from reportlab.lib.pagesizes import A4
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm
from reportlab.lib import colors
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether, PageBreak
)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus.flowables import Flowable
import io

OUTPUT = "/home/daytona/workspace/gut-brain-axis/Gut_Brain_Axis_Physiology_5Marks.pdf"

# ─── Colour palette ───────────────────────────────────────────────
C_NAVY    = colors.HexColor("#1a3a5c")
C_TEAL    = colors.HexColor("#0d7377")
C_LTBLUE  = colors.HexColor("#e8f4f8")
C_LTGREEN = colors.HexColor("#e8f5e9")
C_LTYELLOW= colors.HexColor("#fffde7")
C_LTPURPLE= colors.HexColor("#f3e5f5")
C_LTORANGE= colors.HexColor("#fff3e0")
C_ACCENT  = colors.HexColor("#14a085")
C_DARK    = colors.HexColor("#212121")
C_GRAY    = colors.HexColor("#757575")
C_LGRAY   = colors.HexColor("#f5f5f5")
C_WHITE   = colors.white
C_RED     = colors.HexColor("#c62828")
C_ORANGE  = colors.HexColor("#e65100")

# ─── Document setup ───────────────────────────────────────────────
doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=1.8*cm, rightMargin=1.8*cm,
    topMargin=2*cm, bottomMargin=2*cm,
    title="Gut-Brain Axis Physiology – 5 Mark Exam Answer",
    author="Orris Medical AI"
)

W = A4[0] - 3.6*cm   # usable width

styles = getSampleStyleSheet()

def S(name, **kw):
    """Quick style builder."""
    base = styles.get(name, styles["Normal"])
    return ParagraphStyle(name + str(id(kw)), parent=base, **kw)

# ─── Custom styles ────────────────────────────────────────────────
title_s = S("Normal", fontSize=18, textColor=C_WHITE, alignment=TA_CENTER,
            fontName="Helvetica-Bold", spaceAfter=2)
subtitle_s = S("Normal", fontSize=11, textColor=C_WHITE, alignment=TA_CENTER,
               fontName="Helvetica", spaceAfter=0)
badge_s = S("Normal", fontSize=9, textColor=C_WHITE, alignment=TA_CENTER,
            fontName="Helvetica-Bold")

h1_s = S("Normal", fontSize=13, textColor=C_WHITE, fontName="Helvetica-Bold",
         spaceBefore=6, spaceAfter=4, leftIndent=0)
h2_s = S("Normal", fontSize=11, textColor=C_NAVY, fontName="Helvetica-Bold",
         spaceBefore=8, spaceAfter=3)
h3_s = S("Normal", fontSize=10, textColor=C_TEAL, fontName="Helvetica-Bold",
         spaceBefore=5, spaceAfter=2)
body_s = S("Normal", fontSize=9, textColor=C_DARK, fontName="Helvetica",
           spaceAfter=3, leading=14)
bullet_s = S("Normal", fontSize=9, textColor=C_DARK, fontName="Helvetica",
             spaceAfter=2, leftIndent=14, firstLineIndent=-10, leading=13)
code_s = S("Normal", fontSize=8, textColor=C_DARK, fontName="Courier",
           spaceAfter=2, leading=11, leftIndent=6)
note_s = S("Normal", fontSize=8.5, textColor=C_NAVY, fontName="Helvetica-Oblique",
           spaceAfter=2, leftIndent=8, leading=12)
recall_s = S("Normal", fontSize=9, textColor=C_DARK, fontName="Helvetica",
             spaceAfter=2, leading=13, leftIndent=8)
src_s = S("Normal", fontSize=7.5, textColor=C_GRAY, fontName="Helvetica-Oblique",
          spaceBefore=4, spaceAfter=2, leading=11)


# ─── Helper flowables ─────────────────────────────────────────────
def section_header(text, mark_text=""):
    """Coloured banner for main sections."""
    content = f"<b>{text}</b>"
    if mark_text:
        content += f"  <font size='9' color='#ffe082'>({mark_text})</font>"
    tbl = Table([[Paragraph(content, h1_s)]], colWidths=[W])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), C_NAVY),
        ("ROUNDEDCORNERS", [4]),
        ("TOPPADDING",    (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING",   (0,0), (-1,-1), 10),
    ]))
    return tbl

def info_box(text, bg=C_LTBLUE, border=C_TEAL):
    tbl = Table([[Paragraph(text, note_s)]], colWidths=[W])
    tbl.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), bg),
        ("LINEAFTER",     (0,0), (0,-1),  2, border),
        ("LINEBEFORE",    (0,0), (0,-1),  3, border),
        ("TOPPADDING",    (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING",   (0,0), (-1,-1), 8),
    ]))
    return tbl

def code_block(lines, bg=C_LGRAY):
    rows = [[Paragraph(l, code_s)] for l in lines]
    tbl = Table(rows, colWidths=[W])
    tbl.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), bg),
        ("LINEABOVE",     (0,0), (-1,0),  0.5, C_GRAY),
        ("LINEBELOW",     (0,-1),(-1,-1), 0.5, C_GRAY),
        ("TOPPADDING",    (0,0), (-1,-1), 2),
        ("BOTTOMPADDING", (0,0), (-1,-1), 2),
        ("LEFTPADDING",   (0,0), (-1,-1), 8),
        ("RIGHTPADDING",  (0,0), (-1,-1), 4),
    ]))
    return tbl

def hr(color=C_TEAL, thickness=0.5):
    return HRFlowable(width="100%", thickness=thickness, color=color, spaceAfter=4, spaceBefore=4)

def sp(h=4):
    return Spacer(1, h)

def b(text):
    return f"<b>{text}</b>"

def col(text, c):
    return f'<font color="{c}">{text}</font>'

def bullet(text):
    return Paragraph(f"• {text}", bullet_s)

# ─── Build story ──────────────────────────────────────────────────
story = []

# ══════════════════════════════════════════════════════════════
# TITLE BLOCK
# ══════════════════════════════════════════════════════════════
title_tbl = Table([
    [Paragraph("GUT–BRAIN AXIS", title_s)],
    [Paragraph("Physiology — Exam-Ready 5 Mark Answer", subtitle_s)],
    [Paragraph("Bidirectional | Neural | Hormonal | Immune | Microbial", badge_s)],
], colWidths=[W])
title_tbl.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,-1), C_NAVY),
    ("ROUNDEDCORNERS", [6]),
    ("TOPPADDING",    (0,0), (-1,-1), 10),
    ("BOTTOMPADDING", (0,0), (-1,-1), 10),
    ("LEFTPADDING",   (0,0), (-1,-1), 14),
    ("LINEBELOW",     (0,1), (-1,1),  1, C_ACCENT),
]))
story += [title_tbl, sp(8)]

# ══════════════════════════════════════════════════════════════
# SECTION 1 — DEFINITION
# ══════════════════════════════════════════════════════════════
story += [section_header("1.  DEFINITION & OVERVIEW", "0.5 mark"), sp(4)]
story.append(Paragraph(
    "The <b>gut-brain axis (GBA)</b> is a <b>bidirectional communication network</b> "
    "integrating the CNS, ANS, ENS, HPA axis, immune system, and gut microbiota to "
    "regulate GI function, behavior, mood, and systemic homeostasis.",
    body_s))
story.append(info_box(
    "<b>Memory Hook:</b>  C–A–E–H–I–M  =  CNS · ANS · ENS · HPA · Immune · Microbiota",
    bg=C_LTYELLOW, border=C_ORANGE))
story.append(sp(4))

# Component table
comp_data = [
    [Paragraph(b("Component"), h3_s), Paragraph(b("Role"), h3_s)],
    ["CNS (Brain + Spinal Cord)", "Integration, emotion, cognition, top-down control"],
    ["ANS (Para + Sympathetic)", "Motor output to ENS and gut wall"],
    ["ENS (Myenteric + Submucosal)", '"Second brain" – local GI reflexes'],
    ["HPA Axis", "Stress-hormone pathway; cortisol modulates gut"],
    ["Immune System", "Cytokines cross-talk between gut and brain"],
    ["Gut Microbiota", "Metabolite-mediated bottom-up signalling"],
]
ct = Table(comp_data, colWidths=[W*0.4, W*0.6])
ct.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0),  C_TEAL),
    ("TEXTCOLOR",     (0,0), (-1,0),  C_WHITE),
    ("FONTNAME",      (0,0), (-1,0),  "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [C_WHITE, C_LGRAY]),
    ("GRID",          (0,0), (-1,-1), 0.4, C_GRAY),
    ("TOPPADDING",    (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING",   (0,0), (-1,-1), 6),
]))
story += [ct, sp(8)]

# ══════════════════════════════════════════════════════════════
# SECTION 2 — STRUCTURAL / ENS
# ══════════════════════════════════════════════════════════════
story += [section_header("2.  STRUCTURAL COMPONENTS — The ENS", "0.5 mark"), sp(4)]

story.append(Paragraph(b("ENS = \"Second Brain\" — 200–600 million neurons"), h2_s))
story.append(code_block([
    "                    GUT–BRAIN AXIS",
    "",
    "    BRAIN (Cortex → Limbic → Hypothalamus)",
    "              ↑  Afferent (80%)   ↓  Efferent (20%)",
    "         VAGUS NERVE (CN X)  ←  primary conduit",
    "         SPINAL AFFERENTS    ←  pain / nociception",
    "              ↑                  ↓",
    "    ENS  (Myenteric plexus + Submucosal plexus)",
    "                        ↕",
    "           GI tract effectors",
    "   (smooth muscle · mucosa · immune · secretory)",
]))
story.append(sp(4))

ens_data = [
    [Paragraph(b("Plexus"), h3_s), Paragraph(b("Location"), h3_s), Paragraph(b("Function"), h3_s)],
    ["Myenteric\n(Auerbach's)", "Between longitudinal\n& circular muscle", "Controls motility\n& peristalsis"],
    ["Submucosal\n(Meissner's)", "Between circular\nmuscle & mucosa", "Secretion, blood flow,\nluminal sensing"],
]
et = Table(ens_data, colWidths=[W*0.28, W*0.36, W*0.36])
et.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0),  C_TEAL),
    ("TEXTCOLOR",     (0,0), (-1,0),  C_WHITE),
    ("FONTNAME",      (0,0), (-1,0),  "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [C_WHITE, C_LGRAY]),
    ("GRID",          (0,0), (-1,-1), 0.4, C_GRAY),
    ("TOPPADDING",    (0,0), (-1,-1), 5),
    ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ("LEFTPADDING",   (0,0), (-1,-1), 6),
    ("VALIGN",        (0,0), (-1,-1), "MIDDLE"),
]))
story += [et, sp(4)]
story.append(info_box("ENS can function <b>independently</b> of CNS — complete peristaltic reflex preserved after vagotomy.", bg=C_LTGREEN, border=C_ACCENT))
story.append(sp(8))

# ══════════════════════════════════════════════════════════════
# SECTION 3 — HOW BRAIN CONTROLS GUT
# ══════════════════════════════════════════════════════════════
story += [section_header("3.  HOW THE BRAIN CONTROLS THE GUT  (Top-Down)", "0.5 mark"), sp(4)]
story.append(code_block([
    "BRAIN (Cortex / Limbic / Hypothalamus)",
    "           |                    |",
    "   PARASYMPATHETIC         SYMPATHETIC",
    "   (Vagus + Pelvic n.)     (T5–L2 cord →",
    "           |                Celiac / Mesent. ganglia)",
    "           ↓                    ↓",
    "    ACh → ENS              NE → ENS / smooth muscle",
    "    ↑ Motility              ↓ Motility",
    "    ↑ Secretion             ↓ Secretion",
    "    ↓ Sphincter tone        ↑ Sphincter tone",
    "                            ↓ Mucosal blood flow",
]))
story.append(sp(3))

brain_bullets = [
    "<b>Cephalic phase:</b> Sight/smell of food → vagal efferents → ↑ gastric acid, ↑ pancreatic enzymes, ↑ motility",
    "<b>Stress response:</b> Cortex → limbic → hypothalamus → HPA axis + sympathetic outflow → GI suppression",
    "<b>Emotional modulation:</b> Amygdala & insula directly modulate ENS via vagal efferents",
    "<b>Sleep:</b> Circadian signals from SCN (suprachiasmatic nucleus) → melatonin → regulate gut motility rhythm",
    "<b>Efferent vagal fibres</b> = only 10–20% of vagal fibres; originate from <b>Dorsal Motor Nucleus (DMV)</b>",
]
for b_text in brain_bullets:
    story.append(bullet(b_text))
story.append(sp(8))

# ══════════════════════════════════════════════════════════════
# SECTION 4 — COLLECTIVE FUNCTION
# ══════════════════════════════════════════════════════════════
story += [section_header("4.  BRAIN + ANS + HORMONES — Collective Action on Gut", "1 mark"), sp(4)]
story.append(code_block([
    "  STIMULUS (food / stress / emotion / sleep disruption / infection)",
    "                    |",
    "          ┌─────────┴──────────┐",
    "          ▼                    ▼",
    "     CNS Processing       ENS Processing",
    "   (Hypothalamus,          (Local reflexes,",
    "    Limbic system)          peristalsis)",
    "          |                    |",
    "    ┌─────┘     ┌──────────────┘",
    "    |            |",
    "    ▼            ▼",
    "  ANS OUTPUT              HPA AXIS",
    "  Parasympathetic  →      CRF (hypothalamus)",
    "  • ↑ motility            ↓",
    "  • ↑ secretion           ACTH (pituitary)",
    "  • ↓ sphincter           ↓",
    "                          Cortisol (adrenals)",
    "  Sympathetic    →        ↓",
    "  • ↓ motility            Gut effects:",
    "  • ↑ sphincter           ↑ permeability",
    "  • vasoconstriction       mast cell activation",
    "                           ↑ visceral sensitivity",
]))
story.append(sp(5))

story.append(Paragraph(b("Key Gut Hormones Acting on the Brain"), h2_s))
gh_data = [
    [Paragraph(b("Hormone"), h3_s), Paragraph(b("Source"), h3_s),
     Paragraph(b("Signal route"), h3_s), Paragraph(b("Brain Effect"), h3_s)],
    ["Serotonin (5-HT)", "Enterochromaffin cells\n(95% of body's 5-HT)", "Vagal afferents", "Motility, mood, nausea"],
    ["CCK", "I-cells\n(duodenum/jejunum)", "Vagal afferents → NTS", "Satiety, ↓ food intake"],
    ["GLP-1", "L-cells (ileum/colon)", "Vagal + bloodstream", "Satiety, insulin secretion"],
    ["PYY", "L-cells", "Bloodstream + vagal", "Satiety, ↓ appetite"],
    ["Ghrelin", "X/A cells (stomach)", "Bloodstream", "Hunger ↑ (AgRP/NPY neurons)"],
    ["Leptin", "Adipocytes", "Bloodstream", "Satiety ↑ (POMC/CART neurons)"],
]
ght = Table(gh_data, colWidths=[W*0.2, W*0.25, W*0.22, W*0.33])
ght.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0),  C_NAVY),
    ("TEXTCOLOR",     (0,0), (-1,0),  C_WHITE),
    ("FONTNAME",      (0,0), (-1,0),  "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 8),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [C_WHITE, C_LTBLUE]),
    ("GRID",          (0,0), (-1,-1), 0.4, C_GRAY),
    ("TOPPADDING",    (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING",   (0,0), (-1,-1), 5),
    ("VALIGN",        (0,0), (-1,-1), "MIDDLE"),
]))
story += [ght, sp(8)]

# ══════════════════════════════════════════════════════════════
# SECTION 5 — SLEEP & EMOTION
# ══════════════════════════════════════════════════════════════
story += [section_header("5.  SLEEP & EMOTIONAL DISTURBANCES ON THE AXIS", "0.5 mark"), sp(4)]
story.append(code_block([
    "  SLEEP DEPRIVATION / DISRUPTION",
    "              |",
    "              ▼",
    "  ↑ Cortisol (HPA)  +  ↓ Melatonin  +  ↑ Sympathetic tone",
    "              |",
    "     ┌────────┴──────────────┐",
    "     ▼                       ▼",
    "  GUT EFFECTS            MICROBIOTA EFFECTS",
    "  • ↑ gut permeability    • ↓ Lactobacillus, Bifidobacterium",
    "  • ↑ visceral pain       • ↑ Proteobacteria",
    "  • Altered motility      • ↓ SCFA production",
    "  • ↑ mast cell           • ↓ mucosal immunity",
    "    activation",
    "              ↘            ↙",
    "           ↑ Neuroinflammation",
    "           ↑ Anxiety / Depression",
    "           ↓ BDNF  (brain plasticity)",
]))
story.append(sp(4))
story.append(code_block([
    "  EMOTIONAL DISTURBANCES (Anxiety / Depression / Anger)",
    "              |",
    "              ▼",
    "  Amygdala / ACC activation",
    "              |",
    "     ┌────────┴──────────────────┐",
    "     ▼                           ▼",
    "  ↑ CRF release              ↓ Vagal tone",
    "  ↓ Vagal efferents          ↓ HRV",
    "              |",
    "              ▼",
    "  GI SYMPTOMS:",
    "  • IBS-like motility changes",
    "  • ↑ visceral hypersensitivity",
    "  • ↑ gut permeability (\"leaky gut\")",
    "  • Altered microbiota composition",
]))
story.append(sp(3))
story.append(info_box(
    "<b>Key facts:</b>  Melatonin (pineal + gut EC cells) regulates circadian gut motility. "
    "90% of body serotonin is gut-derived — disrupted sleep → altered 5-HT → mood dysregulation. "
    "Stress-induced CRF → mast cell degranulation → mucosal permeability → bacterial translocation.",
    bg=C_LTYELLOW, border=C_ORANGE))
story.append(sp(8))

# ══════════════════════════════════════════════════════════════
# SECTION 6 — GUT MICROBIOTA & BRAIN
# ══════════════════════════════════════════════════════════════
story += [section_header("6.  GUT MICROBIOTA & THE BRAIN", "1 mark"), sp(4)]
story.append(Paragraph(
    "The gut microbiome (~10¹⁴ organisms, >100× the human genome) communicates with the CNS via <b>four routes</b>:",
    body_s))
story.append(sp(3))
story.append(code_block([
    "GUT MICROBIOTA (10¹⁴ organisms)",
    "               |",
    "    ┌──────────┬──────────┬───────────┐",
    "    ▼          ▼          ▼           ▼",
    "  NEURAL    ENDOCRINE  IMMUNE      METABOLIC",
    "  Vagal     Enterocrine Cytokines  SCFAs, indoles",
    "  afferent  cell       (IL-6,      tryptophan",
    "  (5-HT,   stimulation  IL-10,     metabolites",
    "   SCFAs)  (GLP-1,PYY)  TNF-α)",
    "    |          |          |           |",
    "    └──────────┴──────────┴───────────┘",
    "                       ▼",
    "              CNS EFFECTS:",
    "    • BDNF production       • Neurogenesis",
    "    • Myelination           • BBB integrity",
    "    • Mood / cognition      • Behaviour",
]))
story.append(sp(4))

story.append(Paragraph(b("What Microbiota Produce"), h2_s))
mp_data = [
    [Paragraph(b("Product"), h3_s), Paragraph(b("Source Bacteria"), h3_s), Paragraph(b("Brain Effect"), h3_s)],
    ["SCFAs (butyrate, propionate, acetate)", "Clostridia, Bifidobacteria", "↑ BDNF, BBB integrity, anti-inflammatory"],
    ["GABA", "Lactobacillus, Bifidobacterium", "Anxiolytic; mood regulation"],
    ["Serotonin precursors (tryptophan)", "Spore-forming bacteria", "Mood, gut motility"],
    ["Dopamine precursors", "Bacillus, Serratia", "Reward, motivation"],
    ["BDNF stimulators", "Bifidobacterium longum", "Neuroprotection, neuroplasticity"],
    ["LPS (dysbiosis)", "Gram-negative bacteria", "Neuroinflammation, BBB disruption"],
]
mpt = Table(mp_data, colWidths=[W*0.32, W*0.28, W*0.40])
mpt.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0),  C_TEAL),
    ("TEXTCOLOR",     (0,0), (-1,0),  C_WHITE),
    ("FONTNAME",      (0,0), (-1,0),  "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 8),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [C_WHITE, C_LTGREEN]),
    ("GRID",          (0,0), (-1,-1), 0.4, C_GRAY),
    ("TOPPADDING",    (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING",   (0,0), (-1,-1), 5),
    ("VALIGN",        (0,0), (-1,-1), "MIDDLE"),
]))
story += [mpt, sp(5)]

story.append(Paragraph(b("Top-Down (Brain → Microbiota)"), h3_s))
for b_text in [
    "Stress → ↑ catecholamines → alter gut motility + secretion → change luminal environment → dysbiosis",
    "Cortisol → ↓ mucosal immunity → overgrowth of pathogenic flora",
    "Neurotransmitters (NE) can directly influence bacterial gene expression (microbial endocrinology)",
]:
    story.append(bullet(b_text))
story.append(sp(8))

# ══════════════════════════════════════════════════════════════
# SECTION 7 — NEWER ADVANCES
# ══════════════════════════════════════════════════════════════
story += [PageBreak(), section_header("7.  NEWER ADVANCES & RECENT STUDIES", "0.5 mark"), sp(4)]
adv_data = [
    [Paragraph(b("Advance"), h3_s), Paragraph(b("Key Finding"), h3_s), Paragraph(b("Clinical Implication"), h3_s)],
    ["Psychobiotics", "L. rhamnosus, B. longum reduce anxiety/depression in RCTs (Binda et al., 2024)", "Probiotic therapy for psychiatric disease"],
    ["Fecal Microbiota\nTransplant (FMT)", "Anxiety/depression phenotype transferable via FMT in germ-free mice", "Dysbiosis as causal factor in psychiatric conditions"],
    ["Vagus Nerve\nStimulation (VNS)", "Approved for treatment-resistant depression; anti-inflammatory via cholinergic pathway", "Gut-brain axis as direct therapeutic target"],
    ["Long COVID &\n5-HT axis (2023)", "Gut SARS-CoV-2 → ↓ serotonin availability → dampened vagal signalling → brain fog", "Gut 5-HT depletion explains COVID neurological symptoms"],
    ["Sleep-microbiome\ncycle (Wang et al., 2025)", "Dysbiosis ↔ sleep disturbance form a vicious cycle; circadian rhythm governs microbial composition", "Chrono-probiotics as novel sleep therapy"],
    ["Parkinson's\n\"gut-first\" hypothesis", "Alpha-synuclein pathology begins in ENS; travels via vagus to substantia nigra", "ENS biopsy as early Parkinson's diagnostic"],
    ["Aryl Hydrocarbon\nReceptor (AHR)", "Microbial metabolites activate AHR → regulate T-regulatory cells and microglia", "Target for MS and neuroinflammatory diseases"],
]
at = Table(adv_data, colWidths=[W*0.22, W*0.44, W*0.34])
at.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0),  C_NAVY),
    ("TEXTCOLOR",     (0,0), (-1,0),  C_WHITE),
    ("FONTNAME",      (0,0), (-1,0),  "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 8),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [C_WHITE, C_LTPURPLE]),
    ("GRID",          (0,0), (-1,-1), 0.4, C_GRAY),
    ("TOPPADDING",    (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING",   (0,0), (-1,-1), 5),
    ("VALIGN",        (0,0), (-1,-1), "TOP"),
]))
story += [at, sp(8)]

# ══════════════════════════════════════════════════════════════
# SECTION 8 — APPLIED PHYSIOLOGY
# ══════════════════════════════════════════════════════════════
story += [section_header("8.  APPLIED PHYSIOLOGY", "implicit throughout"), sp(4)]
ap_data = [
    [Paragraph(b("Clinical Scenario"), h3_s), Paragraph(b("Mechanism"), h3_s), Paragraph(b("Axis Involved"), h3_s)],
    ["IBS", "CRF ↑ → mast cells → visceral hypersensitivity + altered motility", "HPA + ENS + Microbiota"],
    ["Functional dyspepsia", "Impaired vagal tone → delayed gastric emptying", "Vagal efferent failure"],
    ["Anxiety → diarrhea", "Amygdala → ↑ CRF → ↑ colonic motility", "Limbic–HPA–ENS"],
    ["Depression → constipation", "↓ 5-HT (95% in gut) → ↓ motility", "Serotonergic GBA"],
    ["Hepatic encephalopathy", "Gut bacteria → NH₃, false neurotransmitters → encephalopathy", "Microbiota–brain axis"],
    ["Autism Spectrum Disorder", "Gut dysbiosis → altered GABA/glutamate signalling", "Microbiota–brain neurodevelopment"],
    ["Post-infectious IBS", "Infection → dysbiosis + sensitised afferents → chronic symptoms", "Immune–ENS–GBA"],
    ["Anorexia nervosa", "Dysregulated ghrelin/leptin/CCK signalling", "Neuroendocrine–GBA"],
]
apt = Table(ap_data, colWidths=[W*0.25, W*0.48, W*0.27])
apt.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0),  C_TEAL),
    ("TEXTCOLOR",     (0,0), (-1,0),  C_WHITE),
    ("FONTNAME",      (0,0), (-1,0),  "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 8),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [C_WHITE, C_LTORANGE]),
    ("GRID",          (0,0), (-1,-1), 0.4, C_GRAY),
    ("TOPPADDING",    (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING",   (0,0), (-1,-1), 5),
    ("VALIGN",        (0,0), (-1,-1), "TOP"),
]))
story += [apt, sp(8)]

# ══════════════════════════════════════════════════════════════
# SECTION 9 — MASTER FLOWCHART
# ══════════════════════════════════════════════════════════════
story += [section_header("9.  MASTER FLOWCHART — Complete Gut-Brain Axis"), sp(4)]
story.append(code_block([
    "  ENVIRONMENTAL INPUT",
    "  (Food · Stress · Sleep · Emotion · Infection)",
    "                    |",
    "         ┌──────────┴──────────┐",
    "         ▼                     ▼",
    "      BRAIN               GUT MICROBIOTA",
    "  (Cortex/Limbic/          (10¹⁴ organisms)",
    "   Hypothalamus)                |",
    "         |             SCFAs · GABA · 5-HT",
    "         |             LPS · cytokines",
    "         |                     |",
    "  ┌──────┴─────────────────────┘",
    "  |",
    "  ├─► HPA AXIS:  CRF → ACTH → Cortisol → ↑ gut permeability",
    "  |",
    "  ├─► ANS PARASYMPATHETIC:  Vagus / Pelvic nerve",
    "  |    → ↑ Motility  ·  ↑ Secretion  (rest-digest)",
    "  |",
    "  ├─► ANS SYMPATHETIC:  NE via celiac ganglia",
    "  |    → ↓ Motility  ·  ↑ Sphincter  (fight-flight)",
    "  |",
    "  └─► ENS (Myenteric + Submucosal plexus)",
    "       → Local reflexes  (peristalsis · secretion)",
    "       → Neurotransmitters: ACh · VIP · 5-HT · NO · Substance P",
    "                    |",
    "                    ▼",
    "             GI EFFECTORS",
    "    Motility | Secretion | Absorption | Sensation | Immune",
    "                    |",
    "                    ▼  (feedback)",
    "         VAGAL AFFERENTS (80%)  +  SPINAL AFFERENTS (pain)",
    "                    |",
    "                    ▼",
    "               BACK TO BRAIN",
    "    (NTS → Hypothalamus → Limbic → Cortex)",
], bg=colors.HexColor("#e3f2fd")))
story.append(sp(8))

# ══════════════════════════════════════════════════════════════
# SECTION 10 — ENS NEUROTRANSMITTERS
# ══════════════════════════════════════════════════════════════
story += [section_header("10. ENS KEY NEUROTRANSMITTERS"), sp(4)]
nt_data = [
    [Paragraph(b("NT"), h3_s), Paragraph(b("Action"), h3_s)],
    ["ACh", "Primary excitatory → ↑ secretion + smooth muscle contraction"],
    ["VIP", "Inhibits smooth muscle; ↑ fluid secretion"],
    ["Substance P", "Excitatory; pain signalling, ascending peristaltic reflex"],
    ["Serotonin (5-HT)", "Initiates peristaltic reflex; activates vagal afferents"],
    ["Nitric oxide (NO)", "Inhibitory motor neuron → smooth muscle relaxation"],
    ["Enkephalins", "Inhibitory; ↓ secretion + motility (opioid effect)"],
    ["Somatostatin", "Inhibitory; ↓ secretion + motility"],
]
ntt = Table(nt_data, colWidths=[W*0.22, W*0.78])
ntt.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0),  C_NAVY),
    ("TEXTCOLOR",     (0,0), (-1,0),  C_WHITE),
    ("FONTNAME",      (0,0), (-1,0),  "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,-1), 8.5),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [C_WHITE, C_LGRAY]),
    ("GRID",          (0,0), (-1,-1), 0.4, C_GRAY),
    ("TOPPADDING",    (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING",   (0,0), (-1,-1), 6),
]))
story += [ntt, sp(8)]

# ══════════════════════════════════════════════════════════════
# QUICK RECALL BOX
# ══════════════════════════════════════════════════════════════
story.append(Paragraph("QUICK RECALL — Last-Minute Revision", S("Normal",
    fontSize=11, textColor=C_WHITE, fontName="Helvetica-Bold", alignment=TA_CENTER)))
recall_lines = [
    ("5 PATHWAYS OF GUT-BRAIN COMMUNICATION", True),
    ("1. Neural    — Vagus nerve (CN X), spinal afferents", False),
    ("2. Endocrine — CCK · GLP-1 · PYY · Ghrelin · 5-HT", False),
    ("3. Immune    — Cytokines (IL-6 · TNF-α · IL-10)", False),
    ("4. HPA       — CRF → ACTH → Cortisol", False),
    ("5. Microbial — SCFAs · GABA · Tryptophan · LPS", False),
    ("", False),
    ("KEY NUMBERS", True),
    ("ENS = 200–600 million neurons  |  2 plexuses", False),
    ("95% of body serotonin is produced in the GUT", False),
    ("Vagus = 80% afferent (gut → brain)  /  20% efferent", False),
    ("FMT can transfer mood/behaviour phenotype (animal studies)", False),
    ("Alpha-synuclein (Parkinson's) may originate in ENS", False),
]
recall_rows = []
for text, is_heading in recall_lines:
    if not text:
        recall_rows.append([Spacer(1, 3)])
    elif is_heading:
        recall_rows.append([Paragraph(text, S("Normal", fontSize=9, fontName="Helvetica-Bold",
                                               textColor=C_NAVY, leading=13))])
    else:
        recall_rows.append([Paragraph(text, recall_s)])

rt = Table(recall_rows, colWidths=[W - 16])
rt.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,-1), C_LTYELLOW),
    ("LINEABOVE",     (0,0), (-1,0),  2, C_ORANGE),
    ("LINEBELOW",     (0,-1),(-1,-1), 2, C_ORANGE),
    ("LINEBEFORE",    (0,0), (0,-1),  4, C_ORANGE),
    ("LINEAFTER",     (0,0), (0,-1),  4, C_ORANGE),
    ("TOPPADDING",    (0,0), (-1,-1), 3),
    ("BOTTOMPADDING", (0,0), (-1,-1), 3),
    ("LEFTPADDING",   (0,0), (-1,-1), 12),
]))
story += [rt, sp(8)]

# ══════════════════════════════════════════════════════════════
# SOURCES
# ══════════════════════════════════════════════════════════════
story.append(hr())
story.append(Paragraph("<b>Sources:</b> Sleisenger & Fordtran's GI and Liver Disease · Medical Physiology (Boron & Boulpaep) · "
    "Harrison's Principles of Internal Medicine 22e · Yamada's Textbook of Gastroenterology 7e · "
    "Ganong's Review of Medical Physiology 26e · Kaplan & Sadock's Comprehensive Textbook of Psychiatry · "
    "Binda et al., Microorganisms 2024 [PMID 38674579] · Wang et al., Brain Medicine 2025", src_s))

# ─── Page numbering ───────────────────────────────────────────────
def add_page_number(canvas, doc):
    canvas.saveState()
    canvas.setFont("Helvetica", 8)
    canvas.setFillColor(C_GRAY)
    canvas.drawRightString(A4[0] - 1.8*cm, 1.2*cm, f"Page {doc.page}")
    canvas.drawString(1.8*cm, 1.2*cm, "Gut-Brain Axis Physiology | Orris Medical AI")
    canvas.restoreState()

doc.build(story, onFirstPage=add_page_number, onLaterPages=add_page_number)
print("PDF generated successfully:", OUTPUT)