A PRACTITIONER’S GUIDE TO PROBIOTICS: Neurological Conditions · clear guidelines for clinical application have yet to be established. This is particularly important as the effectiveness

A PRACTITIONER’S GUIDE TO PROBIOTICS:

Neurological Conditions Probiotic supplements contain beneficial microorganisms, similar to those found in the human gastrointestinal tract. When ingested, these live microorganisms confer a number of health benefits to the host. Particular strains of probiotics can provide neuroactive properties that may induce effects on the human brain, mind, and behavior. These kinds of probiotics are often referred to as psychobiotics. Imbalances in the intestinal microbiota are believed to be involved in the development of certain neurological disorders and may modulate other affective and behavioral responses from the central nervous system (CNS). The signaling that takes place between the GI system and the CNS, the neuroendocrine system, the neuroimmune system, the sympathetic and parasympathetic autonomic nervous systems, and the enteric nervous system is commonly referred to as the gut-brain axis. Probiotic supplements may support a healthy composition of bacteria in the gastrointestinal tract and improve cognitive and behavioral function by a number of mechanisms, including:

● Modulation of neurotransmitters, such as norepinephrine, serotonin, acetylcholine, and corticotropin-releasing factor, involved in the gut-brain axis

● Metabolite conversion in the regulation of the immune and nervous systems ● Modulation of microbial metabolites and inflammatory cytokines that stimulate the vagus nerve ● Downregulation of proinflammatory cytokines through anti-inflammatory modulation ● Modulation of the HPA axis, hormones, and receptors (eg. GABA, opioid-μ, cannabinoid) ● Prevention of dendritic atrophy, promotion of synaptic connections, and neurogenesis ● Production of short-chain fatty acids (SCFAs) that can cross the blood-brain barrier and induce

neuroprotective, cognitive, and antidepressant effects While probiotics are now commonly prescribed therapeutically and clinical research examining the relationship between the gut microbiome and neurological disorders is becoming increasingly available, clear guidelines for clinical application have yet to be established. This is particularly important as the effectiveness of probiotic supplementation may be dependent on the condition, strain, dosing, and duration of therapy. This guide provides an overview of the available research for the clinical application of probiotics in neurological conditions, including dosing and administration for single-strain and multi-strain probiotics.

Probiotics in Neurological Conditions

Condition or Use Strain or Combination

Dosing & Administration Outcomes

Attention-deficit Hyperactivity Disorder (ADHD)

Single Strain

L. rhamnosus GG (ATCC 53103)

Infant: 1x10(10) CFU per day to mothers 4 weeks before delivery, and daily to infants for the first 6 months of life

Reduces the risk of developing ADHD by the age of 13

Alcoholic Psychosis/ Alcohol-induced Liver Injury

Multistrain

B. bifidum & L. plantarum 8PA3

Adult: 9.9x10(8) CFU per day for 5 days

Increases Bifidobacteria & Lactobacilli; reduces AST & ALT activity compared with standard therapy; Px with mild alcoholic hepatitis had associated decreased ALT, AST, GGT, LDH & bilirubin where ALT is reduced compared with standard therapy

Alzheimer’s Disease

Multistrain

B. bifidum, L. acidophilus, L. casei, & L. fermentum

Geriatric: 2x10(9) CFU/g in milk product for 12 weeks

Improves mini-mental state examination score, & insulin sensitivity index; reduces hsCRP, HOMA-IR, HOMA-B, TGs, VLDL, & MDA

B. bifidum W23, B. lactis W51 & W52, L. acidophilus W22, L. casei W56, L. paracasei W20, L. plantarum W62, L. salivarius W24 & Lc. lactis W19 (OMNI-BIOTIC® STRESS Repair)

Geriatric: 7x10(9) CFU per day for 4 weeks

Reduces fecal zonulin; increases Faecalibacterium prausnitzii, & serum kynurenine; correlation between change of neopterin & kynurenine:tryptophan ratio observed

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Anxiety Single Strain

B. longum 1714 Adult: 1x10(9) CFU per day for 4 weeks

Associated reduction in cortisol stress response & subjective anxiety

L. plantarum DR7 Adult: 1x10(9) CFU per day for 12 weeks

Reduces stress, anxiety & total psychological scores after 8 weeks, plasma cortisol, interferon-γ, & TGF-α; increases IL-10, attention, emotional cognition, associate learning, & serotonin pathway; normalizes dopamine pathway

L. rhamnosus HN001

Adult (postpartum): 6x10(9) CFU per day from 14 weeks gestation till 6 months after birth

Reduces depression & anxiety scores postpartum

Multistrain

B. lactis CNCM I-2494, L. acidophilus, L. bulgaricus CNCM I-1632 & I-1519, L. plantarum, L. reuteri DSM 17938, Lc. lactis CNCM I-1631, S. thermophilus CNCM I-1630

Adult: 1.5x10(11) CFU per day for 3 weeks

Reduces total HAMA score

Asperger Syndrome

Single Strain

L. rhamnosus GG (ATCC 53103)

Infant: 1x10(10) CFU per day to mothers 4 weeks before delivery, and daily to infants for the first 6 months of life

Reduces the risk of developing Asperger syndrome by the age of 13




Autism Spectrum Disorder

Single Strain

L. plantarum PS128 L. plantarum WCFS1

Pediatric: 3x10(10) CFU per day for 4 weeks in boys Pediatric: 4.5x10(10) CFU per day for 3 weeks

Reduces scores of body & object use (ABC-T), total SRS, anxiety & rule-breaking behaviors (CBCL), total SNAP-IV, hyperactivity, impulsivity, opposition, & defiance (SNAP-IV). Effects observed particularly in younger ages Increases formed stools, lactobacilli & enterococci groups; reduces hard stool, Clostridium cluster XIVa, median scores for disruptive/antisocial & self-absorbed behaviors, communication disturbances, & anxiety problems compared with baseline

Multistrain

B. bifidum, L. acidophilus, & L. rhamnosus

Pediatric: 1x10(8) CFU per day for 3 months

Improves autism severity (ATEC) & GI symptoms; increases Bifidobacteria & Lactobacillus levels; reduces body weight

B. bifidum, B. longum, L. acidophilus, L. casei, & L. delbrueckii (Delpro®) + L. rhamnosus (Del-Immune V®)

Pediatric: 1x10(10) CFU + 8mg Del-Immune V® per day for 6 months

Approx. half Px respond with reduced diarrhea & constipation severity. Reduces ATEC score in most px (88%); improves subscores of speech/language/ communication, sociability, sensory/cognitive awareness, & health/ physical/behavior

Chronic Fatigue Syndrome/ Fibromyalgia

Single Strain

B. infantis 35624 Adult: 1x10(10) CFU per day for 8 weeks

Reduces CRP, TNF-α, & IL-6

L. casei strain Shirota Adult: 8x10(9) CFU three times per day for 8 weeks

Reduces anxiety symptoms; increases Lactobacillus & Bifidobacteria




Chronic Fatigue Syndrome/ Fibromyalgia

Multistrain

B. lactis BB12, L. acidophilus NCFB 1748, & L. paracasei F19

Adult: 2x10(10) CFU twice per day for 4 weeks

Improves VAS score for neurocognitive functions of short-term memory & concentration

B. bifidum, L. acidophilus, L. casei, & L rhamnosus GG (ERGYPHILUS Plus®)

Adult: 1.2x10(10) CFU twice per day for 8 weeks

Reduces the frequency of impulsive choices

Cognition Single Strain

B. breve A1 Adult: 2x10(10) CFU following meals for 12 weeks

Increases immediate memory score of the RBANS scale & total score of the MMSE in px with memory complaints

B. longum 1714 Adult: 1x10(9) CFU per day for 4 weeks

Increases visuospatial memory performance

Multistrain

B. breve DSM 24732, B. infantis DSM 24737, B. longum DSM DSM 24736, L. acidophilus DSM 24735, L. delbrueckii subs bulgaricus DSM 24734, L. paracasei DSM 24733, L. plantarum DSM 24730, & S. thermophilus DSM 24731 (Visbiome®) B. bifidum W23, B. lactis W51 & W52, L. acidophilus W22, L. casei W56, L. paracasei W20, L. plantarum W62, L. salivarius W24, & Lc. lactis W19 (Ecologic®825)

Adult: 1.8x10(12) CFU in two divided doses for 6 months in HIV-1 px Adult: 2.2x10(7) CFU per day for 4 weeks

Improves test scores for immediate & delayed recall, phonological verbal fluency (PVF) test, Toronto alexithymia scale‐20 (Tas‐20), State‐trait anxiety inventory Y‐2 (STAY Y‐2), & time and weight estimation test (STEP) Reduces decision changes in response to unpleasant stimuli (emotional attention); increases response accuracy to unpleasant stimuli




Depression Note: benefits may require concomitant antidepressant therapy (49)

Single Strain

B. coagulans MTCC 5856

Adult: 2x10(9) CFU per day for 3 months in px with concurrent major depression and IBS

Improves HAM-D, MADRS, CES-D, & IBS-QoL after 60 days and maintained thereafter. Improves scores for clinical global impressions-improvement & severity, total dementia frequency & sleepiness scores, & GI-discomfort score

C. butyricum MIYAIRI 558

Adult: 60mg per day for 8 weeks with concurrent antidepressants

Reduces depression scores with 70% response rate & 35% remission rate

L. rhamnosus HN001 Adult (Postpartum): 6x10(9) CFU per day from 14 weeks gestation till 6 months after birth

Reduces depression & anxiety scores postpartum

Multistrain

B. longum, & L. helveticus

Adult: 1x10(10) CFU per day for 8 weeks with concurrent antidepressants

Reduces Beck Depression Inventory score

B. bifidum, L. acidophilus, & L. casei

Adult: 6x10(9) CFU per day for 8 weeks with concurrent antidepressants

Reduces Beck Depression Inventory total scores, serum insulin, HOMA-IR, & serum hs-CRP; increases plasma GSH




Hepatic encephalopathy Note: recent meta-analyses generally support the use of probiotics for treating minimal HE and preventing overt HE compared with placebo/no treatment There are inconsistent reports from meta-analyses on superiority between probiotics, lactulose, rifaximin, and L-ornithine L- aspartate effectiveness

Single Strain

L. acidophilus Adult: 1x10(6) CFU three times per day for 1 month

Improves psychometric tests & blood ammonia; increases myoinositol:creatinin and choline + myoinositol:glutamine + glutamate ratios; reduces risk of overt HE, glutamine+glutamate:creatinin ratio; more tolerable than lactulose

L. plantarum 299v Adult: 1x10(10) CFU twice per day for 12 weeks

Improves minimal HE reversal rate, number connection test scores (psychometric performance) & BAEP score; reduces fasting NH3; prevented overt HE development

L. rhamnosus GG ATC strain 53103


Reduces endotoxemia, TNF-α, & level of Enterobacteriaceae; increases level of Clostridiales Incertae Sedis XIV & Lachnospiraceae. No cognitive effects observed

E. faecium SF68 Adult: 1.5x10(8) CFU three times per day for 10 days 1.5x10(8) CFU three times per day for 4 weeks

Improves mental state & psychometric performance; reduces blood ammonia similarly to lactulose but effects had longer duration after cessation Improves number connection test score; reduces blood ammonia more than lactulose and maintains effects in chronic HE

Multistrain

B. infantis CGMCC0313-2, & C. butyricum CGMCC0313-1 B. mesentricus, C. butyricum, lactic acid bacillus, & S. faecalis

Adult: 1.6x10(7) CFU three times per day for 3 months with conventional hep-B-virus associated cirrhosis therapy Adult: 1.6x10(8) CFU three times per day for 1 month

Improves NCT-A & DST psychometric scores, & QoL scores; increases beneficial Clostridium cluster I & Bifidobacterium, & LPS & D-lactate (intestinal permeability); reduces venous ammonia, enterococcus & Enterobacteriaceae, & DAO (mucosal damage) in minimal HE Improves abnormal psychometry & P300ERP tests, & venous ammonia levels similarly to lactulose and in combination




Hepatic encephalopathy

Multistrain

B. breve, B. longum, L. acidophilus, L. bulgaricus, L. casei, L. rhamnosus, & S. thermophilus


Improves psychometric score; probiotics maintain effects after 8 weeks while lactulose does not

B. breve, B. infantis, B. longum, L. acidophilus, L. delbrueckii subs. bulgaricus, L. paracasei, L. plantarum, & S. thermophilus (VSL#3®)

Adult: 1x10(8) CFU per three times per day for 3 months 1.1x10(11) CFU two-three times per day for 3-6 months 4.5x10(11) CFU twice per day for 2 months

Increases HE psychometric scores, & critical flicker fusion threshold; reduced, arterial ammonia, SIBO, GI transit time, & the risk of developing overt HE Reduces secondary prophylaxis of HE similarly to lactulose; compared with no treatment, improves recovery rate, minimal HE, & SIP/QoL scores; reduces arterial ammonia, & rate of overt HE development similarly to lactulose & L-ornithine L-aspartate Normalizes prior abnormal neuropsychometric/neurophysiological tests; serum ammonia decreased in px with improved minimal HE; similar effectiveness as lactulose

B. breve, B. infantis, B. longum, L. acidophilus, L. casei, L. plantarum, L. rhamnosus, S. boulardii, & S. thermophilus (Vegult®)

Adult: 5x10(9) CFU twice per day for 2 months

Improves psychometric tests, & critical flicker frequency equally to rifaximin in minimal HE

Mania Multistrain

Bifidobacterium animalis subs. lactis BB12, & Lactobacillus rhamnosus GG

Adult: 1x10(8) CFU per day for 24 weeks

Reduces rate of rehospitalization & days rehospitalized especially in px with high systemic inflammation




Mild Cognitive Impairment

Single Strain

Lactobacillus plantarum C29

Adult: 1x10(10) CFU per day in soybean powder for 12 weeks

Improves combined cognition, particularly attention; improvements associated with increased serum BDNF

Mood *note: improvements in depressive mood symptoms may only be significant in depressed individuals, though positive effects are also seen for depressive, anxious, and stress symptoms in healthy individuals

Single Strain

L. casei strain Shirota Adult: 6.5x10(9) CFU per day for 3 weeks in milk product

Improves mood in individuals in higher rated baseline depression/elation Note: an unanticipated reduction in performance in memory tasks observed

L. gasseri CP2305 Adult: 1x10(10) CFU per day for 4 weeks

Improves depressive mood, anxiety & sleep quality; reduces salivary cortisol release, & Enterobacteriaceae growth

Multistrain

B. longum BL04, L. fermentum LF16, L. plantarum LP01, & L. rhamnosus LR06


Improves LEIDS-R acceptance subscale, mood state for depression, anger-hostility, & fatigue

B. bifidum W23, B. lactis W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, & Lc. lactis W19 & W58 (Ecologic®Barrier) B. bifidum W23, B. lactis W51 & W52, L. acidophilus W22, L. casei W56, L. paracasei W20, L. plantarum W62, L. salivarius W24, & Lc. lactis W19 (Ecologic®825)

Adult: 5x10(9) CFU per day for 4 weeks Adult: 2.2x10(7) CFU per day for 4 weeks

Reduces rumination & aggressive thoughts Increases positive affect; reduces depression vulnerability for hopelessness & risk aversion




Multiple Sclerosis

Multistrain

B. breve, B. infantis, B. longum, L. acidophilus, L. delbrueckii subs. bulgaricus, L. paracasei, L. plantarum, & S. thermophilus (VSL#3®)

Adult: 3.6x10(12) CFU in two divided doses per day for 2 months concomitant with glatiramer acetate

Associated with decreased frequency of intermediate monocytes (CD14highCD16low) ; trends towards increased frequency of effector memory CD8 T cells, & IL-10+ T regs; trend towards decreased Th1 & Th17 cells; reduces mean fluorescence intensity of CD80 on monocytes and HLA-DR on dendritic cells; associated increase in Lactobacillus, Streptococcus, & Bifidobacterium species Associated with reduced MS risk allele HLA-DQA1 in healthy controls; associated increases in Lactobacillus & Bifidobacterium with MS risk allele HLA.DPB1 in healthy controls

Parkinson’s Disease

Single Strain

L. casei strain Shirota Adult: 6.5x10(9) CFU in milk per day for 5 weeks

Increases days with normal stool consistency; reduces days of abdominal pain & feeling of incomplete emptying

Multistrain

B. infantis & L. acidophilus

Adult: 60mg twice per day, one-hour after meals for 3 months

Reduces abdominal pain & bloating similarly to trimebutine treatment

B. bifidum, L. acidophilus, L. fermentum, & L. reuteri

Adult: 8x10(9) CFU per day for 3 months

Reduces MDS-UPDRS, hs-CRP, MDA, insulin, insulin resistance, & expression of IL-1, IL-8, & TNF-α in PBMCs; increases GSH, insulin sensitivity, & expression of TGF-β & PPAR-γ in PBMCs

Schizophrenia *note: effects are typically limited to GI health and metabolism of antipsychotics

Single Strain

B. breve A-1 Adult: 1x10(11) CFU per day for 4 weeks

Improves total HADS & PANSS anxiety/depression scores; In responders, reduces negative symptoms; increases level of Parabacteroides, expression of IL-22 & TRANCE




Schizophrenia Multistrain

B. animalis subs lactis BB12 & L. rhamnosus GG

Adult: 2x10(9) CFU per day for 14 weeks with stable antipsychotics

Reduces Candida albicans IgG in males but not females; improves bowel issues in C. albicans seropositive males, improvement trend for positive psychiatric symptoms in males Reduces the likelihood of severe bowel difficulties (19), von Willebrand factor, & trend for reductions in MCP-1, BDNF, RANTES, & MIP-1

Sleep Single Strain

L. gasseri CP2503 Adult: 1x10(10) CFU per day for 4-5 weeks

Improves sleep quality (esp. in males); reduces sleep latency, & increases duration in males; reduces diarrhea, & Bacteroides vulgatus growth; increases Dorea longicatena growth Improves depressive mood, anxiety, & sleep quality; reduces salivary cortisol release & Enterobacteriaceae growth

L. helveticus CM4 Geriatric: 100g of L. helveticus- fermented milk for 3 weeks

Improves sleep efficiency & instances of wakening

S. cerevisiae Adult: 500 mg per day, one-hour before sleep for 4 hours

Reduces morning subjective sleepiness & fatigue; increases delta power of slow-wave sleep in first cycle & awakening growth hormone

Multistrain

B. longum BL04, L. fermentum LF16, L. plantarum LP01, & L. rhamnosus LR06


Improves Pittsburgh Sleep Quality Index




Stress Note: meta-analyses support the use of probiotics to alleviate perceived stress

Single Strain

B. bifidum R0071 Adult: 3x10(9) CFU per day for 6 weeks

Reduces stress-related diarrhea symptoms & self-reported stress Reduces number of cold/flu days during acute stress

L. casei strain Shirota Adult: 1x10(11) CFU per day in milk product for 8 weeks

Decreases VAS-stress score, abdominal discomfort & pain score, Bacteroidaceae; increases microbiota alpha-diversity index; prevented increases in salivary cortisol & leukocyte expression before stress exposure Reduces stress-induced sleep quality disturbances Prevents increases in salivary cortisol & plasma L-tryptophan before stress exposure; reduces number & days of abdominal & cold symptoms; increases fecal serotonin 2-weeks after stressor

L. plantarum DR7 Adult: 1x10(9) CFU per day for 12 weeks

Reduces stress, anxiety, & total psychological scores after 8 weeks, reduces plasma cortisol, interferon-γ, & TGF-α; increases IL-10, attention, emotional cognition, associate learning, & serotonin pathway; normalizes dopamine pathway

Multistrain

B. longum R0175 & L. helveticus R0052

Adult: 3x10(9) CFU per day for 30 days

Improves psychological distress severity, somatisation, depression, anger-hostility, anxiety, problem solving, & cortisol levels

B. longum Rosell-175 & Lc. acidophilus Rosell-52


Reduces stress-related abdominal pain & nausea/vomiting

B. breve, B. longum, L. acidophilus, L. bulgaricus, L. casei, L. rhamnosus, & S. thermophilus

Adult: 2.8x10(10) CFU per day for 6 weeks

Improves general mental health (GHQ) & depression, anxiety, and stress scale (DASS) scores


Safety Considerations & Contraindications While probiotics are considered safe, rare short term side effects, such as gas and bloating, may occur. Isolated cases of bacteremia or fungemia have been associated with probiotics, though population data also indicates that there is no widespread risk of these complications. There is some limited evidence that probiotics should not be administered in critically ill patients, as demonstrated by an increased risk of mesenteric ischemia and mortality in a trial of patients with predicted severe acute pancreatitis.


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A PRACTITIONER’S GUIDE TO PROBIOTICS: Neurological Conditions · clear guidelines for clinical application have yet to be established. This is particularly important as the effectiveness