レビュー論文：催眠療法とIBS: ENSにおける暗黙の長期ストレス記憶？(Hypnotherapy and IBS: Implicit, long-term stress memory in the ENS?)
出典：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9849985/
Heliyon. 2023 Jan; 9(1): e12751.
Published online 2022 Dec 30. doi: 10.1016/j.heliyon.2022.e12751
PMCID: PMC9849985
PMID: 36685398
Author
N. Császár-Nagy and I. Bókkon
Copyright © 2023 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Abstract
The association between irritable bowel syndrome (IBS) and psychiatric and mood disorders may be more fundamental than was previously believed. Prenatal, perinatal, postnatal, and early-age conditions can have a key role in the development of IBS. Subthreshold mental disorders (SMDs) could also be a significant source of countless diverse diseases and may be a cause of IBS development. We hypothesize that stress-induced implicit memories may persist throughout life by epigenetic processes in the enteric nervous system (ENS). These stress-induced implicit memories may play an essential role in the emergence and maintenance of IBS. In recent decades, numerous studies have proven that hypnosis can improve the primary symptoms of IBS and also reduce noncolonic symptoms such as anxiety and depression and improve quality of life and cognitive function. These significant beneficial effects of hypnosis on IBS may be because hypnosis allows access to unconscious brain processes.
過敏性腸症候群 (IBS) と精神疾患および気分障害との関連は、これまで考えられていたよりも根本的なものである可能性がある。出生前、周産期、出生後、および若年期の状態がIBSの発症に重要な役割を果たす可能性がある。閾値下精神障害 (SMDs) も無数の多様な疾患の重要な原因であり、IBS発症の原因である可能性がある。ストレス誘導潜在記憶は腸神経系 (ENS) におけるエピジェネティックプロセスにより生涯持続すると仮定した。これらのストレス誘導潜在記憶はIBSの出現と維持に重要な役割を果たす可能性がある。ここ数十年、多数の研究が、催眠がIBSの一次症状を改善し、不安や抑うつなどの非結腸症状を軽減し、生活の質と認知機能を改善できることを証明している。IBSに対する催眠のこれらの有意な有益な効果は、催眠によって無意識の脳プロセスにアクセスできるためである可能性がある。
Keywords: IBS, Subthreshold mental disorders, Gut-brain axis, ENS with Implicit epigenetic long-term memory, Hypnotherapy
1. Introduction
There is growing evidence that psychiatric and mood disorders play a key role in the development of irritable bowel syndrome (IBS) [1–4]. IBS, a condition affecting the colon, is almost mystical because no anatomical cause can be detected on laboratory tests, X-rays, or biopsies. Although IBS is not life-threatening, it has a significant economic impact as well as a huge impact on quality of life and mental health [5,6].
精神障害と気分障害が過敏性腸症候群 (IBS) の発症に重要な役割を果たしているという証拠が増えている [1-4] 。IBSは結腸を侵す疾患であり、臨床検査、X線検査、または生検で解剖学的原因を検出できないため、ほとんど神秘的である。IBSは生命を脅かすものではないが、生活の質と精神衛生に大きな影響を与えるだけでなく、経済的にも大きな影響を与える [5, 6]。
We hypothesize that stress-induced implicit memories in the enteric nervous system (ENS) may persist throughout life by epigenetic mechanisms [7]; Furness, 2000). These stress-induced memories may play a key role in the emergence and maintenance of IBS. Namely, it is possible that IBS starts in the gut, and the gut probably drives psychological alterations in a main group of cases with functional gastrointestinal disorders (FGIDs) [8].
著者らは、腸神経系 (ENS) におけるストレス誘発性の潜在記憶が、後成的機構により生涯持続する可能性があるという仮説を立てている [7];(Furness, 2000)。これらのストレス誘発性記憶はIBSの発生と維持に重要な役割を果たす可能性がある。すなわち、IBSは腸で始まる可能性があり、腸はおそらく機能性胃腸障害 (FGID) の主要な症例群における心理的変化を駆動する [8]。
We also point out that the significant beneficial effects of hypnosis on IBS may be because hypnosis allows access to unconscious brain processes that modulate stress-associated unconscious (implicit) information via the gut-brain axis (GBA) [9–11]. As a result, subjective pain perception (visceral hypersensitivity, somatization) decreases in the CNS as well as the stress-related inflammatory response in the gut.
私たちはまた、IBSに対する催眠の有意な有益な効果は、催眠が腸脳軸 (GBA) を介してストレスに関連する無意識 (潜在的) 情報を調整する無意識の脳プロセスにアクセスすることができるためである可能性があることを指摘している [9–11]。結果として、主観的痛覚(内臓過敏症、身体化)は腸におけるストレス関連炎症反応と同様に中枢神経系(CNS)において減少する。
2. The enteric nervous system and the gut-brain axis(腸管神経系と脳腸相関)
The enteric nervous system (ENS) is the nervous system of the gastrointestinal (GI) tract that has evolved over hundreds of millions of years. Recently, Spencer et al. [12] showed how the ENS produces propulsion along the gut that behaves similarly to other neural networks in the brain and spinal cord. Spencer et al. [12] revealed how all different neurochemical classes of myenteric neurons are temporally and spatially activated along the colon and generate propulsive contractions. This study confirmed again that the ENS is the ‘first brain’ in the evolutionary process.
腸神経系 (ENS) は、数億年にわたって進化してきた胃腸 (GI) 管の神経系である。最近、Spencerら[12] は、ENSがどのようにして脳や脊髄の他の神経ネットワークと同様に作用する腸に沿った推進力を生み出すかを示した。Spencerら[12] は、すべての異なる神経化学的クラスの腸筋ニューロンが結腸に沿って時間的および空間的に活性化され、推進性収縮を生じる仕組みを明らかにした。この研究は、ENSが進化の過程における「最初の脳」であることを再確認した。
The ENS is a very complex, autonomous nervous system that develops before and independently of the central nervous system (CNS) [13]. Although the ENS can function independently, the ENS and CNS communicate bidirectionally [14]. The ENS is the largest part of the peripheral nervous system that regulates and coordinates all bowel functions, and contains approximately 200–600 million neurons in humans [15,16]. The diversity of neuronal and glial subtypes and neurotransmitters in the ENS is as rich as that in the CNS [17]. The ENS is a network of neurons and glial cells located within the gut wall that is essential for control of gastrointestinal function. The ENS communicates with other cell types, including intestinal epithelial, endocrine, and immune cells, which influence numerous physiological responses at the level of the gut [14]. During embryonic development, neurons and glial cells of the ENS are mainly derived from pluripotent stem cells of the vagal neural crest that invade, proliferate, and migrate through the intestinal wall until the entire bowel is colonized [18,19]. The intestinal microbiome interacts with the ENS and affects intestinal physiology [20].
ENSは非常に複雑な自律神経系であり、中枢神経系 (CNS) に先行して独立して発達する [13]。ENSは独立して機能することができるが、ENSとCNSは双方向に通信する [14]。ENSは、すべての腸機能を調節し、調整する末梢神経系の最大の部分であり、ヒトでは約2億～6億のニューロンを含む[15, 16]。ENSにおける神経、グリアのサブタイプと神経伝達物質の多様性は、CNSと同様に豊富である [17]。ENSは消化管機能の制御に不可欠な腸壁内に位置するニューロンとグリア細胞のネットワークである。ENSは腸上皮細胞、内分泌細胞、免疫細胞などの他の細胞と連絡をとり、腸のレベルで多くの生理的反応に影響を与える [14]。胎生期には、ENSのニューロンおよびグリア細胞は主に迷走神経堤の多能性幹細胞に由来し、迷走神経堤は腸壁に侵入して増殖し、腸壁全体に定着するまで移動する[18, 19]。腸内微生物叢はENSと相互作用し、腸の生理学に影響を及ぼす [20]。
The gut-brain axis (GBA) is a bidirectional communication system between the gastrointestinal tract and brain. The GBA (broadly defined) includes the CNS; neuroendocrine system; neuroimmune systems; the hypothalamic pituitary adrenal axis (HPA); sympathetic and parasympathetic arms of the autonomic nervous system (ANS); ENS; vagus nerve; and gut microbiota and its metabolites, such as essential vitamins, secondary bile acids, amino acids, short-chain fatty acids (SCFAs), neurotransmitters, and hormones [21,22]. Kano et al. [23] found that IBS involves corticotropin-releasing hormone (CRH)-dependent dysregulation of the GBA. This supports the conceptualization of IBS as a disorder of brain-gut interactions with stress response systems, such as the ANS and HPA axis, serving as an important interface.
腸‐脳軸 (GBA) は胃腸管と脳の間の双方向コミュニケーションシステムである。GBA (広義) には中枢神経系が含まれる；神経内分泌系；神経免疫系；視床下部下垂体副腎軸 (HPA)；自律神経系 (ANS) の交感神経と副交感神経の両腕；ENS；迷走神経；腸内細菌及びその代謝物、必須ビタミン、二次胆汁酸、アミノ酸、短鎖脂肪酸 (SCFA)、神経伝達物質及びホルモン等について検討した[21, 22]。Kanoら [23] は、IBSに副腎皮質刺激ホルモン放出ホルモン(CRH)依存性のGBA調節異常が関与していることを明らかにした。これは、重要なインターフェースとして機能するANSおよびHPA軸のようなストレス応答系との脳‐腸相互作用の障害としてのIBSの概念化を支持する。
Through the GBA, these pathways and metabolites can influence behaviour, memory, learning, locomotion, stem cell proliferation and differentiation, neurotransmission pathways, activity-dependent synaptic plasticity, brain development, mental and neurodegenerative disorders, hormonal and immune system pathways, etc. [[24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]]. Microbe-derived metabolites can also modulate host metabolism via epigenetic regulators [36,37]. In addition, Kaelberer et al. [38] demonstrated the existence of a direct link between enteroendocrine (EC) cells and the brain. Namely, EC cells synapse with vagal neurons to transduce millisecond-long intestinal luminal signals by glutamate as a neurotransmitter. Furthermore, intestinal microbiota changes brain mechanisms that aid in threat processing [39].
GBAを介して、これらの経路および代謝産物は、行動、記憶、学習、運動、幹細胞増殖および分化、神経伝達経路、活動依存性シナプス可塑性、脳発達、精神および神経変性障害、ホルモンおよび免疫系経路などに影響を及ぼす[24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35]。微生物由来の代謝産物はまた、エピジェネティック調節因子を介して宿主の代謝を調節することができる[36, 37]。さらに、Kaelbererら [38]は、腸内分泌 (EC) 細胞と脳との直接的な関連の存在を実証した。すなわち、EC細胞は迷走神経ニューロンとシナプスし、神経伝達物質としてグルタミン酸によりミリ秒長の腸管内腔シグナルを伝達する。さらに、腸内細菌叢は脅威の処理を助ける脳のメカニズムを変化させる [39]。
Exposure to various factors, such as diet, toxins, drugs, antibiotics, pathogens, and psychological stress, can perturb the normal microbiota that causes dysbiosis, impairing communication via the GBA [[40], [41], [42]]. Impaired communication between the gut and brain axis can produce numerous intestinal and extraintestinal disorders (obesity, type 2 diabetes, glucose intolerance, insulin resistance, acne, atopic dermatitis, psoriasis, colorectal cancer, nonalcoholic fatty liver disease, IBS, Crohn's disease, ulcerative colitis, fibromyalgia, chronic pain, stroke, lung disease, celiac disease, and metabolic syndrome) as well as disorders of the nervous system [[43], [44], [45], [46], [47], [48]]. There is increasing evidence that the GBA axis plays a key role in the maintenance of brain homeostasis as well as in the development of major neurological and psychiatric disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), autism spectrum disorder (ASD), and major depressive disorder (MDD) [46,49,50]. It seems that the gut microbiota can affect almost all aspects of human development and health [51].
食事、毒素、薬物、抗生物質、病原体、および心理的ストレスなどの様々な因子への曝露は、腸内毒素症を引き起こす正常な微生物叢を乱し、GBAを介した情報伝達を阻害する [40, 41, 42]。腸軸と脳軸の間の情報伝達障害は、神経系の疾患と同様に、多くの腸および腸外疾患(肥満、2型糖尿病、耐糖能異常、インスリン抵抗性、にきび、アトピー性皮膚炎、乾癬、大腸がん、非アルコール性脂肪肝疾患、IBS、クローン病、潰瘍性大腸炎、線維筋痛症、慢性疼痛、脳卒中、肺疾患、セリアック病、メタボリックシンドローム)を引き起こす可能性がある[43, 44, 45, 46, 47, 48]。GBA軸が脳の恒常性の維持ならびにパーキンソン病 (PD)、アルツハイマー病 (AD)、多発性硬化症 (MS)、自閉症スペクトラム障害 (ASD) および大うつ病性障害 (MDD) などの主要な神経学的および精神医学的障害の発症において重要な役割を果たすという証拠が増加している [46, 49, 50]。腸内細菌叢は、人間の発達と健康のほぼすべての側面に影響を及ぼす可能性があるようである [51]。
3. The enteric nervous system may have long-term memory(腸管神経系は長期記憶を持つ可能性がある)
Studies have suggested that the ENS may be able of learning and memorizing [7,52,53]. Recently, Schemann et al. [7] proposed that the ENS may perform memorization and implicit learning; thus, it may work similarly to a “little brain” in the gut. One of the main comments by Gershon [54] on Schemann's statement [7] was that enteric neurons cannot survive for a lifetime, since 88% of ENS may be lost every two weeks [55]. Thus, the rapid exchange of enteric neurons is difficult to reconcile with the notion that the ENS has circuits that are able to cope with complex processes such as learning and memory [54].
研究では、ENSは学習し記憶することができる可能性が示唆されている[7, 52, 53]。最近、Schemannら [7] は、ENSが記憶と暗黙の学習を行う可能性があることを提案した；そのため、腸内の「小さな脳」と同じような働きをする可能性があります。Schemannの声明 [7] に対するGershon [54] の主なコメントの１個は、ENSの88%が２週間ごとに失われるため、腸ニューロンは一生生存できないというものであった [55]。このように、腸ニューロンの迅速な交換は、ENSが学習や記憶のような複雑なプロセスに対処できる回路を持っているという考えと一致させるのは難しい [54] 。
However, there are studies that do not suggest such a high degree of neurogenesis [20,56] in the ENS, as reported by Kulkarni et al. [55]; and we should consider that the origin of differentiating cells is currently under debate. In addition, the latest studies question the 70-year-old paradigm, the Hebbian hypothesis of neuroscience plasticity, according to which the brain learns by modifying the strength of synapses [57,58]. Hodassman et al. [57] proposed that the neuron is not a binary unit that can fire or not and that a single neuron can realize learning algorithms that previously required an artificially complex network of thousands of interconnected neurons and synapses.
しかしながら、Kulkarniら [55]が報告しているように、ENSにおける神経新生がそれほど高度であることを示唆していない研究もある[20, 56]；そして分化細胞の起源は現在議論されていると考えるべきである。さらに、最新の研究は、脳がシナプスの強さを変更することによって学習することによると、70年前のパラダイム、神経科学の可塑性のヘビアン仮説に疑問を投げかけている [57, 58]。Hodassmanら [57]は、ニューロンは発火するかしないかのバイナリユニットではなく、単一のニューロンは、以前は何千もの相互接続されたニューロンとシナプスの人工的に複雑なネットワークを必要とした学習アルゴリズムを実現できることを提案した。
Furthermore, several studies have suggested that long-term memory (LTM) may exist by epigenetic mechanisms at the cellular level [[59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69]These findings support the notion that simple stress-induced implicit LTM may also persist throughout life by epigenetic mechanisms in the ENS.
さらに、いくつかの研究は、長期記憶 (LTM) が細胞レベルでのエピジェネティックなメカニズムによって存在する可能性があることを示唆している [59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69]。これらの知見は、単純なストレスが誘導する潜在的LTMもENSにおけるエピジェネティックなメカニズムによって生涯を通じて持続する可能性があるという考えを支持する。
4. Irritable bowel syndrome(過敏性腸症候群)
Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder (FGID) [70] that has no organic cause and cannot be detected by routine laboratory tests. The aetiology and pathogenesis of IBS are multifactorial. Hence, the underlying pathogenesis of IBS is complex, and the molecular pathophysiology is far from understood. According to Van Oudenhove et al. [71,72]: “It is generally accepted that functional gastrointestinal disorders (FGIDs) result from complex and reciprocal interactions between biological, psychological, and social factors, rather than from linear monocausal etiopathogenetic processes.”
過敏性腸症候群 (IBS)は最も一般的な機能性胃腸疾患 (FGID) [70] であり、器質的原因がなく、通常の臨床検査では検出されない。IBSの病因および発症機序は多因子性である。したがって、IBSの根底にある病因は複雑であり、分子病態生理学は全く理解されていない。Van Oudenhoveら [71, 72]によると：「機能性胃腸疾患 (FGID) は、直線的な単一原因の病因過程よりむしろ生物学的、心理学的および社会的因子間の複雑で相互的な相互作用から生じることが一般的に受け入れられている。」
According to the ROME III criteria in 2006, patients with IBS belong to one of the three predominant subtypes: IBS with constipation (IBS–C); IBS with diarrhoea (IBS-D); mixed IBS with alternating diarrhoea and constipation (IBS-M); and IBS-U is an unsubtyped IBS for people who do not fit into the IBS-D, IBS-C, and IBS-M types [73]. In 2016, the Rome IV criteria defined IBS as an FGID in which recurrent abdominal pain is associated with defecation or a change in bowel habits. This produced greater heterogeneity within diagnostic categories [74]. Namely, there was a 3-fold increase in the rate of a functional dyspepsia FD/IBS overlap diagnosis. However, the diagnosis of IBS is still controversial and is partly made on the basis of the exclusion of other diseases.
2006年のROME III基準によると、IBS患者は以下の３個の主要な亜型のいずれかに属する：便秘を伴うIBS (IBS–C)；下痢を伴うIBS (IBS-D)；下痢と便秘が交互に起こる混合型IBS (IBS-M)；IBS-UはIBS-D型、IBS-C型、IBS-M型に当てはまらない人々のためのサブタイプのないIBSである [73]。2016年、Rome IV基準はIBSを、反復性腹痛が排便または用便習慣の変化と関連するFGIDと定義した。これにより、診断カテゴリー内の異質性が増大した [74]。すなわち、機能性消化不良FD/IBS重複診断率が3倍に増加した。しかしながら、IBSの診断はまだ議論の余地があり、部分的には他の疾患の除外に基づいて行われる。
IBS substantially impairs quality of life, and the overall health-care costs are high. The prevalence of IBS ranges from 5% to 20%, depending on the country and criteria used to diagnose IBS [75]. If the incidence of IBS remains unchanged, projections of global population growth alone indicate that many more people will suffer from IBS worldwide in the future [76]. IBS is more frequent in women than men [77]. Various predisposing factors have been suggested for IBS, such as sex, age, psychological stress factors, early life events, gastrointestinal infections, altered gut microbiota, asthma and atopic disorders, diet, socioeconomic, family, and environmental factors, among others [[78], [79], [80]].
IBSは生活の質を著しく低下させ、全体的な医療費は高い。IBSの有病率は5%~20%であり、国およびIBSの診断に用いられる基準によって異なる [75]。IBSの発生率が変化しなければ、世界人口の増加の予測だけでも、将来、世界中でさらに多くの人々がIBSに苦しむことを示している [76]。IBSは男性よりも女性に多くみられる [77]。IBSには、性別、年齢、心理的ストレス因子、幼少期の出来事、胃腸感染症、腸内細菌叢の変化、喘息およびアトピー性疾患、食事、社会経済的因子、家族および環境因子など、様々な素因が示唆されている [78, 79, 80]。
IBS is now considered a disorder of altered brain-gut interactions, where a biopsychosocial model helps in understanding the symptoms (see Fig. 1) [81]. The biopsychosocial model of IBS is useful in understanding FGIDs as complex conditions that involve complex interplay between biological, psychological, and (psycho)social factors. A 2019 meta-analysis [3] found that PTSD is significantly associated with an increased likelihood of IBS. This supports a biopsychosocial understanding and model for IBS. In addition, there is growing evidence that dysregulation in immune function is associated with IBS and could contribute to either aetiology or symptoms. Mast cells are immune cells in the gastrointestinal tract that are regarded as key components in inflammatory reactions and IBS pathophysiology [82,83].
IBSは現在、脳と腸の相互作用が変化する疾患と考えられており、生物心理社会的モデルが症状の理解に役立つ(図1参照) [81] 。IBSの生物心理社会的モデルは、生物学的、心理学的、および(心理的)社会的因子間の複雑な相互作用を含む複雑な状態としてFGIDを理解するのに有用である。2019年のメタアナリシス [3]は、PTSDがIBSの可能性の増加と有意に関連していることを明らかにした。これはIBSの生物心理社会的理解とモデルを支持する。さらに、免疫機能の調節不全がIBSと関連し、病因または症状のいずれかに寄与する可能性があるという証拠が増えている。肥満細胞は、炎症反応およびIBS病態生理における重要な成分とみなされる消化管の免疫細胞である [82, 83]。
Fig. 1
Simple illustration about the biopsychosocial model of IBS with IBS symptoms and factors involved in IBS pathogenesis in the gut and CNS.
図 1
IBS の症状と腸と中枢神経系におけるIBS発症に関与する因子を示す、IBSの生物心理社会的モデルの簡単な図解。
Current approaches in IBS treatment include dietary, probiotic, pharmacological (depending on the subtype, including antidepressants, antibiotics, peripherally restricted opioids, cannabis), psychotherapeutic (cognitive behavioral therapy and gut-directed hypnotherapy), and microbiota transplantation approaches, among others [[84], [85], [86], [87], [88], [89]]. Unfortunately, the present diagnostic criteria for FGIDs, as well as disease severity, frequency, duration, and treatment efficacy, are based solely on subjective patient reports without objective biomarkers [90,91].
IBS治療における現在のアプローチには、食事、プロバイオティクス、薬理学的アプローチ(サブタイプに応じて、抗うつ薬、抗生物質、末梢制限オピオイド、大麻を含む)、心理療法的アプローチ(認知行動療法および腸管誘導催眠療法)、微生物移植アプローチなどがある [84, 85, 86, 87, 88, 89]。残念ながら、FGIDに対する現在の診断基準は、疾患の重症度、頻度、期間、および治療効果と同様に、客観的なバイオマーカーのない主観的な患者報告のみに基づいている [90, 91]。
5. IBS: comorbidity with mental diseases and subthreshold mental disorders(IBS: 精神疾患および閾値下精神障害との併存)
Although the role and importance of psychological factors in IBS are debated, a growing number of studies suggest that psychiatric and mood disorders may play a key role in the development and maintenance of IBS. Thirty to forty percent of patients with IBS have comorbid depression or anxiety disorder [92,93]. Approximately 60% of those seeking medical treatment for FGIDs suffer from a psychiatric illness [94]. Suicidal ideation occurs in 15–38% of patients with IBS [95]. A systematic review and meta-analysis found that the prevalence of IBS varies from 1% to more than 45%, according to the geographic location of the population under study [96]. Kabra and Nadkarni [97] found that the prevalence of depression and anxiety in IBS patients was 37.1 and 31.4%, respectively, in an Indian population. Newer meta-analysis studies show that depression and anxiety are significantly higher in IBS patients than in healthy controls [98,99]. A multivariate analysis of 769 IBS patients by Midenfjord et al. [2] revealed that the prevalence of depression and anxiety was 25.7% and 44.9%, respectively, in IBS patients. Hu et al. [100] conducted a network meta-analysis of 18 studies with 7095 participants. The authors found that IBS-C had the highest incidence of depression (38%) and anxiety (40%), followed by IBS-D, IBS-M, and IBS-U. In addition, IBS-M was associated with higher levels of depression and anxiety, and IBS-C had the highest prevalence of depression and anxiety. According to a systematic review and meta-analysis by Zamani et al. [101]; IBS patients presented threefold increased odds of either anxiety or depression compared to healthy controls. A 2019 meta-analysis by Ng et al. [3] contained a total of 648,375 subjects, specifically examining the association between PTSD and IBS, and found that PTSD was significantly associated with an increased likelihood of IBS. Interestingly, a large Korean study by Lee et al. [102] reported that the incidence rate of IBS was higher in patients with mild depression than in those with severe depression. Referring to the biopsychosocial model, Person and Keefer [103] wrote: “In this model, gastrointestinal disease can be seen as more than just an isolated pathophysiological process, but in the context of psychosocial factors that may be a key to the genesis and maintenance of the illness."
IBSにおける心理的因子の役割と重要性は議論されているが、精神疾患と気分障害がIBSの発症と維持に重要な役割を果たす可能性を示唆する研究が増えている。IBS患者の30~40%はうつ病または不安障害を併発している [92, 93]。FGIDの治療を求める人の約60%が精神疾患を患っている [94]。自殺念慮はIBS患者の15~38%に生じる [95]。系統的レビューとメタ分析により、IBSの有病率は研究対象集団の地理的位置によって1%から45%以上まで異なることが明らかにされた [96]。KabraとNadkarni [97]は、インド人集団におけるIBS患者の抑うつおよび不安の有病率がそれぞれ37.1および31.4%であることを見出した。最近のメタアナリシス研究では、抑うつおよび不安はIBS患者の方が健常対照者よりも有意に高いことが示されている [98, 99]。Midenfjordら [2]によるIBS患者769人の多変量解析では、IBS患者における抑うつおよび不安の有病率はそれぞれ25.7%および44.9%であった。Huら [100] は、被験者7095人を対象とした18件の研究のネットワークメタ分析を実施した。IBS-Cは抑うつ状態 (38%) および不安 (40%) の発生率が最も高く、次いでIBS-D、IBS-M、IBS-Uの順であったことを、同著者らは見出した。さらに、IBS-Mは高レベルの抑うつ状態および不安と関連しており、IBS-Cは抑うつ状態および不安の有病率が最も高かった。Zamaniら [101]の系統的レビューおよびメタ解析によると；IBS患者は、健常対照者と比較して不安または抑うつ状態のオッズが３倍高かった。Ngら [3] による2019年のメタアナリシスでは、合計648,375名の被験者が含まれ、特にPTSDとIBSとの関連性が検討され、PTSDがIBSの可能性の増大と有意に関連していることが見出された。興味深いことに、Leeらによる大規模な韓国の研究 [102]では、IBSの発生率は重度のうつ病患者よりも軽度のうつ病患者で高いことが報告されている。生物心理社会的モデルに言及して、PersonとKeefer [103] は次のように書いている：「このモデルでは、胃腸疾患は単なる孤立した病態生理学的プロセス以上のものとして見ることができ、病気の発生と維持の鍵となるかもしれない心理社会的要因との関連で見ることができる。」
Subthreshold mental disorders (SMDs) (that do not meet full diagnostic criteria for mental disorders) are attracting increased attention in scientific research because SMDs can be an important source of countless other diseases and poor quality of life and thus may also be a cause of IBS development [[104], [105], [106], [107], [108], [109], [110], [111], [112], [113]]. SMDs are often undiagnosed, although the prevalence of SMDs is higher than that of diagnosed mental disorders [104]. Furthermore, SMDs include the same symptoms as diagnosed mental disorders, except that they differ in the number, duration, severity, and frequency of symptoms and exclusion criteria [107]. It is very probable that many people may have SMDs for a shorter or longer period of time or throughout their lives without diagnosis [112,114]. Therefore, SMDs could be a significant source of countless diverse diseases and may also be a cause of IBS development.
閾値下精神障害 (SMD) (精神障害の完全な診断基準を満たさない)は、他の無数の疾患および生活の質の低下の重要な原因となりうるため、IBS発症の原因となる可能性もあるため、科学的研究においてますます注目を集めている [104, 105, 106, 107, 108, 109, 110, 111, 112, 113]。SMDの有病率は診断された精神障害の有病率よりも高いが、SMDは診断されないことが多い [104]。さらに、SMDは診断された精神障害と同じ症状を含むが、症状の数、期間、重症度、頻度および除外基準が異なる [107]。多くの人々が診断されることなく、短期間または長期間、あるいは生涯を通じてSMDを有する可能性が非常に高い [112, 114]。したがって、SMDは無数の多様な疾患の重要な原因であり、IBS発症の原因でもある可能性がある。
6. IBS: structural and functional brain changes(IBS: 脳の構造的および機能的変化)
Although various studies have investigated structural and functional brain changes associated with IBS, the IBS-associated exact neural substrate is still unclear. Seminowicz et al. [115] found that IBS is associated with decreased grey matter density (GMD), including the medial prefrontal and ventrolateral prefrontal cortex, the posterior parietal cortex, the ventral striatum, and the thalamus. They proposed that morphometric alterations take place mainly in brain networks concerned with attention and emotion modulation, as well as in cortio-limbic pontine pain modulatory systems, and to a lesser degree, in networks processing interoceptive information.
様々な研究がIBSに関連する構造的および機能的脳変化を調査しているが、IBSに関連する正確な神経基質はまだ不明である。Seminowiczら [115]は、IBSが内側前頭前皮質および腹外側前頭前皮質、後頭頂皮質、腹側線条体、視床などの灰白質密度 (GMD) の低下と関連していることを見出した。彼らは、形態計測的変化は主に注意と感情の調節に関係する脳のネットワークや、皮質-辺縁系橋の疼痛調節系で起こり、程度は低いが、内受容情報を処理するネットワークで起こると提案した。
The study by Zhao et al. [116] found that elderly IBS patients presented reduced fractional anisotropy (FA) in the callosum, upper corona, fornix, internal capsule, and caudex cerebri, indicating that white matter abnormalities occurred in IBS patients with grey matter abnormalities. Weng et al. [117]; by resting-state functional magnetic resonance imaging (rsfMRI), observed that IBS patients presented widely perturbed functional connectivity density (FCD). Furthermore, some areas with altered FCD had abnormal functional relationships in brain regions involved in the pain matrix of IBS patients.
Zhaoら [116] の研究では、高齢IBS患者で脳梁、上冠、脳円蓋、内包、大脳尾核の異方性度 (FA) の低下を発見し、灰白質異常を伴うIBS患者では白質異常が発生したことを認められることが示された。Wengら [117]；安静時機能的磁気共鳴画像法 (rsfMRI) により、IBS患者は広範囲に乱れた機能的結合密度 (FCD) を示すことが観察された。さらに、変化したFCDを有するいくつかの領域は、IBS患者の疼痛マトリックスに関与する脳領域において異常な機能的関係を有した。
Labus et al. [118] found increases and decreases in GMV and alterations in regional network properties in predominantly premenopausal female IBS patients. These changes could reflect different pathophysiological components of the disease processes underlying IBS symptoms. Namely, increased sensitivity to somatic and visceral stimuli (higher GMV in S1) was associated with an increase in emotional arousal (lower GMV in the hippocampus in IBS) and other chronic pain-related mechanisms (lower GMV in insula and cingulate cortices, differences in insula, cingulate, thalamus and brain stem network properties).
Labusら [118]は、主に閉経前女性のIBS患者において、灰白質の容積(GMV)の増減および局所ネットワーク特性の変化を見出した。これらの変化は、IBS症状の根底にある疾患プロセスの異なる病態生理学的要素を反映している可能性がある。つまり、体性刺激および内臓刺激に対する感受性の増加 (S1におけるより高いGMV) は、感情的興奮の増加 (IBSにおける海馬のより低いGMV) および他の慢性疼痛関連機序(島皮質と帯状皮質のGMV低下、島皮質、帯状皮質、視床、脳幹ネットワーク特性の差)と関連していた。
IBS is strongly associated with a high level of somatization and psychosocial morbidities [71,72,119]. In magnetic resonance imaging (MRI) experiments, Grinsvall et al. [120] found that somatization level was associated with differences in local grey matter covariance, mainly in regions of the prefrontal cortex, insula, and cerebellum in IBS. The authors proposed that prefrontal mechanisms may be more important than insular mechanisms in the neurobiological sensitization process associated with IBS high somatization.
IBSは高レベルの身体化と心理社会的病的状態と強く関連している[71, 72, 119]。磁気共鳴画像法 (MRI) 実験において、Grinsvallら [120]は、身体化レベルがIBSにおいて主に前頭前野、島および小脳の領域における局所的な灰白質共分散の差と関連していることを見出した。著者らは、IBSの高度身体化に関連する神経生物学的感作プロセスにおいて、前頭前野のメカニズムが島のメカニズムよりも重要である可能性を提案した。
Icenhour et al. [121]; by rsfMRI, studied resting-state functional connectivity (rsFC) within the default mode network (DMN), salience and sensorimotor networks in IBS patients with and without visceral hypersensitivity compared to healthy controls. Namely, the authors investigated group differences in FC in insular and cingulate subregions, thalamus, and amygdala, since it was demonstrated that these brain regions are activated by visceral stimulation [122]. Icenhour et al. [121] proposed that group differences related to visceral sensitivity under resting conditions could be caused by enhanced sensory input from the gut or by centrally mediated modulatory mechanisms.
Icenhourら [121]；rsfMRIにより、健常対照者と比較して内臓過敏症の有無のIBS患者におけるデフォルトモードネットワーク (DMN)、顕著性および感覚運動ネットワーク内の安静時機能的結合性 (rsFC) を検討した。具体的には、島皮質および帯状のサブ領域、視床、扁桃体が内臓刺激により活性化されることが示されたことから、これらの領域におけるFCのグループ間の差を著者らは調査した [122] 。Icenhourら [121] は、安静時の内臓過敏症に関連したグループ間の差は、腸管からの感覚入力の増加または中枢性の調節機構によって引き起こされる可能性があると提唱した。
The habenula is a small epithalamic complex nucleus that connects the limbic forebrain and midbrain. The habenula is involved in nociception, sleep-wake cycles, reproductive behaviour, and mood and has been implicated in the pathogenesis of various psychiatric disorders and pain [123,124]. Mao et al. [125] investigated habenular function in IBS patients by rsfMRI. They showed that IBS patients had altered rsfMRI and effective connectivity of the habenula associated with pain. These results may indicate the dysregulation of affective and pain processing in these disease conditions.
手綱核は、辺縁系の前脳と中脳をつなぐ小さな視床上部複合核である。手綱核は痛覚、睡眠-覚醒サイクル、生殖行動、および気分に関与しており、様々な精神疾患および疼痛の病因に関係があるとされている [123, 124]。Maoら [125] は、IBS患者の手綱機能をrsfMRIで調査した。IBS患者はrsfMRIが変化しており、手綱核の有効な連結性が疼痛と関連していることを彼らは示した。これらの結果は、これらの疾患状態における感情および疼痛処理の調節不全を示す可能性がある。
MRI investigations of patients with IBS with depressive symptoms (DEP-IBS) by Li et al. [32,33] suggest that depressive symptoms can act as mediators between gastrointestinal symptoms and GMV in the left insula, right medial prefrontal cortex, and right middle frontal gyrus, whereas gastrointestinal symptoms can act as mediators between depression and GMV in these areas. This suggests that convergent syndromic atrophy develops in the pain and emotional systems of patients with DEP-IBS. Li et al. [126,127], using rsfMRI, found that patients with DEP-IBS present abnormal functional connectivity (FC) in brain areas associated with the fronto-limbic and sensorimotor networks, especially the insula and supplementary motor area (SMA), which can elucidate the vicious circle between negative emotions and gastrointestinal symptoms in IBS.
Liら[32, 33]による抑うつ症状を伴うIBS患者 (DEP-IBS) のMRI調査は、抑うつ症状が左島皮質、右内側前頭前皮質、および右中前頭回における胃腸症状とGMVとの間の仲介者として作用しうる一方、胃腸症状がこれらの領域における抑うつとGMVとの間の仲介者として作用しうることを示唆している。このことは、収束性症候群性萎縮がDEP‐IBS患者の疼痛および感情系で発生することを示唆する。Liら [126, 127] は、rsfMRIを用いて、DEP-IBS患者が前頭-辺縁系および感覚運動ネットワークに関連する脳領域、特に島皮質および補足運動野 (SMA) に異常な機能的結合 (FC) を示すことを見出した、それはIBSにおける否定的感情と胃腸症状の間の悪循環を解明することができる。
7. IBS: prenatal, perinatal, postnatal, and early age stress, familial clustering and transfer across generations(IBS: 出生前、周産期、産後、幼少期のストレス、家族内集積、世代間伝達)
According to foetal programming theory, exposure to prenatal suboptimal intrauterine conditions in later adulthood can predispose a person to developing chronic diseases [128]. However, there is growing evidence that prenatal, perinatal, postnatal, and early age conditions could predispose to developing chronic diseases in later adulthood [[129], [130], [131], [132]]. Maternal prenatal and postnatal anxiety and depression, neonatal maternal separation, and early adverse life events (EALs), such as sexual and physical abuse or emotional trauma, are significant vulnerability factors that predispose individuals to gastrointestinal diseases and development of adult IBS [133,134]. Maternal depression and anxiety are most common during pregnancy and the postpartum period [135]. Maternal prenatal stress influences the neurodevelopment and birth outcomes of offspring [136].
胎児プログラミング理論によれば、成人後期に出生前の次善の子宮内環境にさらされると、慢性疾患を発症しやすくなる [128]。しかしながら、出生前、周産期、出生後、および早期の状態が成人期後期の慢性疾患発症の素因となりうることを示す証拠が増えている[129, 130, 131, 132]。母親の出生前および出生後の不安および抑うつ、新生児の母親の分離、および性的虐待や身体的虐待または精神的外傷のような初期の有害な人生の出来事 (EAL) は、個人を胃腸疾患および成人IBSの発症にかかりやすくする重要な脆弱性因子である [133, 134]。母親の抑うつおよび不安は妊娠中および分娩後に最もよくみられる [135]。母親の出生前ストレスは神経発達と子供の出生結果に影響する [136]。
We identified neonatal maternal separation (MS) as an essential risk factor for neurodevelopmental disorders [137]. There is also growing evidence that perinatal, postnatal, and early age conditions can have an essential role in the development of IBS. Various studies have pointed out that MS, as an early adverse life event, can be particularly dangerous to newborns and induce visceral hypersensitivity [[138], [139], [140], [141], [142]].
神経発達障害の重要な危険因子として新生児の母性分離 (MS) を同定した [137]。また、周産期、出生後、および若年期の状態がIBSの発症に重要な役割を果たす可能性があるという証拠も増えている。様々な研究は、初期の有害な人生の出来事として、MSが新生児に特に危険であり、内臓過敏症を誘発することを指摘している [138, 139, 140, 141, 142]。
Various studies have pointed out that IBS can accumulate in families and be inherited across generations [[143], [144], [145]]. Aguas et al. [146] found that the incidence of IBS was higher in first-degree blood relatives than in spouses of patients. The authors also suggested that genetic and psychological factors are more important than environmental factors. van den Wijngaard et al. [147] showed that MS-produced visceral hypersensitivity could be transferred across generations. In addition, this transfer depended on maternal care, which suggests that the MS model can be used to determine early life adverse triggers and mechanisms relevant to IBS. Twin studies also emphasize that genetic and psychological processes may explain familial clustering of IBS and that both heredity and social learning contribute to its aetiology [148–150]. A recent population-based twin cohort study [148] demonstrated that familial as well as intrauterine factors have significant roles in the cooccurrence of IBS and symptoms of anxiety and depression. The authors also revealed that both genetic factors and intrauterine factors can influence the associations between IBS, anxiety, and depression. In addition, IBS presents a higher concordance rate among monozygotic compared to dizygotic twins [151,152].
IBSは家族内に蓄積し、世代を超えて遺伝することが様々な研究で指摘されている[143, 144, 145]。Aguasら [146]は、IBSの発生率が患者の配偶者よりも１親等血縁者で高いことを明らかにした。著者らはまた、遺伝的および心理的因子が環境因子よりも重要であることを示唆した。van den Wijngaardら [147]は、MSによる内臓過敏症が世代を超えて伝達される可能性があることを示した。さらに、この移行は母親のケアに依存しており、MSモデルはIBSに関連する幼少期の有害な誘因および機序を決定するために使用できることが示唆される。双生児研究はまた、遺伝的および心理的過程がIBSの家族内集積を説明し、遺伝と社会的学習の両方がその病因に寄与することを強調している [148–150] 。最近の集団ベースの双生児コホート研究 [148] は、子宮内因子と同様に家族性因子がIBSと不安および抑うつ症状の併発に重要な役割を果たすことを実証した。著者らはまた、遺伝因子および子宮内因子の両方がIBS、不安および抑うつ状態の関連性に影響を及ぼす可能性があることを明らかにした。さらに、IBSは二卵性双生児と比較して一卵性双生児間でより高い一致率を示す [151, 152]。
In their large cohort study, Waehrens et al. [153] revealed that many perinatal and familial factors could be independently associated with an increased risk of IBS. This suggests that perinatal and familial factors may have an important long-term role in the development of IBS. The increased risk of IBS among first-degree, second-degree, and third-degree relatives suggests an important genetic component of the family grouping of IBS [153]. Nevertheless, nongenetic factors also contribute to the increased risk among spouses, and the genetic component plays an essential role in the familial clustering of IBS [154]. According to Gazouli et al. [155]; environmental factors such as childhood trauma, physical and psychological stress, pathogens, and perturbed gut microbiota have key roles in the development of IBS.
Waehrensら [153]の大規模コホート研究では、多くの周産期因子および家族因子がIBSのリスク増大と独立して関連している可能性があることが明らかにされた。このことは、周産期および家族性因子がIBSの発症に重要な長期的役割を持つ可能性を示唆する。１親等、２親等、３親等近親者におけるIBSリスクの上昇は、IBSの家族分類における重要な遺伝的要素を示唆している [153]。それにもかかわらず、非遺伝的因子も配偶者間のリスク増加に寄与しており、遺伝的要素はIBSの家族内集積に不可欠な役割を果たしている [154]。Gazouliら [155] によると；幼少期のトラウマ、身体的および心理的ストレス、病原体、腸内細菌叢の乱れなどの環境因子がIBSの発症に重要な役割を果たしている。
8. Hypnosis(催眠)
Hypnosis can be considered an altered state of consciousness (trancelike state) that allows the individual to recall memories or instruct the individual to change a particular behaviour. Using electroencephalography (EEG) and imaging methods, hypnosis can be well distinguished from other states of consciousness, such as normal wakefulness, deep relaxation, sleep, or meditation [156].
催眠は、個人が記憶を思い出したり、特定の行動を変えるように指示したりすることを可能にする意識の変容状態 (トランスのような状態) と考えることができる。脳波検査 (EEG) や画像診断法を用いることで、催眠状態を、通常の覚醒状態、深いリラクゼーション状態、睡眠状態、瞑想状態などの他の意識状態と明確に区別することができる [156]。
Numerous studies have revealed that hypnosis is a nonpharmacological and cost-effective method that can be used as an effective and safe method for the management of diverse conditions, such as pain, anxiety, mood disorders, sleep problems, depression and anxiety, wound healing, haemorrhage, stress and pain associated with medical and surgical procedures, and gastrointestinal disorders [9, [157], [158], [159], [160], [161], [162], [163], [164], [165], [166], [167], [168], [169], [170], [171], [172], [173], [174]].
数多くの研究は、催眠が、疼痛、不安、気分障害、睡眠問題、抑うつおよび不安、創傷治癒、出血、医学的および外科的処置に関連するストレスおよび疼痛、ならびに胃腸障害などの多様な状態の管理のための効果的かつ安全な方法として使用できる非薬理学的かつ費用対効果の高い方法であることを明らかにしている[9, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174]。
At present, the hypnosis-induced neurophysiological mechanisms are not yet well understood. Although various models have been suggested to explain these effects, the biopsychosocial model of hypnosis (biological, psychological, and social factors and their interactions) may serve as a better integration model [175].
現在、催眠誘導の神経生理学的メカニズムはまだ十分に理解されていない。これらの効果を説明するために様々なモデルが提案されているが、催眠の生物心理社会的モデル(生物学的、心理学的、社会的要因とそれらの相互作用)はより良い統合モデルとして役立つかもしれない [175]。
According to neuroimaging studies, hypnosis suggestions create an altered functional association. These subjective changes are associated with corresponding changes in specific psychological functions within brain regions. Although there are methodological and subjective differences, numerous experiments suggest that a hypnotic state includes the insular cortex, anterior cingulate cortex (ACC), thalamus, increased pituitary-mesencephalic brainstem, increased activation of the occipital and dorsolateral prefrontal cortex (DLPFC), amygdaloid memory system, and decreased activation of the precuneus [9,[176], [177], [178]]. In addition, recently, we [9] and others [179] pointed out that hypnosis may produce changes in neuroplasticity and that epigenetic mechanisms may underlie these changes in synaptic plasticity.
神経画像研究によると、催眠暗示は機能的関連性を変化させる。これらの主観的変化は、脳領域内の特定の心理的機能における対応する変化と関連している。方法論的および主観的な違いがあるが、数多くの実験は、催眠状態が島皮質、前帯状皮質 (ACC)、視床、下垂体‐中脳脳幹の増加、後頭葉および背外側前頭前皮質 (DLPFC) の活性化の増加、扁桃体記憶系、楔前部の活性化の減少を含むことを示唆する[9, 176, 177, 178]。加えて、最近、私たち [9] と他の研究者 [179]は、催眠が神経可塑性の変化を生じる可能性があり、エピジェネティックなメカニズムがシナプス可塑性のこれらの変化の根底にあるかもしれないことを指摘した。
Since hypnosis allows access to the unconscious brain and could modulate unconscious (implicit) information, it could be a significant adjuvant technique that is not used in everyday practice and is basically just being researched [10,180,181].
催眠は無意識の脳へのアクセスを可能にし、無意識の (潜在的な) 情報を調整することができるので、日常診療では使用されず、基本的には研究されているだけの重要な補助技術となる可能性がある [10, 180, 181]。
9. Hypotherapy and IBS(低用量療法とIBS)
Since 1984, when Whorwell et al. published their outcomes of a small clinical trial in the Lancet that showed that hypnotherapy could relieve several of the symptoms of IBS, there has been an increased interest in researching the effectiveness of psychological treatment for IBS. Numerous experiments and studies have demonstrated the significant efficacy of hypnosis in the treatment of IBS [85,[182], [183], [184], [185], [186], [187], [188], [189], [190], [191], [192], [193]].
Whorwellらが、催眠療法がIBSの症状のいくつかを緩和できることを示した小規模臨床試験の結果をLancet誌に発表した1984年以来、IBSに対する心理療法の有効性の研究に対する関心が高まっている。数多くの実験および研究は、IBSの治療における催眠の有意な有効性を示している [85, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193]。
Gut-focused hypnotherapy (GFH) can not only improve the primary symptoms of IBS but also reduce noncolon symptoms, anxiety, and depression and improve quality of life and cognitive function [194,195]. Hypnotherapy is particularly effective in children with IBS [189,196,197]. Hasan et al. [198] demonstrated that Skype hypnotherapy, regarding IBS, produced significant improvements and was almost as effective as face-to-face treatment (outcomes of Skype hypnotherapy were 65% and face-to-face treatment was 76%). Rutten et al. [199] performed a randomized controlled trial to compare the cost-effectiveness of individual hypnotherapy performed by a qualified therapist with gut-directed hypnotherapy (GHT) by means of CD-recorded self-exercises at home in children with IBS or functional abdominal pain (FAP). They found that hypnotherapy with CD was comparable to (or slightly lower) hypnotherapy with a therapist. Peter et al. [200] studied the microbial composition of patients with IBS and psychological distress before and after GHT. The authors found that GHT reduced IBS symptoms and psychological burden. Nevertheless, only small changes were found in intestinal microbiota composition. The authors proposed that GHT may act by means of central nervous impact and further factors that are basically independent of microbiota composition, modulating the brain-gut axis, perhaps alterations in vagus nerve functioning and microbiota metabolism. Shahbazi et al. [201] compared the efficacy of standard medical treatment alone and hypnotherapy plus standard medical treatment on quality of life in IBS patients. The authors found that psychological intervention, especially hypnotherapy, in addition to standard medical therapy, can contribute to improving quality of life, pain and fatigue, and psychiatric disorders in treatment-resistant patients with IBS. In addition, therapeutic costs, hospital stays, and days off work can be reduced, and patient efficiency increased. Shahbazi et al. [201] suggested that gastroenterologists, psychologists, nurses, and psychiatrists cooperate in treating IBS patients. Hasan et al. [183] performed the largest randomized study of gut-focused hypnotherapy (GFH) to date. The authors found that six sessions of hypnotherapy produced similar levels of improvement in IBS symptoms compared with 12 sessions. However, the main limitation of this randomized study was the lack of long-term follow-up data to determine the persistence of the effects of abbreviated hypnotherapy, which should be examined in the future. The relevant studies supporting the utility of hypnotherapy in IBS treatment are shown in Table 1 [85,[182], [183], [184], [185], [186], [187], [188], [189],191,[193], [194], [195], [196], [197],199,202].
腸管焦点催眠療法 (GFH) はIBSの初期症状を改善するだけでなく、結腸以外の症状、不安、抑うつを軽減し、生活の質と認知機能を改善する [194, 195]。催眠療法はIBSの小児に特に有効である [189, 196, 197]。Hasanら [198]は、IBSに関してSkype催眠療法が有意な改善をもたらし、対面治療とほぼ同等の効果があったことを示した (Skype催眠療法の転帰は65%、対面治療は76%)。Ruttenら [199]は、IBSまたは機能性腹痛 (FAP) の小児を対象にランダム化比較試験を実施し、資格のある療法士による個別の催眠療法の費用対効果を、CDに記録した自宅での自己運動による腸管指向催眠療法(GHT)と比較した。CDによる催眠療法は、セラピストによる催眠療法と同程度(またはわずかに低い)であることを、同研究者らは見出した。Peterら [200] は、IBS患者およびGHT前後の精神的苦痛の微生物組成を調査した。著者らは、GHTがIBS症状および心理的負担を軽減することを見出した。それにもかかわらず、腸内微生物叢組成の変化はわずかであった。著者らは、GHTが中枢神経への影響と、基本的に微生物叢の組成に依存しないさらなる因子、脳-腸軸の調節、おそらく迷走神経機能および微生物叢代謝の変化によって作用する可能性を提唱した。Shahbaziら [201]は、IBS患者の生活の質(QOL)に対する標準的薬物療法単独と催眠療法+標準的薬物療法の有効性を比較した。著者らは、心理学的介入、特に催眠療法は、標準的な薬物療法に加えて、治療抵抗性のIBS患者のQOL、疼痛および疲労、精神障害の改善に寄与する可能性があることを見出した。さらに、治療費、入院期間、および休職日を減らすことができ、患者の効率が向上する。Shahbaziら [201] は、消化器専門医、心理学者、看護師、精神科医がIBS患者の治療に協力することを提案している。Hasanら [183] は、腸焦点催眠療法 (GFH) に関するこれまでで最大規模のランダム化試験を実施した。同著者らは、6回の催眠療法では、12回の催眠療法と比較してIBS症状が同程度に改善したことを見出した。しかしながら、このランダム化研究の主な限界は、短縮催眠療法の効果の持続性を決定する長期追跡データがないことであり、これは将来調査されるべきである。IBS治療における催眠療法の有用性を支持する関連研究を表1に示す[85, 182, 183, 184, 185, 186, 187, 188, 189, 191, 193, 194, 195, 196, 197, 199, 202]。
表１：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9849985/table/tbl1/
10. Summary with hypothesis(仮説を伴う要約)
The ENS is the “first brain’ in the evolutionary process that is specifically a complex, autonomous nervous system that develops before and independently of the CNS [12,13]. The diversity of neuronal and glial subtypes and neurotransmitters in the ENS is similarly rich as in the CNS [17]. It was proposed that the ENS may perform implicit learning and memorization, and therefore, it may work similarly to a “little brain” in the gut [7,52,53].
腸管神経系(ENS)は進化の過程における『最初の脳』であり、特に複雑な自律神経系であり、中枢神経系(CNS)よりも前に独立して発達する[12, 13]。ENSにおけるニューロンおよびグリアのサブタイプと神経伝達物質の多様性は、CNSと同様に豊富である [17]。ENSは潜在的な学習と記憶を行う可能性があり、したがって、腸内の[7, 52, 53]と同様に機能する可能性があると提唱されている。
Numerous studies have suggested that psychiatric and mood disorders may play a key role in the development and maintenance of IBS [2,[92], [93], [94],97].
数多くの研究から、精神疾患や気分障害がIBSの発症と維持に重要な役割を果たしている可能性が示唆されている[2, 92, 93, 94, 97]。
SMDs could also be a considerable source of IBS development [104–113].
SMDもIBS発症の重要な原因となりうる [104-113]。
IBS develops mainly during the prenatal, perinatal, postnatal, and early adolescent stages, when the developing ENS is still very vulnerable to stress factors, which produces dysfunctions of the ENS and contributes to the development of chronic diseases in later adulthood [[129], [130], [131], [132],203,204]. Maternal prenatal and postnatal anxiety and depression, neonatal maternal separation (MS), and early adverse life events such as sexual and physical abuse or emotional trauma are substantial vulnerability factors that predispose to gastrointestinal diseases and development of adult IBS [133–142].
IBSは主に出生前、周産期、出生後、および青年期初期に発症し、この時期には発達中のENSがストレス因子に対して依然として非常に脆弱であり、ストレス因子はENSの機能障害を引き起こし、成人期後期の慢性疾患発症の一因となる[129, 130, 131, 132, 203, 204]。母親の出生前および出生後の不安および抑うつ、新生児の母親分離 (MS)、および性的虐待および身体的虐待または精神的トラウマのような人生の初期の有害事象は、胃腸疾患および成人IBSの発症の素因となる実質的な脆弱性因子である [133–142]。
IBS can accumulate in families and be inherited across generations [143–145]. MS-induced visceral hypersensitivity can be transferred across generations [147]. The incidence of IBS is higher in first-degree blood relatives than in spouses of patients, and genetic and psychological factors can be more important than environmental factors [146]. Twin studies emphasize that genetic and psychological processes may explain familial clustering of IBS and that both heredity and social learning contribute to its aetiology [[148], [149], [150], 205, 206].
IBSは家族内に蓄積し、世代を超えて遺伝する可能性がある [143-145]。MS誘発性の内臓過敏症は世代を超えて伝達する可能性がある [147]。IBSの発生率は患者の配偶者よりも１親等血縁者で高く、遺伝的および心理的要因が環境要因よりも重要である可能性がある [146]。双生児研究は、遺伝的および心理学的プロセスがIBSの家族内集積を説明し、遺伝と社会的学習の両方がその病因に寄与することを強調している [148, 149, 150, 205, 206]。
Quoted from Hurwitz [207]; “Somatization is the psychological mechanism whereby psychological distress is expressed in the form of physical symptoms”. IBS is strongly associated with somatization and psychosocial morbidities [71,72,119]. It is not surprising that somatization is often associated with psychological distress [208,209,210].
Hurwitz [207] からの引用：「身体化とは、心理的な苦痛が身体的な症状という形で表現される心理的なメカニズムです。」IBSは身体化および心理社会的病的状態と強く関連している[71, 72, 119]。身体化がしばしば心理的苦痛と関連していることは驚くにあたらない [208, 209, 210]。
Various studies have demonstrated the significant efficacy of hypnosis in the treatment of IBS [85,[183], [184], [185], [186], [187], [188], [189], [190], [191], [192], [193]]. Gut-directed hypnotherapy can not only improve the primary symptoms of IBS but also reduce noncolon symptoms, anxiety, and depression and improve quality of life and cognitive function [194,195]. Hypnotherapy is particularly effective in children with IBS [189,196,197]. The favourable effects of hypnosis on IBS may be because hypnosis allows access to unconscious brain processes that could modulate stress-associated unconscious (implicit) information originating from the ENS [9,10,180,181] and the mind-brain axis in patients with IBS [11].
様々な研究がIBSの治療における催眠の有意な有効性を示している [85, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193]。腸管指向催眠療法はIBSの主要症状を改善するだけでなく、結腸以外の症状、不安、抑うつを軽減し、生活の質と認知機能を改善する [194, 195]。催眠療法はIBSの小児に特に有効である [189, 196, 197]。IBSに対する催眠の好ましい効果は、IBS患者のENS [9, 10, 180, 181]および心-脳軸 [11]から生じるストレス関連の無意識の (潜在的) 情報を調節する可能性のある無意識の脳プロセスへのアクセスを可能にするためであろう。
HYPOTHESIS (see Fig. 2): In most cases, mainly during prenatal, perinatal, postnatal, and early age states, (when the developing ENS and CNS are still very vulnerable) epigenetically inherited or/and psychologically induced stress (maternal separation, depression, anxiety, etc.) produce stress-induced long-term implicit memories in the ENS. These stress-induced memories may persist throughout life by epigenetic processes in the ENS. The ENS and CNS normally communicate bidirectionally via the gut-brain axis; however, the ENS can also function independently.
仮説(図2参照)：ほとんどの場合、主に出生前、周産期、出生後、および若年齢期(発達中のENSとCNSがまだ非常に脆弱なとき)に、エピジェネティックに遺伝的または心理的に誘発されたストレス(母親の離別、抑うつ、不安など。)によって、ENSにストレス誘発性の長期潜在記憶が生じる。これらのストレス誘発記憶は、ENSにおけるエピジェネティック過程により生涯持続する可能性がある。ENSとCNSは通常、腸-脳軸を介して双方向に連絡している；ただし、ENSは独立して機能することもできます。
Fig. 2
Visualization of the key aspects of our hypothesis.
図 2
私たちの仮説の重要な側面の視覚化。
Stress-induced long-term implicit ENS information can be transmitted to the CNS via the gut-brain axis, causing structural and functional abnormalities and dysregulation of affective and pain processing in the CNS. As a result, perturbed cortical-limbic circuits in the CNS produce psychological alterations with increased subjective pain perception (somatization) and negative emotions. The CNS tries to decrease the effect of the stress-induced signal from the ENS, although the ENS continuously sends stress-induced long-term (implicit) epigenetic information to the CNS via the gut-brain axis.
ストレスが誘導する長期潜在的ENS情報は、腸‐脳軸を介してCNSに伝達され、CNSにおける構造的および機能的異常と情動および疼痛処理の調節不全を引き起こす。その結果、CNSの皮質‐辺縁系回路の乱れは、主観的な痛覚 (身体化) および否定的感情の増加を伴う心理的変化を引き起こす。CNSはENSからのストレス誘導シグナルの影響を減らそうとするが、ENSは腸‐脳軸を介してCNSにストレス誘導長期(潜在的)エピジェネティック情報を継続的に送る。
Under the hypnotic state, patients with IBS can access their emotional level, i.e., the cortical-limbic circuit, via top-down induced processes, which could decrease subjective pain perception (visceral hypersensitivity, somatization) in the CNS as well as the stress-related inflammatory response in the gut. This hypothesis may partially explain why there is no real effective treatment for IBS (i.e., it due to the stress-related long-term implicit information from ENS) and why hypnosis may be one of the most effective methods for alleviating the symptoms of IBS.
催眠状態下で、IBS患者はトップダウン誘導プロセスを介して感情レベル、すなわち皮質‐辺縁系回路にアクセスすることができ、これは腸におけるストレス関連の炎症反応と同様にCNSにおける主観的疼痛知覚(内臓過敏症、身体化)を減少させる可能性がある。この仮説は、IBSに実際に効果的な治療法がない理由(すなわち、ENSからのストレス関連長期暗黙情報によるものである。)と、催眠がIBSの症状を緩和する最も効果的な方法の１個である理由を部分的に説明する可能性がある。
Funding
This work was not supported by any funding.
Author contributors
I.B. developed the concept. N.Cs-N. and I.B. contributed to the writing of the manuscript.
Declaration of competing interest
The authors report no financial and non-financial conflicts of interests. The authors alone are responsible for all the content.
Acknowledgments
The authors are grateful for the critical comments by Prof. Michael Schemann.
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