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Bile acid abnormality induced by intestinal dysbiosis might explain lipid metabolism in Parkinson’s disease
Medical Hypotheses 134 (2020) 109436
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Bile acid abnormality induced by intestinal dysbiosis might explain lipid metabolism in Parkinson’s disease
T
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Yuhei Hasuikea,b, , Takuyuki Endoa, Michiyo Koroyasua, Misa Matsuia, Chiaki Moria, Misaki Yamaderaa, Harutoshi Fujimuraa, Saburo Sakodaa,c a
Department of Neurology, NHO Osaka Toneyama Medical Center, Toyonaka, Osaka, Japan Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan c Organic Clinic, Toyonaka, Osaka, Japan b
A B S T R A C T
Intestinal dysbiosis refers to an imbalance in the intestinal flora. The concept of small intestinal bacterial overgrowth (SIBO), a condition of abnormal proliferation of the small intestine microbiota, has been proposed as a form of small intestine dysbiosis. In Parkinson’s disease patients, weight loss and metabolic disorders such as lipid abnormalities are frequently encountered. This was a prospective investigation of the presence of SIBO using the lactulose breath test, Parkinson’s disease symptoms, medications, abdominal symptoms, and blood data involving 39 Parkinson’s disease patients. Of the 39 patients, 19 were positive for SIBO, 16 were negative, and 4 were equivocal. SIBO-positive patients had a significantly smaller dopaminergic drug load (dopamine replacement of Parkinson’s disease drug potency) (P = 0.009) and significantly lower serum triglyceride (TG) (P = 0.024) and total bilirubin (P = 0.019) levels. No relationship was seen between the presence or absence of SIBO and motor or abdominal symptoms. The following hypothesis was developed with regard to the possibility that intestinal bacterial overgrowth has various effects that are exhibited via bile acid metabolism in Parkinson’s disease patients. Serum bilirubin levels become higher as bilirubin metabolism declines with decreases in the intestinal bacteria. At the same time, bile acid is broken down due to increased intestinal bacteria, and lipid absorption decreases. This induces low serum TG levels and leads to weight loss. By a similar mechanism, there is less absorption of vitamin D as bile acid levels decrease, leading to osteoporosis and fractures. The possibility that some of the non-motor manifestations accompanying Parkinson’s disease are caused by intestinal dysbiosis needs to be considered.
Introduction Parkinson’s disease (PD) is a neurodegenerative disorder with muscle rigidity, tremors, and bradykinesia as the predominant manifestations. The pathological signs of PD are α-synuclein (Lewy bodies) deposited in the central nervous system and the gradual spread of lesions that first appear in the dorsal motor nucleus of the vagal nerves and anterior olfactory nucleus and then spread toward the cortical area via the brainstem [1]. In addition to the motor manifestations of PD, non-motor manifestations are important clinically, and sensory impairment (anosmia, dysgeusia, numbness, pain), cognitive dysfunction (executive function disorders), neuropsychiatric disorders (depression, apathy, anxiety), and autonomic dysfunction (constipation, orthostatic hypotension) are well known [2]. Osteoporosis has also attracted attention as a “hidden nonmotor face of Parkinson’s disease” [3]. In a number of observational and casecontrol studies, PD has been shown to be independently associated with lower bone mineral density (BMD) [4]. Lumbar compression fractures are especially common in PD [5], and such fractures lower activities of daily living (ADL) and shorten remaining life expectancy.
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Weight loss and reduced BMI are other reported signs of PD [6]. The causes are explained to include poor oral intake, dysphagia, and decreased muscle strength, but weight loss preceding a diagnosis of PD is seen in some cases [7] and is thought to be an independent factor leading to significantly decreased quality of life (QOL) [8,9]. Serological abnormalities have also been found in PD patients. Examples are decreased triglyceride (TG), very-low-density lipoprotein cholesterol (VLDL-C), and apolipoprotein B (apoB) [10] levels, decreased vitamin D [11], and elevated bilirubin levels [12,13]. However, little effort has been made to grasp the overall picture. In this study, an attempt was made to understand the findings reported above based on abnormalities in intestinal flora. Hypothesis It has been reported that, in PD, α-synuclein is deposited in gastrointestinal tract nerve plexuses during the stage before pathological involvement of the central nervous system [14]. Gastrointestinal α-synuclein has been shown to promote intestinal permeability and may also be related to increased Gram-negative bacteria [15], suggesting the
Corresponding author at: Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565–0871, Japan. E-mail address: [email protected] (Y. Hasuike).
https://doi.org/10.1016/j.mehy.2019.109436 Received 8 July 2019; Received in revised form 9 September 2019; Accepted 14 October 2019 0306-9877/ © 2019 Elsevier Ltd. All rights reserved.
Medical Hypotheses 134 (2020) 109436
Y. Hasuike, et al.
possibility that PD is associated with intestinal flora. An abnormality in the composition of intestinal bacterial species is called dysbiosis. This term is taken as an antonym of symbiosis, which in this context means a normal symbiotic relationship between intestinal flora and host. It refers to changes such as a decrease in the number or variety of bacterial species, an abnormal increase in a specific bacterial species, or a decrease in a bacterial species that normally should be predominant [16]. The possibility of a relationship between intestinal dysbiosis and not only gastrointestinal diseases such as irritable bowel syndrome (IBS) and functional gastrointestinal (GI) disorders, but also various other diseases including obesity, diabetes mellitus, and autism has attracted attention [17,18]. Small intestinal dysbiosis may also be related to various symptoms. In the normal state, the ileal valve blocks retrograde migration of bacteria from the colon to the ileum, and the small intestinal bacteria exist only in numbers less than 100,000/ml of small intestinal aspirate. However, abnormal proliferation of small intestinal bacteria may occur for some reason (above 105 colony-forming units/mL in culture of small intestinal aspirate), and this is called small intestinal bacterial overgrowth (SIBO). The major symptoms of SIBO are abdominal pain, a sense of abdominal fullness, diarrhea, and malabsorption [19]. SIBO is reportedly associated with inflammatory bowel diseases such as IBS, liver disease, obesity, and autism, among others [20–22]. Compared with healthy people, PD patients are reported to have a decreased number and variety of bacterial species [23,24]. The relationship between PD and Helicobacter pylori has also been reported [25,26]. No studies have directly surveyed the bacterial flora in the small intestine in PD patients, but it has been assessed with breath tests that indirectly measure hydrogen-producing bacteria in the small intestine. The prevalence of SIBO is said to be 25–50% in PD patients, higher than that in healthy people [27–30]. Physiologically, intestinal bacteria in the small intestine serve important roles in the metabolism of bile acid and bilirubin. We considered the possibility that, in PD, non-motor manifestations such as osteoporosis and weight loss and blood test abnormalities, including of lipid, bilirubin, and vitamin levels, are induced by intestinal dysbiosis.
test sugar (10 g lactulose, 100 g glucose, 50 g lactose). PD patients having reduced swallowing function are at high risk for aspiration. Therefore, the LBT was performed to achieve higher diagnostic accuracy and safety. In the LBT, hydrogen gases are measured in the breath at time intervals of 15 min for 4 h after the intake of 10 g of lactulose. Tests were judged as positive for SIBO when hydrogen gas levels rose by an abnormal amount (over 20 ppm) above baseline. Since PD patients have slow gastrointestinal transit, hydrogen gas levels rising within 2 h is positive, and gas levels rising in 2–3.5 h is equivocal for SIBO. Subjects completed questionnaires on gastrointestinal symptoms and a food frequency questionnaire using Excel Eiyo-kun Food Frequency Questionnaire Based on Food Groups FFQg Ver.3.5, and laboratory tests were conducted. PD symptoms were assessed using section III of the Unified Parkinson’s Disease Rating Scale (UPDRS part III) in the ON-medication state. Dyskinesia was judged by a neurologist when the patient was in the ON-medication state. Wearing off and delayed-on were judged based on symptom diaries completed by the patients. To assess PD medication, the dopaminergic drug load was determined, which was calculated by referring to total drug burden (TDB) defined by the total daily intake of L-dopa equivalent over a 24-h period based on the National Institute for Health and Clinical Excellence (NICE) Clinical Guideline 35 [31]. To detect Helicobacter pylori, all patients were examined by three tests, the urea breath test, antibody measurement in the blood, and the rapid urease test. If even one test was positive, it was judged positive for H. pylori. Data are expressed as means and standard deviations. The chisquared test and Mann-Whitney test were used to compare differences. All statistical analyses were performed with SPSS for Windows, version 24.0. Differences were considered significant when the P value was less than 0.05. Results Of the 39 patients enrolled, 19 tested positive, 16 tested negative, and 4 tested equivocal for SIBO. The SIBO prevalence was 54.3%. SIBOpositive patients had significantly lower total drug burden, expressed as dopamine replacement of PD drug potency (P = 0.009), and showed lower serum triglyceride (TG) (P = 0.024) and total bilirubin (P = 0.019) levels. SIBO was not significantly associated with gastrointestinal symptoms and motor function (Table 2).
Study subjects Data were collected prospectively from a consecutive case series of PD patients. A total of 39 PD patients were prospectively evaluated for SIBO using the lactulose breath test (LBT). Patients with a diagnosis of type 2 diabetes mellitus, systemic diseases that potentially affect gastrointestinal motility, and who were using drugs that affect the intestinal flora (such as antibiotics) were excluded (Table 1).
Discussion In this study, the dosage of antiparkinsonian drugs was significantly lower in SIBO-positive patients, and serum TG and bilirubin levels were lower, even though there was no difference in caloric intake.
Protocols
Parkinson’s disease and intestinal dysbiosis
Although aspiration of the small bowel is considered to be the current gold standard for diagnosis of SIBO, hydrogen breath tests using various substrates such as glucose, lactulose, and fructose are commonly used because of their non-invasiveness. Subjects need to ingest a
In previous studies, reports of greater numbers of unpredictable off, delayed-on, and no-on in SIBO-positive patients are occasionally seen, and it is conjectured that drug absorption may be blocked by the increased small intestinal bacteria, prolonging the off time [29,30]. However, no such trend was seen in the present patients, and the total dosage of antiparkinsonian drugs was lower in SIBO-positive patients, despite there being no difference in motor function. The reasons are thought to be as follows. When there is an increase in bacteria that generate hydrogen among the intestinal bacteria, it is possible that the condition of PD itself is improved. No studies have directly suggested an effect of hydrogen-producing bacteria on PD, but it has been shown molecularly that hydrogen lessens oxidative stress and is a potential means of treatment [32]. Clostridium, a genus of bacteria that is presumed to produce hydrogen, contributes to the differentiation and proliferation of regulatory T cells in the intestines [33], and it may be a factor that regulates intestinal inflammation and
Table 1 Clinical features of patients with Parkinson’s disease. Overall (n = 39) Male/female Age (y) BMI (kg/m2) Disease duration (y) Levodopa intake (mg/day) dopaminergic drug load (mg/day) UPDRS Part III
17/22 66.9 ± 10.4 22.3 ± 4.3 7.2 ± 5.1 257.1 ± 184.8 619.1 ± 593.6 27.5 ± 11.6
BMI, body mass index; UPDRS part III, motor section of the Unified Parkinson’s Disease Rating Scale 2
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Bilirubin and intestinal dysbiosis in Parkinson’s disease patients
Table 2 Clinical symptoms and laboratory data in relation to SIBO.
Male/female Age (y) BMI (kg/㎡) Disease duration (y) Levodopa intake (mg/day) dopaminergic drug load (mg/ day) UPDRS Part III, Wearing off (%) Dyskinesia (%) Delayed-on (%) Gastrointestinal symptom Bloating (%) Abdominal pain (%) Abdominal discomfort (%) Diarrhea (%) Constipation (%) Helicobacter pylori-positive (%)
Total protein (g/dl) Albumin (g/dl) Total bilirubin (mg/dl) Total cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) TG (mg/dl) Total energy (kcal/day) Protein (g/day) Fat (g/day) Carbohydrate (g/day)
SIBO− (n = 16)
SIBO＋ (n = 19)
P value
7/9 68.0 ± 5.4 22.5 ± 2.2 7.6 ± 2.5 315.6 ± 105.5 878.1 ± 411.6
9/10 64.9 ± 6.3 22.1 ± 2.2 6.5 ± 2.0 207.9 ± 78.0 401.1 ± 117.0
0.301 0.481 0.589 0.117 0.009
25.8 ± 6.0 11(68.8) 8(50.0) 4(25.0)
29.3 ± 5.7 9(47.4) 6(31.6) 2(10.5)
0.385 0.306 0.268 0.379
5(31.3) 1(6.3) 3(18.8) 3(18.8) 13(81.3) 7(43.8)
6(31.6) 2(10.5) 4(21.1) 2(10.5) 14(73.7) 6(31.6)
0.983 0.566 0.602 0.415 0.452 0.458
SIBO− (n = 16)
SIBO＋ (n = 19)
P value
6.9 ± 0.4 3.9 ± 0.2 0.98 ± 0.21 205 ± 27 60.4 ± 13.4 121.7 ± 19.4 100.2 ± 28.6 1722 ± 199 64.7 ± 7.7 56.0 ± 6.8 230.8 ± 28.9
6.6 ± 0.3 3.7 ± 0.2 0.86 ± 0.26 190 ± 30 55.6 ± 9.8 121.5 ± 21.0 72.8 ± 12.7 1570 ± 131 60.8 ± 6.5 48.0 ± 7.1 215.3 ± 22.7
0.607 0.410 0.019 1.000 0.813 0.820 0.024 0.357 0.442 0.091 0.301
Bilirubin is a component of hemoglobin that undergoes glucuronidation in the liver to become conjugated bilirubin and is secreted as part of the bile into the duodenum. It is reduced by the action of the intestinal flora and metabolized to urobilinogen. A certain amount is reabsorbed in the small intestine and excreted in the urine via the kidneys. There is no consensus with regard to serum bilirubin in PD, but there are reports that the bilirubin level is elevated [12,13], and that high bilirubin levels are correlated with worse motor function [13]. The bilirubin level increases due to overexpression of heme oxygenase (HO) from the compensatory response of oxidative stress, and the possibility that it is a useful marker for the initial diagnosis of PD has been suggested [13]. In hyperbilirubinemic rats (Gunn rats), eradication of intestinal bacteria that break down bilirubin with oral antibiotics resulted in high serum bilirubin levels and low urobilinogen levels in feces [35]. A relationship between serum bilirubin and intestinal bacteria has also been shown in humans, and physiologic jaundice, a type of neonatal jaundice, may be caused by delayed development of the intestinal flora [36]. Hyperbilirubinemia is more frequent in preterm infants than in full-term infants [37]. Normally obligate anaerobes such as Bifidobacterium become dominant 3–4 days after birth [38], but in premature infants, fewer obligate anaerobes are seen [39,40]. The possibility that intestinal bacteria centered on Bifidobacterium prevent hyperbilirubinemia has been suggested [41]. In PD, the intestinal bacteria count decreases with progression of the disease, and the decrease in Bifidobacterium over the course has been shown to be significantly related to lower UPDRS scores [42]. These findings suggest that intestinal bacteria, particularly obligate anaerobes, play important roles related to bilirubin metabolism in PD patients. Especially in patients with decreased hydrogen-producing bacteria in the small intestine (SIBO-negative patients), bilirubin metabolism may decline, and conjugated bilirubin may increase with the decrease in obligate anaerobes, thereby increasing serum bilirubin levels.
BMI, body mass index; UPDRS part III, motor section of the Unified Parkinson’s Disease Rating Scale LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; TG: triglycerides
promotes intestinal permeability, inhibiting the accumulation of gastrointestinal α-synuclein. Although no studies have surveyed the actual bacterial flora in the small intestine, in a study comparing the bacterial flora in stool in PD patients with that in healthy people, the total bacteria count itself was lower in PD patients. Clostridium coccoides, C. leptum, and Bacteroides fragilis were significantly decreased, and Lactobacillus was increased [24]. Most Clostridium and B. fragilis are thought to be bacteria that produce hydrogen [34], suggesting a decrease in hydrogen-producing bacterial flora. PD patients who were negative on the LBT included some in whom no elevation at all was seen in the hydrogen level until after 4 h, and it may be that, in patients negative on the breath test, there is a decrease in bacteria that produce hydrogen not only in the small intestine, but in the large intestine as well. Intestinal dysbiosis due to such a decrease in hydrogen-producing bacteria may contribute to a worsening of oxidative stress in PD. A relationship has been suggested between SIBO, centered on IBS and other gastrointestinal diseases, constipation, a sense of abdominal fullness, and other conditions. However, despite the large number of PD patients who complain of abdominal symptoms such as constipation and a sense of abdominal fullness, almost no studies have suggested an important relationship between SIBO and abdominal symptoms. The present study also did not find a relationship between SIBO and abdominal symptoms. In PD, there is a large change not only in bacteria that produce hydrogen, but also in the composition of the intestinal flora [24]. The LBT identifies only hydrogen-producing bacteria in the small intestine, and it may not reflect the proliferation of total bacteria in the small intestine accurately.
Bile acid and intestinal dysbiosis in Parkinson’s disease patients Bile acid is synthesized from cholesterol in the liver and secreted into the duodenum via the gallbladder and bile duct as the main component of bile. Primary bile acids produced in hepatocytes are metabolized into secondary bile acids by intestinal bacteria in the small intestine. Afterwards, like the primary bile acids, the secondary bile acids are also reabsorbed in the small intestine, and together about 95% of bile acids are returned to the liver via the portal vein and secreted in bile. This cycle is called the enterohepatic circulation. Intestinal bacteria convert bile acid conjugated with amino acids in the liver into unconjugated bile acids in which the amino acids have been deconjugated by bile acid’s own enzyme, bile salt hydrolase (BSH). Following this metabolic conversion, dehydroxylation of bile salts is catalyzed by 7α-dehydroxylase or other enzymes in intestinal bacteria, and secondary bile acids are produced [43]. The farnesoid X receptor (FXR) is famous as a sensor that senses bile acids. Intestinal cells themselves also detect bile acid with FXR and inhibit bile acid synthesis in the liver through a small heterodimer partner (SHP) [43]. Antibiotic administration decreases secondary bile acids, which significantly increases bile acid levels by reducing FXR activity [44]. Bile acid has antibacterial activity and is a major regulator of intestinal bacteria. With decreased bile acid, the environment becomes such that abnormal proliferation of intestinal bacteria is more likely to occur [45]. One of the functions of bile acid is to emulsify lipids and form fatty acids or monoglycerides and micelles to assist in lipid absorption of food. Bile acids are also thought to be involved in the regulation of lipid 3
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levels were significantly lower. SIBO is one concept of intestinal dysbiosis, but the breath tests currently used in diagnosis assess only the amount of bacteria that produce hydrogen. They do not consider nonhydrogen-producing bacteria or the composition of bacterial species. Proliferation of hydrogen-producing bacteria in the small intestine is not necessarily bad, and the possibility that it exerts a positive effect in PD has been suggested. The prevalence of gallstones is also thought to be high in PD [49], one of the reasons for which may be the decreased bilirubin metabolism and elevated bilirubin level from decreased intestinal bacteria, including in the large intestine. Low serum triglyceride levels may be due to decreased bile acid and decreased lipid absorption from increased intestinal bacteria, and may explain the relationship between PD and weight loss. Vitamin D absorption may be lower from decreased bile acid with the same mechanism, suggesting that it may be related to osteoporosis and fractures. Intestinal dysbiosis including the small intestine is complex, and further progress in research is awaited. Acknowledgement
Fig. 1. Abnormal lipid metabolism induced by SIBO.
This work was supported by JSPS KAKENHI JP17K00911.
and glucose metabolism through the nuclear receptor FXR [43]. It may be that, when bacteria in the small intestine proliferate abnormally, unconjugated bile acids become dominant, bile acid synthesis is inhibited, and the bile acid level becomes low. Lipid absorption is decreased with decreased bile acid, and serum TG levels may become low. In the SIBO-positive patients in the present study, the low TG levels can be explained by this. It is known that, in PD, there are decreases in BMI and weight in many cases despite nutritional intake. Moreover, PD patients were reported to have reduced body fat with relatively preserved skeletal muscle mass [46], and loss of body fat may be an early phenomenon in PD. Such poor lipid absorption due to intestinal dysbiosis may be one possible reason for this. However, linking intestinal dysbiosis to clinical assessments and an understanding of blood test data is exceedingly difficult. Intestinal dysbiosis is not a condition that can be explained simply by decreases or increases in specific bacterial species, but it is a complex interweaving of type and composition of bacterial strains and the sites of bacterial colonization and, perhaps even more importantly, alterations in metabolic function [47]. Bone fractures are also common in PD. There is a particularly high risk of lumbar compression fractures [5], and PD has been shown to be independently associated with lower BMD [4,48]. Causes of decreased bone density have been shown to include decreased activity and decreased muscle strength, but vitamin D deficiency is also a major cause. Vitamin D deficiency leads to hypocalcemia and compensatory hyperparathyroidism, and excessive parathyroid hormone stimulates osteoclast activity and induces bone resorption [4]. It has also been shown that low serum vitamin D levels tend to occur in PD. Lack of outdoor activity and sun exposure has been given as a reason, but no definite reason has been elucidated [11]. Bile acid function decreases due to SIBO, and not only is lipid absorption decreased, but absorption of lipid-soluble vitamins, mainly vitamin D, is also impaired, and vitamin D levels decrease, which may be related to osteoporosis (Fig. 1). There are some limitations in this study. There is no gold standard for diagnosing SIBO, and it is especially difficult to assess the presence or absence of SIBO in PD with the LBT. Decreased intestinal motility in PD makes accurate assessment of breath tests difficult. Moreover, SIBO evaluates only intestinal bacteria that produce hydrogen, not all intestinal bacteria.
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Conclusion Intestinal dysbiosis is thought to be related to various symptoms in PD, including motor symptoms, lipid abnormalities, and weight loss. In the SIBO-positive group in the present study, the dosage of antiparkinsonian drugs was lower, and serum bilirubin and triglyceride 4
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Bile acid abnormality induced by intestinal dysbiosis might explain lipid metabolism in Parkinson’s disease
T
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Yuhei Hasuikea,b, , Takuyuki Endoa, Michiyo Koroyasua, Misa Matsuia, Chiaki Moria, Misaki Yamaderaa, Harutoshi Fujimuraa, Saburo Sakodaa,c a
Department of Neurology, NHO Osaka Toneyama Medical Center, Toyonaka, Osaka, Japan Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan c Organic Clinic, Toyonaka, Osaka, Japan b
A B S T R A C T
Intestinal dysbiosis refers to an imbalance in the intestinal flora. The concept of small intestinal bacterial overgrowth (SIBO), a condition of abnormal proliferation of the small intestine microbiota, has been proposed as a form of small intestine dysbiosis. In Parkinson’s disease patients, weight loss and metabolic disorders such as lipid abnormalities are frequently encountered. This was a prospective investigation of the presence of SIBO using the lactulose breath test, Parkinson’s disease symptoms, medications, abdominal symptoms, and blood data involving 39 Parkinson’s disease patients. Of the 39 patients, 19 were positive for SIBO, 16 were negative, and 4 were equivocal. SIBO-positive patients had a significantly smaller dopaminergic drug load (dopamine replacement of Parkinson’s disease drug potency) (P = 0.009) and significantly lower serum triglyceride (TG) (P = 0.024) and total bilirubin (P = 0.019) levels. No relationship was seen between the presence or absence of SIBO and motor or abdominal symptoms. The following hypothesis was developed with regard to the possibility that intestinal bacterial overgrowth has various effects that are exhibited via bile acid metabolism in Parkinson’s disease patients. Serum bilirubin levels become higher as bilirubin metabolism declines with decreases in the intestinal bacteria. At the same time, bile acid is broken down due to increased intestinal bacteria, and lipid absorption decreases. This induces low serum TG levels and leads to weight loss. By a similar mechanism, there is less absorption of vitamin D as bile acid levels decrease, leading to osteoporosis and fractures. The possibility that some of the non-motor manifestations accompanying Parkinson’s disease are caused by intestinal dysbiosis needs to be considered.
Introduction Parkinson’s disease (PD) is a neurodegenerative disorder with muscle rigidity, tremors, and bradykinesia as the predominant manifestations. The pathological signs of PD are α-synuclein (Lewy bodies) deposited in the central nervous system and the gradual spread of lesions that first appear in the dorsal motor nucleus of the vagal nerves and anterior olfactory nucleus and then spread toward the cortical area via the brainstem [1]. In addition to the motor manifestations of PD, non-motor manifestations are important clinically, and sensory impairment (anosmia, dysgeusia, numbness, pain), cognitive dysfunction (executive function disorders), neuropsychiatric disorders (depression, apathy, anxiety), and autonomic dysfunction (constipation, orthostatic hypotension) are well known [2]. Osteoporosis has also attracted attention as a “hidden nonmotor face of Parkinson’s disease” [3]. In a number of observational and casecontrol studies, PD has been shown to be independently associated with lower bone mineral density (BMD) [4]. Lumbar compression fractures are especially common in PD [5], and such fractures lower activities of daily living (ADL) and shorten remaining life expectancy.
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Weight loss and reduced BMI are other reported signs of PD [6]. The causes are explained to include poor oral intake, dysphagia, and decreased muscle strength, but weight loss preceding a diagnosis of PD is seen in some cases [7] and is thought to be an independent factor leading to significantly decreased quality of life (QOL) [8,9]. Serological abnormalities have also been found in PD patients. Examples are decreased triglyceride (TG), very-low-density lipoprotein cholesterol (VLDL-C), and apolipoprotein B (apoB) [10] levels, decreased vitamin D [11], and elevated bilirubin levels [12,13]. However, little effort has been made to grasp the overall picture. In this study, an attempt was made to understand the findings reported above based on abnormalities in intestinal flora. Hypothesis It has been reported that, in PD, α-synuclein is deposited in gastrointestinal tract nerve plexuses during the stage before pathological involvement of the central nervous system [14]. Gastrointestinal α-synuclein has been shown to promote intestinal permeability and may also be related to increased Gram-negative bacteria [15], suggesting the
Corresponding author at: Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565–0871, Japan. E-mail address: [email protected] (Y. Hasuike).
https://doi.org/10.1016/j.mehy.2019.109436 Received 8 July 2019; Received in revised form 9 September 2019; Accepted 14 October 2019 0306-9877/ © 2019 Elsevier Ltd. All rights reserved.
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possibility that PD is associated with intestinal flora. An abnormality in the composition of intestinal bacterial species is called dysbiosis. This term is taken as an antonym of symbiosis, which in this context means a normal symbiotic relationship between intestinal flora and host. It refers to changes such as a decrease in the number or variety of bacterial species, an abnormal increase in a specific bacterial species, or a decrease in a bacterial species that normally should be predominant [16]. The possibility of a relationship between intestinal dysbiosis and not only gastrointestinal diseases such as irritable bowel syndrome (IBS) and functional gastrointestinal (GI) disorders, but also various other diseases including obesity, diabetes mellitus, and autism has attracted attention [17,18]. Small intestinal dysbiosis may also be related to various symptoms. In the normal state, the ileal valve blocks retrograde migration of bacteria from the colon to the ileum, and the small intestinal bacteria exist only in numbers less than 100,000/ml of small intestinal aspirate. However, abnormal proliferation of small intestinal bacteria may occur for some reason (above 105 colony-forming units/mL in culture of small intestinal aspirate), and this is called small intestinal bacterial overgrowth (SIBO). The major symptoms of SIBO are abdominal pain, a sense of abdominal fullness, diarrhea, and malabsorption [19]. SIBO is reportedly associated with inflammatory bowel diseases such as IBS, liver disease, obesity, and autism, among others [20–22]. Compared with healthy people, PD patients are reported to have a decreased number and variety of bacterial species [23,24]. The relationship between PD and Helicobacter pylori has also been reported [25,26]. No studies have directly surveyed the bacterial flora in the small intestine in PD patients, but it has been assessed with breath tests that indirectly measure hydrogen-producing bacteria in the small intestine. The prevalence of SIBO is said to be 25–50% in PD patients, higher than that in healthy people [27–30]. Physiologically, intestinal bacteria in the small intestine serve important roles in the metabolism of bile acid and bilirubin. We considered the possibility that, in PD, non-motor manifestations such as osteoporosis and weight loss and blood test abnormalities, including of lipid, bilirubin, and vitamin levels, are induced by intestinal dysbiosis.
test sugar (10 g lactulose, 100 g glucose, 50 g lactose). PD patients having reduced swallowing function are at high risk for aspiration. Therefore, the LBT was performed to achieve higher diagnostic accuracy and safety. In the LBT, hydrogen gases are measured in the breath at time intervals of 15 min for 4 h after the intake of 10 g of lactulose. Tests were judged as positive for SIBO when hydrogen gas levels rose by an abnormal amount (over 20 ppm) above baseline. Since PD patients have slow gastrointestinal transit, hydrogen gas levels rising within 2 h is positive, and gas levels rising in 2–3.5 h is equivocal for SIBO. Subjects completed questionnaires on gastrointestinal symptoms and a food frequency questionnaire using Excel Eiyo-kun Food Frequency Questionnaire Based on Food Groups FFQg Ver.3.5, and laboratory tests were conducted. PD symptoms were assessed using section III of the Unified Parkinson’s Disease Rating Scale (UPDRS part III) in the ON-medication state. Dyskinesia was judged by a neurologist when the patient was in the ON-medication state. Wearing off and delayed-on were judged based on symptom diaries completed by the patients. To assess PD medication, the dopaminergic drug load was determined, which was calculated by referring to total drug burden (TDB) defined by the total daily intake of L-dopa equivalent over a 24-h period based on the National Institute for Health and Clinical Excellence (NICE) Clinical Guideline 35 [31]. To detect Helicobacter pylori, all patients were examined by three tests, the urea breath test, antibody measurement in the blood, and the rapid urease test. If even one test was positive, it was judged positive for H. pylori. Data are expressed as means and standard deviations. The chisquared test and Mann-Whitney test were used to compare differences. All statistical analyses were performed with SPSS for Windows, version 24.0. Differences were considered significant when the P value was less than 0.05. Results Of the 39 patients enrolled, 19 tested positive, 16 tested negative, and 4 tested equivocal for SIBO. The SIBO prevalence was 54.3%. SIBOpositive patients had significantly lower total drug burden, expressed as dopamine replacement of PD drug potency (P = 0.009), and showed lower serum triglyceride (TG) (P = 0.024) and total bilirubin (P = 0.019) levels. SIBO was not significantly associated with gastrointestinal symptoms and motor function (Table 2).
Study subjects Data were collected prospectively from a consecutive case series of PD patients. A total of 39 PD patients were prospectively evaluated for SIBO using the lactulose breath test (LBT). Patients with a diagnosis of type 2 diabetes mellitus, systemic diseases that potentially affect gastrointestinal motility, and who were using drugs that affect the intestinal flora (such as antibiotics) were excluded (Table 1).
Discussion In this study, the dosage of antiparkinsonian drugs was significantly lower in SIBO-positive patients, and serum TG and bilirubin levels were lower, even though there was no difference in caloric intake.
Protocols
Parkinson’s disease and intestinal dysbiosis
Although aspiration of the small bowel is considered to be the current gold standard for diagnosis of SIBO, hydrogen breath tests using various substrates such as glucose, lactulose, and fructose are commonly used because of their non-invasiveness. Subjects need to ingest a
In previous studies, reports of greater numbers of unpredictable off, delayed-on, and no-on in SIBO-positive patients are occasionally seen, and it is conjectured that drug absorption may be blocked by the increased small intestinal bacteria, prolonging the off time [29,30]. However, no such trend was seen in the present patients, and the total dosage of antiparkinsonian drugs was lower in SIBO-positive patients, despite there being no difference in motor function. The reasons are thought to be as follows. When there is an increase in bacteria that generate hydrogen among the intestinal bacteria, it is possible that the condition of PD itself is improved. No studies have directly suggested an effect of hydrogen-producing bacteria on PD, but it has been shown molecularly that hydrogen lessens oxidative stress and is a potential means of treatment [32]. Clostridium, a genus of bacteria that is presumed to produce hydrogen, contributes to the differentiation and proliferation of regulatory T cells in the intestines [33], and it may be a factor that regulates intestinal inflammation and
Table 1 Clinical features of patients with Parkinson’s disease. Overall (n = 39) Male/female Age (y) BMI (kg/m2) Disease duration (y) Levodopa intake (mg/day) dopaminergic drug load (mg/day) UPDRS Part III
17/22 66.9 ± 10.4 22.3 ± 4.3 7.2 ± 5.1 257.1 ± 184.8 619.1 ± 593.6 27.5 ± 11.6
BMI, body mass index; UPDRS part III, motor section of the Unified Parkinson’s Disease Rating Scale 2
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Bilirubin and intestinal dysbiosis in Parkinson’s disease patients
Table 2 Clinical symptoms and laboratory data in relation to SIBO.
Male/female Age (y) BMI (kg/㎡) Disease duration (y) Levodopa intake (mg/day) dopaminergic drug load (mg/ day) UPDRS Part III, Wearing off (%) Dyskinesia (%) Delayed-on (%) Gastrointestinal symptom Bloating (%) Abdominal pain (%) Abdominal discomfort (%) Diarrhea (%) Constipation (%) Helicobacter pylori-positive (%)
Total protein (g/dl) Albumin (g/dl) Total bilirubin (mg/dl) Total cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) TG (mg/dl) Total energy (kcal/day) Protein (g/day) Fat (g/day) Carbohydrate (g/day)
SIBO− (n = 16)
SIBO＋ (n = 19)
P value
7/9 68.0 ± 5.4 22.5 ± 2.2 7.6 ± 2.5 315.6 ± 105.5 878.1 ± 411.6
9/10 64.9 ± 6.3 22.1 ± 2.2 6.5 ± 2.0 207.9 ± 78.0 401.1 ± 117.0
0.301 0.481 0.589 0.117 0.009
25.8 ± 6.0 11(68.8) 8(50.0) 4(25.0)
29.3 ± 5.7 9(47.4) 6(31.6) 2(10.5)
0.385 0.306 0.268 0.379
5(31.3) 1(6.3) 3(18.8) 3(18.8) 13(81.3) 7(43.8)
6(31.6) 2(10.5) 4(21.1) 2(10.5) 14(73.7) 6(31.6)
0.983 0.566 0.602 0.415 0.452 0.458
SIBO− (n = 16)
SIBO＋ (n = 19)
P value
6.9 ± 0.4 3.9 ± 0.2 0.98 ± 0.21 205 ± 27 60.4 ± 13.4 121.7 ± 19.4 100.2 ± 28.6 1722 ± 199 64.7 ± 7.7 56.0 ± 6.8 230.8 ± 28.9
6.6 ± 0.3 3.7 ± 0.2 0.86 ± 0.26 190 ± 30 55.6 ± 9.8 121.5 ± 21.0 72.8 ± 12.7 1570 ± 131 60.8 ± 6.5 48.0 ± 7.1 215.3 ± 22.7
0.607 0.410 0.019 1.000 0.813 0.820 0.024 0.357 0.442 0.091 0.301
Bilirubin is a component of hemoglobin that undergoes glucuronidation in the liver to become conjugated bilirubin and is secreted as part of the bile into the duodenum. It is reduced by the action of the intestinal flora and metabolized to urobilinogen. A certain amount is reabsorbed in the small intestine and excreted in the urine via the kidneys. There is no consensus with regard to serum bilirubin in PD, but there are reports that the bilirubin level is elevated [12,13], and that high bilirubin levels are correlated with worse motor function [13]. The bilirubin level increases due to overexpression of heme oxygenase (HO) from the compensatory response of oxidative stress, and the possibility that it is a useful marker for the initial diagnosis of PD has been suggested [13]. In hyperbilirubinemic rats (Gunn rats), eradication of intestinal bacteria that break down bilirubin with oral antibiotics resulted in high serum bilirubin levels and low urobilinogen levels in feces [35]. A relationship between serum bilirubin and intestinal bacteria has also been shown in humans, and physiologic jaundice, a type of neonatal jaundice, may be caused by delayed development of the intestinal flora [36]. Hyperbilirubinemia is more frequent in preterm infants than in full-term infants [37]. Normally obligate anaerobes such as Bifidobacterium become dominant 3–4 days after birth [38], but in premature infants, fewer obligate anaerobes are seen [39,40]. The possibility that intestinal bacteria centered on Bifidobacterium prevent hyperbilirubinemia has been suggested [41]. In PD, the intestinal bacteria count decreases with progression of the disease, and the decrease in Bifidobacterium over the course has been shown to be significantly related to lower UPDRS scores [42]. These findings suggest that intestinal bacteria, particularly obligate anaerobes, play important roles related to bilirubin metabolism in PD patients. Especially in patients with decreased hydrogen-producing bacteria in the small intestine (SIBO-negative patients), bilirubin metabolism may decline, and conjugated bilirubin may increase with the decrease in obligate anaerobes, thereby increasing serum bilirubin levels.
BMI, body mass index; UPDRS part III, motor section of the Unified Parkinson’s Disease Rating Scale LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; TG: triglycerides
promotes intestinal permeability, inhibiting the accumulation of gastrointestinal α-synuclein. Although no studies have surveyed the actual bacterial flora in the small intestine, in a study comparing the bacterial flora in stool in PD patients with that in healthy people, the total bacteria count itself was lower in PD patients. Clostridium coccoides, C. leptum, and Bacteroides fragilis were significantly decreased, and Lactobacillus was increased [24]. Most Clostridium and B. fragilis are thought to be bacteria that produce hydrogen [34], suggesting a decrease in hydrogen-producing bacterial flora. PD patients who were negative on the LBT included some in whom no elevation at all was seen in the hydrogen level until after 4 h, and it may be that, in patients negative on the breath test, there is a decrease in bacteria that produce hydrogen not only in the small intestine, but in the large intestine as well. Intestinal dysbiosis due to such a decrease in hydrogen-producing bacteria may contribute to a worsening of oxidative stress in PD. A relationship has been suggested between SIBO, centered on IBS and other gastrointestinal diseases, constipation, a sense of abdominal fullness, and other conditions. However, despite the large number of PD patients who complain of abdominal symptoms such as constipation and a sense of abdominal fullness, almost no studies have suggested an important relationship between SIBO and abdominal symptoms. The present study also did not find a relationship between SIBO and abdominal symptoms. In PD, there is a large change not only in bacteria that produce hydrogen, but also in the composition of the intestinal flora [24]. The LBT identifies only hydrogen-producing bacteria in the small intestine, and it may not reflect the proliferation of total bacteria in the small intestine accurately.
Bile acid and intestinal dysbiosis in Parkinson’s disease patients Bile acid is synthesized from cholesterol in the liver and secreted into the duodenum via the gallbladder and bile duct as the main component of bile. Primary bile acids produced in hepatocytes are metabolized into secondary bile acids by intestinal bacteria in the small intestine. Afterwards, like the primary bile acids, the secondary bile acids are also reabsorbed in the small intestine, and together about 95% of bile acids are returned to the liver via the portal vein and secreted in bile. This cycle is called the enterohepatic circulation. Intestinal bacteria convert bile acid conjugated with amino acids in the liver into unconjugated bile acids in which the amino acids have been deconjugated by bile acid’s own enzyme, bile salt hydrolase (BSH). Following this metabolic conversion, dehydroxylation of bile salts is catalyzed by 7α-dehydroxylase or other enzymes in intestinal bacteria, and secondary bile acids are produced [43]. The farnesoid X receptor (FXR) is famous as a sensor that senses bile acids. Intestinal cells themselves also detect bile acid with FXR and inhibit bile acid synthesis in the liver through a small heterodimer partner (SHP) [43]. Antibiotic administration decreases secondary bile acids, which significantly increases bile acid levels by reducing FXR activity [44]. Bile acid has antibacterial activity and is a major regulator of intestinal bacteria. With decreased bile acid, the environment becomes such that abnormal proliferation of intestinal bacteria is more likely to occur [45]. One of the functions of bile acid is to emulsify lipids and form fatty acids or monoglycerides and micelles to assist in lipid absorption of food. Bile acids are also thought to be involved in the regulation of lipid 3
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levels were significantly lower. SIBO is one concept of intestinal dysbiosis, but the breath tests currently used in diagnosis assess only the amount of bacteria that produce hydrogen. They do not consider nonhydrogen-producing bacteria or the composition of bacterial species. Proliferation of hydrogen-producing bacteria in the small intestine is not necessarily bad, and the possibility that it exerts a positive effect in PD has been suggested. The prevalence of gallstones is also thought to be high in PD [49], one of the reasons for which may be the decreased bilirubin metabolism and elevated bilirubin level from decreased intestinal bacteria, including in the large intestine. Low serum triglyceride levels may be due to decreased bile acid and decreased lipid absorption from increased intestinal bacteria, and may explain the relationship between PD and weight loss. Vitamin D absorption may be lower from decreased bile acid with the same mechanism, suggesting that it may be related to osteoporosis and fractures. Intestinal dysbiosis including the small intestine is complex, and further progress in research is awaited. Acknowledgement
Fig. 1. Abnormal lipid metabolism induced by SIBO.
This work was supported by JSPS KAKENHI JP17K00911.
and glucose metabolism through the nuclear receptor FXR [43]. It may be that, when bacteria in the small intestine proliferate abnormally, unconjugated bile acids become dominant, bile acid synthesis is inhibited, and the bile acid level becomes low. Lipid absorption is decreased with decreased bile acid, and serum TG levels may become low. In the SIBO-positive patients in the present study, the low TG levels can be explained by this. It is known that, in PD, there are decreases in BMI and weight in many cases despite nutritional intake. Moreover, PD patients were reported to have reduced body fat with relatively preserved skeletal muscle mass [46], and loss of body fat may be an early phenomenon in PD. Such poor lipid absorption due to intestinal dysbiosis may be one possible reason for this. However, linking intestinal dysbiosis to clinical assessments and an understanding of blood test data is exceedingly difficult. Intestinal dysbiosis is not a condition that can be explained simply by decreases or increases in specific bacterial species, but it is a complex interweaving of type and composition of bacterial strains and the sites of bacterial colonization and, perhaps even more importantly, alterations in metabolic function [47]. Bone fractures are also common in PD. There is a particularly high risk of lumbar compression fractures [5], and PD has been shown to be independently associated with lower BMD [4,48]. Causes of decreased bone density have been shown to include decreased activity and decreased muscle strength, but vitamin D deficiency is also a major cause. Vitamin D deficiency leads to hypocalcemia and compensatory hyperparathyroidism, and excessive parathyroid hormone stimulates osteoclast activity and induces bone resorption [4]. It has also been shown that low serum vitamin D levels tend to occur in PD. Lack of outdoor activity and sun exposure has been given as a reason, but no definite reason has been elucidated [11]. Bile acid function decreases due to SIBO, and not only is lipid absorption decreased, but absorption of lipid-soluble vitamins, mainly vitamin D, is also impaired, and vitamin D levels decrease, which may be related to osteoporosis (Fig. 1). There are some limitations in this study. There is no gold standard for diagnosing SIBO, and it is especially difficult to assess the presence or absence of SIBO in PD with the LBT. Decreased intestinal motility in PD makes accurate assessment of breath tests difficult. Moreover, SIBO evaluates only intestinal bacteria that produce hydrogen, not all intestinal bacteria.
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Conclusion Intestinal dysbiosis is thought to be related to various symptoms in PD, including motor symptoms, lipid abnormalities, and weight loss. In the SIBO-positive group in the present study, the dosage of antiparkinsonian drugs was lower, and serum bilirubin and triglyceride 4
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