.M. ∙ Clarke, R.E. ...

Processed foods drive intestinal barrier permeability and microvascular diseases

Sci. Adv. 2021; 7:eabe4841

Crossref

Scopus (88)

PubMed

Google Scholar

7.

Tran, M.T. ∙ Zsengeller, Z.K. ∙ Berg, A.H. ...